Nejmoa2306185 Protocol

Protocol
Protocol for: Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholan-
gitis. N Engl J Med 2024;390:795-805. DOI: 10.1056/NEJMoa2306185
This trial protocol has been provided by the authors to give readers additional information about the work.
Page 1
This supplement contains the following items:

1 The original protocol (GFT505B-319-1 Original Protocol v1.0, 22 July 2020 - p2-p115.
2 The final protocol (GFT505B-319-1 Final Protocol v5.0, 20 December 2022 - p116-248.
3 GFT505B-319-1 Summary of Amended Protocol Changes v1.0 - v5.0 – p117-292.
4 The original Statistical Analysis Plan (GFT505B-319-1 Statistical Analysis Plan
(Double-Blind Period) v1.0, 28 July 2020 – p293-379.
5 The final Statistical Analysis Plan (GFT505B-319-1 Statistical Analysis Plan (Double-
Blind Period) v4.0, 10 May 2023 – p380-514.
6 GFT505B-319-1 Summary of SAP changes v1.0 to v4.0 - p515.
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Clinical Trial GFT505B-319-1
Protocol version 1.0 22 July 2020
CLINICAL PROTOCOL – PHASE 3
Protocol N° GFT505B-319-1
EudraCT N°2019-004941-34 IND number: 132202
Version 1.0– Release date 22 July 2020
A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the
Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate
Response or Intolerance to Ursodeoxycholic Acid
International
Coordinating PPD MB Toronto Centre for Liver Disease, University
Investigator BChir, P hD Health Network and University of Toronto,
Committee Professor of Medecine, Toronto, Canada
Division of Gastroenterology Phone: +1 416-340-4548
Email: PPD
Elson S. Floyd College of Medicine

PPD MD Washington State University
Director, Liver Institute 3216 NE 45th Place, Suite 212
Northwest Seattle, WA, USA 98105
Clinical Professor Phone: +1 206-459-8479
Email P
P
D
Department of Medicine
University Medical Center Mainz
PPD MD Langenbeckstraße,1
Director, Metabolic Liver 55131 Mainz, Germany
Research Program Phone: +49 6131 176074
Email: PPD
Sponsor GENFIT Parc Eurasanté
885, Avenue Eugène Avinée
59120 Loos, France
Represented by: PPD MD Phone: +33 320 16 40 38
Deputy CMO Email P
P
CONFIDENTIAL - This document is the property of the Sponsor and may not D
- in full or part - be passed on, reproduced,
published or used by authorities or other applicants for approval or registration purposes without express permission of the
Sponsor.
GENFIT CONFIDENTIAL Page 1 of 114

Page 3
CLINICAL STUDY PROTOCOL SIGNATURE PAGE
Protocol N°: GFT505B-319-1

Version number: Version 1
Release date: 22 July 2020
TITLE: A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to
Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with
Inadequate Response or Intolerance to Ursodeoxycholic Acid
In signing below, I give agreement to the protocol.
On behalf of (the Sponsor):
GENFIT
Parc Eurasanté
59120 LOOS – France
Name: PPD MD
PPD
_ _________________ 24-July-2020
________________________
Signature Date (dd-mmm-yyyy)

Page 4
a
€linical Trial GFT505B-319-1
Proio'col version t.O 22 luly 2O2O

::,
Protocol No: GFT505B-319-1

Release date: 22July 2O2O

TITLE: A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term E)dension to
Evaluate the Efficary and Safety of Elafibranor 80 mg in Patients with Primary Bitiary Cholangitis with
GENFIT
Parc Eurasant6
885, Avenue Eugdne Avin6e
59120 LOOS - France
Name: PPD MD
PPD
Z3- 7ur- zo a-e
Signature Date (dd-mmm-yyyy)

Page 5
Protocol version 1.022 July 2020


GENFIT
Pa rc Eurasante
885, Avenue Eugene Avinee
59120 LOOS — France
PPD
Name:
ZsD o
Signatu Date (dd-mmm-yyyy)
CONFIDENTIAL Page 4 of 114

GENFIT
Page 6


GENFIT
Parc Eurasanté
59120 LOOS - France
Name: PPD MD
Deputy CMO
PPD
g/T- JuL- iclp
Date (dd-mmm-yyyy)

Page 7
CLINICAL STUDY PROTOCOL - INVESTIGATOR SIGNATURE PAGE
PROTOCOL TITLE:
A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the
Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response
or Intolerance to Ursodeoxycholic Acid
PROTOCOL CODE: GFT505B-319-1
EudraCT Number: 2019-004941-34
IND Number: 132202
CLINICAL PHASE: Phase 3
VERSION: Version 1
DATE: 22 July 2020
SPONSOR: GENFIT,
Parc Eurasanté,
885 Avenue Eugène Avinée,
59120 LOOS - France
In signing below, I confirm having read the protocol and agree to conduct the clinical study with this clinical
study protocol and in compliance with the Good Clinical Practice and all applicable regulatory requirements.
INVESTIGATOR NAME: _______________________________________

INSTITUTION NAME: _______________________________________
INSTITUTION ADDRESS:_______________________________________
_______________________________________
PHONE CONTACT : _______________________________________
SIGNATURE: _______________________________________
DATE: _____ /_______ /________
Day Month Year

Page 8
STUDY CONTACTS
Protocol N°: GFT505B-319-1 / EudraCT N° 2019-004941-34 / IND n° 132202

International PPD Toronto Centre for Liver Disease, University
Coordinating Professor of Medicine, Division Health Network and University of Toronto,
Investigator of Gastroenterology Toronto, Canada
Committee Phone:+1 416-340-4548
Email PPD
PPD MD Elson S. Floyd College of Medicine

Director, Liver Institute Washington State University
Northwest 3216 NE 45th Place, Suite 212
Seattle, WA, USA 98105
Clinical Professor
Phone: +1 206-459-8479
Email P
P
D
PPD MD University Medical Center Mainz
Director Metabolic Liver Langenbeckstraße,1
Research Program 55131 Mainz, Germany
Phone: +49 6131 176074
Email P
P
Sponsor Parc Eurasanté
D
59120 Loos, France
Represented by: PPD MD Phone: +33 320 16 40 38
Deputy CMO Email P
P
CRO for project Covance Covance
D Clinical and Periapproval Services
management, Limited,
regulatory Osprey House, Maidenhead Office Park,
activities, site Westacott Way, Maidenhead,
data monitoring SL6 3QH, UK
and medical
monitoring and
Clinical Study
Report
CRO for data Cytel Cytel
management & 39 rue d’Aboukir
statistics 75002 Paris , France
Pharmacovigilance SGS Life Science Services SGS
Medical Affairs Generaal De Wittelaan 19A bus 5
2800 Mechelen – Belgium
Study drug ALMAC ALMAC Clinical Services
supplier 9 Charlestown Road,
Seagoe Industrial Estate Craigavon
BT63 5PW, UK
IXRS Suvoda Suvoda LLC
9 Plaça de Catalunya, Floor 5
Barcelona, Spain, 08002

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Central laboratory Cerba Research NV 3, Industriepark Zwijnaarde
B-9052 Ghent, Belgium
BARC USA Inc

5 Delaware Drive
Lake Success
NY 11042-1114, United States
PK assessments ADME-bioanalysis 75, Chemin de Sommières
30310 Vergèze – France
ePRO ERT ERT
1818 Market Street, Suite 1000, Philadelphia,
Pennsylvania 19103, USA

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LIST OF ABBREVIATIONS
Ab Antibody
ABV alcohol by volume
ADR adverse drug reaction
AE adverse event
AESI adverse event of special interest
AFP Alfa-fetoprotein
AIH autoimmune hepatitis
ALCOA attributable, legible, contemporaneous, original and accurate
ALD alcoholic liver disease
ALP alkaline phosphatase
ALT alanine aminotransferase
AMA anti-mitochondrial antibodies
ANA antinuclear antibodies
AST aspartate aminotransferase
AT aminotransferase
AUCss Area Under Curve steady state
BP blood pressure
BUN blood urea nitrogen
C4 serum 7α-hydroxy-4-cholesten-3-one
CA cholic acid
CCl4 carbon tetrachloride
CDCA chenodeoxycholic acid
CEC clinical events committee
CFR Code of Federal Regulations
CI confidence interval
CK-18 cytokeratin-18
CKD-EPI Chronic Kidney Disease - Epidemiology Collaboration
CPK creatine phosphokinase
CRF case report form
CRO clinical research organization
CSR clinical study report
CT computed tomography
CTA Clinical Trial Agreement
CTFG Clinical Trial Facilitation Group
CYP cytochrome P450
DB double blind
DCA deoxycholic acid
DDI drug-drug interaction
DILI drug-induced liver injury
DSMB data safety monitoring board
DSUR development safety update report
EAIR exposure adjusted incidence rates
EASL European Association for the Study of the Liver
ECG electrocardiogram
eCRF electronic case report form

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eGFR estimated glomerular filtration rate

ELF enhanced liver fibrosis
ELISA enzyme-linked immunosorbent assay
EOS end of study
EOT end of treatment
ePRO electronic patient-reported outcomes
ESS Epworth Sleepiness Scale
FDA Food and Drug Administration
FGF19 fibroblast growth factor 19
FPG Fasting plasma glucose
GCA glycocholic acid
GCDCA glycochenodeoxycholic acid
GCP Good Clinical Practice
GDCA glycodeoxycholic acid
GGT gamma-glutamyl transferase
GLCA glycolithocholic acid
HAV hepatitis A virus
HBsAg hepatitis B surface antigen
hCG human chorionic gonadotropin
HCV hepatitis C virus
HCV Ab hepatitis C virus Antibody
HDL-C High-density lipoprotein cholesterol
hHSC human hepatic stellate cells
HIV human immunodeficiency virus
HRQoL health-related quality of life
hsCRP high sensitivity C-reactive protein
IB Investigator’s Brochure
ICE Intercurrent event
ICF Informed Consent Form
ICH International Conference on Harmonization
IEC independent ethics committee
IgG immunoglobulin G
IgM immunoglobulin M
IL interleukin
INR international normalized ratio
IRB institutional review board
IRT interactive response technology
ITT intent-to-treat
IXRS interactive voice/web response system
LCA lithocholic acid
LDL-C low-density lipoprotein cholesterol
LLN lower limit of normal
LTE long term extension
LVDB last visit double blind
MAR missing at random
MCP monocyte chemotactic protein
MDR3 multidrug resistance protein type 3

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MDRD modification of diet in renal disease

MedDRA medical dictionary for regulatory activities
MELD-Na Model for End-Stage Liver Disease-Sodium
MMRM mixed model with repeated measurement
MRI magnetic resonance imaging
NA not applicable
NASH nonalcoholic steatohepatitis
NF-κB nuclear factor kappa B
NOAEL no observed adverse effect level
NRS numeric rating scale
OATP1B3 organic anion transporting polypeptide 1B3
OCA obeticholic acid
PAI Plasminogen activator inhibitor
PBC primary biliary cholangitis
PBI placebo-based multiple imputation
PDGF platelet-derived growth factor
PGIC patient global impression of change
PGIS patient global impression of severity
PK pharmacokinetics
PKS pharmacokinetics set
PP per-protocol
PPAR peroxisome proliferator-activated receptor
PRO patient reported outcome
PROMIS Patient Reported Outcome Measurement Information System
PSC Primary sclerosing cholangitis
PT prothrombin time
QoL quality of life
RNA ribonucleic acid
SADR serious adverse drug reaction
SAE serious adverse event
SAP statistical analysis plan
SD standard deviation
SMA smooth muscle antibodies
SOP standard operating procedure
SS safety set
SUSAR suspected unexpected serious adverse reaction
SV screening visit
TB total bilirubin
TC total cholesterol
TCA taurocholic acid
TCDCA taurochenodeoxycholic acid
TDCA taurodeoxycholic acid
TE transient elastography
TG triglycerides
TGF-β transforming growth factor beta
TIPS transjugular intrahepatic portosystemic shunts
TLCA taurolithocholic acid

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TNFα tumor necrosis factor-alpha

UDCA ursodeoxycholic acid
UK United Kingdom
ULN upper limit of normal
Urine ACR Urine albumin to creatinine ratio
UV-LLNA UV- local lymph node assay
VLDL very low density lipoprotein
WBC white blood count
WOCBP women of childbearing potential

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CLINICAL STUDY SYNOPSIS

Sponsor: Study Drug: Protocol Number:
GENFIT Elafibranor GFT505B-319-1
Title of the study:

A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate
the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate
Response or Intolerance to Ursodeoxycholic Acid
Phase: 3
Indication: Primary Biliary Cholangitis (PBC)
Study Design and dose levels:
This is a phase 3 double-blind (DB), randomized, placebo-controlled study with an open-label long term
extension (LTE) evaluating the efficacy and safety of Elafibranor 80 mg once daily versus placebo in patients
with PBC and inadequate response or intolerance to ursodeoxycholic acid (UDCA).
In the DB period, patients will be randomized in a 2:1 ratio to receive Elafibranor 80 mg or placebo, once
daily. The DB period will last until the last completed week 52 (V6) or until a maximum of 104 weeks DB
period, whichever happens first, to further collect safety and clinical outcomes data in a DB manner. After
the DB period, all patients will receive Elafibranor 80 mg daily for up to 5 years during the LTE period.
When applicable, patients should continue their pre-study dose of UDCA throughout the study participation.
Schema 1: GFT505B-319-1 Study Design
Footnotes:
a. If receiving UDCA at randomization, continue throughout study participation
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last
completed V6 (W52), whichever occurs first
c. The LTE duration is up to 5 years after end of the DB period or until the patient’s total treatment duration
is 6 years, whichever occurs first
d. Safety follow-up 4 weeks after last dose of study drug

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Route of Administration: Oral

Primary Objective:
To evaluate the effect of Elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint over
52 weeks of the treatment compared to placebo
Key Secondary Objectives:

To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP) over 52
weeks of the treatment compared to placebo
To evaluate the effect of Elafibranor (80 mg/day) on pruritus over 52 weeks of the treatment compared to
placebo
Secondary Objectives:
1) To evaluate the effect of Elafibranor (80 mg/day) over 52 weeks of treatment compared to placebo on:
a) Hepatobiliary injury and liver function markers
b) Inflammation and hepatic fibrosis
c) Lipid parameters
d) Bile acids
e) Pruritis Patient Reported Outcomes (PROs)
f) Patient-reported Fatigue
g) Patient-reported Sleep
h) Health-related Quality of Life (HRQoL)
i) Health utility
j) Liver histology (both efficacy and safety criteria)
k) Safety and tolerability
2) To determine the pharmacokinetics (PK) parameters of elafibranor and its active metabolite GFT1007, at
steady state following daily oral administration at 80 mg in PBC patients
3) To evaluate the effect of Elafibranor (80 mg/day) during the LTE period on:
a) Safety and tolerability
b) Maintenance of efficacy from the DB period
Patient Population: Patients with PBC and inadequate response or intolerance to UDCA
Number of Randomized Patients (Approximately): 150
Number of Participating Centers (Approximately): 100
Number of Participating Countries (Approximately): 20
Study Duration per Patient: Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the screening
period, 52 to 104 weeks for the DB period, 208 to 260 weeks for the LTE period, and 4 weeks for safety
follow-up).

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Inclusion Criteria:
Patients must meet all of the following inclusion criteria to be eligible for randomization into the study:
1) Must have provided written informed consent and agree to comply with the study protocol
2) Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)
3) Definite or probable PBC diagnosis as demonstrated by the presence of ≥ 2 of the following
3 diagnostic criteria:
a. History of elevated ALP levels for ≥ 6 months prior to randomization (V1)
b. Positive anti-mitochondrial antibodies (AMA) titers (> 1/40 on immunofluorescence or
M2 positive by enzyme-linked immunosorbent assay [ELISA]) or positive PBC-specific
antinuclear antibodies (ANA)
c. Liver biopsy consistent with PBC
4) Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to
have:
a. 1 liver biopsy during the Screening Period (if no historical biopsy within 12 months
before screening is available)
b. 1 liver biopsy after 52-weeks of treatment
5) ALP ≥ 1.67x upper limit of normal (ULN)
6) Total bilirubin (TB) ≤ 2x ULN
To ensure adequate representation of moderately advanced disease or patients at risk of
progression to clinical outcomes, at least 10% of randomized patients will be moderately
advanced per Rotterdam Criteria (TB > ULN or Albumin < lower limit of normal [LLN]) and
at least 20% will have a TB > 0.6 x ULN (patients at risk of progression)
7) Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS) during
each of the 7 day intervals in the 14 days prior to randomization (V1), for a total of at least
8 values for PBC Worst Itch NRS in the last 14 days prior to randomization (V1)
8) UDCA for at least 12 months (stable dose ≥ 3 months) prior to randomization, or unable to
tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to randomization (per country
standard-of-care dosing)
9) If on colchicine must be on a stable dose for ≥ 3 months prior to randomization
10) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or
sertraline) must be on a stable dose for ≥ 3 months prior to randomization
11) Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to
randomization
12) Females participating in this study must be of non-child bearing potential or must be using
highly efficient contraception for the full duration of the study and for 1 month after the last
drug intake:
• Non-child bearing potential: cessation of menses for at least 12 months due to ovarian
failure or surgical sterilization such as bilateral oophorectomy, hysterectomy, or
medically documented ovarian failure for > 6 months prior to randomization
• If required by local Institutional Review Board (IRB) / Independent Ethics Committee
(IEC) and/or national regulations, sexual abstinence may be considered adequate (the
reliability of sexual abstinence needs to be evaluated in relation to the duration of the
clinical study and the preferred and usual lifestyle of the patient)
• Using a highly effective non-hormonal medical contraception (bilateral tubal occlusion,
vasectomized partner or intra-uterine device) for ≥ 3 months prior to screening

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• Highly effective contraception with barrier or highly effective hormonal method of
contraception (oral, intravaginal or transdermal combined estrogen and progestogen
hormonal contraception associated with inhibition of ovulation, oral, injectable or
implantable progestogen-only hormonal contraception associated with inhibition of
ovulation or intrauterine hormone-releasing system). The hormonal contraception must
be started at least one month prior to screening
Exclusion Criteria:
Patients presenting any of the following exclusion criteria will not be eligible for randomization into the
study:
1) History or presence of other concomitant liver disease including:
a) Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or positive
hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus (HCV) ribonucleic
acid (RNA) (tested for in case of known cured HCV infection or positive HCV Ab at
screening)
b) Primary sclerosing cholangitis (PSC)
c) Alcoholic liver disease (ALD)
d) Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if there is
suspicion and evidence of overlap AIH features, that cannot be explained alone by
insufficient response to UDCA
e) Nonalcoholic steatohepatitis (NASH)
f) Gilbert’s Syndrome (exclusion due to interpretability of bilirubin levels)
g) Known history of alpha-1 antitrypsin deficiency
2) Clinically significant hepatic decompensation, including:
a) History of liver transplantation, current placement on a liver transplant list, current
Model for End-Stage Liver Disease-Sodium (MELD-Na) score ≥ 12 linked to hepatic
impairment
b) Patients with cirrhosis/portal hypertension complications, including known esophageal
varices, ascites, history of variceal bleeds or related interventions (e.g., insertion of
variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), and hepatic
encephalopathy, history or presence of spontaneous bacterial peritonitis, hepatocellular
carcinoma
c) Hepatorenal syndrome (type I or II)
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease) or
which may diminish life expectancy to < 2 years, including known cancers
4) Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2 at
screening, or patient is known to have tested positive for HIV
5) Evidence of any other unstable or untreated clinically significant immunological, endocrine,
hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the
investigator
6) Other clinically significant medical conditions that are not well controlled or for which
medication needs are anticipated to change during the study
7) History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day
for men, and more than 20 g pure alcohol per day for women, or other substance abuse
within 1 year prior to screening visit (SV1)
8) For female patients: known pregnancy, or has a positive urine pregnancy test (confirmed
by a positive serum pregnancy test), or lactating

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9) Administration of the following medications are prohibited as specified below:
a) 2 months prior to randomization and throughout the study (up to the last study visit):
fibrates and glitazones
b) 3 months prior to randomization and throughout the study (up to the last study visit):
Obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate,
pentoxifylline, budesonide and other systemic corticosteroids; potentially hepatotoxic
drugs (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
c) 12 months prior to randomization and throughout the study (up to the last study visit):
antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or
chemokines
10) Patients who are currently participating in, plan to participate in, or have participated in an
investigational drug study or medical device study containing active substance within 30
days or five half-lives, whichever is longer, prior to screening; patients with previous
exposure to seladelpar are excluded.
11) Patients with previous exposure to elafibranor
12) SV value of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5x
ULN
13) SV value of albumin < 3.0 g/dL
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < LLN)
15) SV value of international normalized ratio (INR) > 1.3 due to altered hepatic function
16) SV value of creatine phosphokinase CPK > 2X ULN
17) Screening serum creatinine > 1.5 mg/dL
18) Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as
patients with markers of kidney failure damage or estimated glomerular filtration rate
[eGFR] < 60 mL/min/1,73 m2) calculated by modification of diet in renal disease (MDRD)
19) Platelet count < 150 X 103/µL
20) Alfa-fetoprotein (AFP) > 20 ng/mL with 4-phase liver computed tomography (CT) or
magnetic resonance imaging (MRI) suggesting presence of liver cancer
Randomization:
Patients who satisfy all eligibility criteria will be randomized in a 2:1 ratio to one of the following groups:
• Elafibranor 80 mg
• Placebo
A central randomization system (Interactive Voice/Web Response system (IXRS)) will be used.
The randomization will be stratified on two factors (ALP > 3 x ULN or bilirubin > ULN and Worst Itch score
averaged - over the 14 days preceding baseline - ≥ 4) at baseline (V1). During the LTE period, all patients
will receive Elafibranor 80 mg, once daily, for up to 5 years.
To ensure inclusion of a relevant ratio of patients with substantial risk of long term clinical outcome
moderate disease stage, a minimum of 15 patients (at least 10% of the total randomized patients) will
present a TB above ULN or albumin below LLN and a minimum of 30 patients (at least 20% of the total
randomized patients) will present a TB above 0.6x ULN.
Criteria for Evaluation:

Primary Endpoint:

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Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%.
Secondary Endpoints:
Key Secondary Endpoints:
Response to treatment based on ALP normalization at week 52.
Change in pruritus from baseline through week 52 on PBC Worst Itch NRS score.
Other Secondary Endpoints:

1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
2) ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
3) Response to treatment at week 52 according to:
a) ALP < 1.5x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b) ALP < 3x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
c) ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris II)
d) TB response rate of 15% change
e) Normalization of abnormal TB and/or albumin (Rotterdam)
f) TB ≤ 0.6 x ULN
g) ALP ≤ 1.67x ULN and TB ≤ 1 mg/dL [1]
h) No worsening of TB defined as level of TB≤ ULN at week 52 or no increase from baseline of more
than 0.1XULN at week 52
4) PBC risk scores at week 52: United Kingdom (UK) PBC score [2] and GLOBE score [3]
5) Response based on bilirubin normalization (TB ≤ ULN) at week 52
6) Response based on albumin normalization at week 52
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, ALT,
gamma-glutamyl transferase (GGT), 5’ NT, total and conjugated bilirubin, albumin, INR and ALP
fractionated (hepatic)
8) Change from baseline to week 52 in biomarkers of inflammation as measured by high-sensitivity C-
Reactive Protein (hsCRP), fibrinogen, haptoglobin and tumor necrosis factor-alpha (TNF-α)
9) Change from baseline to week 52 in immune response as measured by immunoglobulin G (IgG) and IgM
10) Change from baseline to week 52 in biomarkers, non-invasive and invasive measures of hepatic fibrosis
as measured by enhanced liver fibrosis (ELF)(HA, PIINP, TIMP-1), plasminogen activator inhibitor-1 (PAI-
1), transforming growth factor beta (TGF-β), cytokeratin-18 (CK-18) (M65 and M30), Pro-C3 and liver
stiffness measured by Transient Elastography (TE) (continuous)
11) Change from baseline to week 52 in lipid parameters as measured by total cholesterol (TC), low-density
lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), calculated VLDL-C and TG
12) Change from baseline to week 52 in fasting plasma glucose (FPG)
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile
acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF-19)
14) Proportion of patients with no worsening of pruritus from baseline to week 52 as measured by the PBC
Worst Itch NRS
15) Response in PBC Worst Itch NRS defined as at least 30% reduction from baseline of NRS at week 52 in
patients with a baseline NRS ≥ 4

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16) Change from baseline to week 52 in 5D-Itch
17) Change from baseline to week 52 in Patient Reported Outcome Measurement Information System
(PROMIS) Fatigue Short Form 7a
18) Change from baseline to week 52 in the Epworth Sleepiness Scale (ESS)
19) Change from baseline to week 52 in PBC-40
20) Change from baseline to week 52 in health utility as measured by the EQ-5D-5L
21) Onset of clinical outcomes described as a composite endpoint composed of:
a) Progression to histological cirrhosis for non cirrhotic patients at baseline
b) MELD-Na > 14 for patients with baseline MELD-Na ≤12
c) Liver transplant
d) Uncontrolled ascites requiring treatment
e) Hospitalization for new onset or recurrence of any of the following:
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven/Conn score of 2 or more
iii) spontaneous bacterial peritonitis
f) Death
22) Change from baseline in the histological scores
a) Fibrosis stage according to Nakanuma scoring
b) Bile duct scores
c) Cholangitis activity
d) Interface Hepatitis activity
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct score)
f) Other exploratory scores (Fibrosis according to mdodifeid Ishak scoring, portal inflammation,
ductular reaction, cholestasis, concentric periductal fibrosis)
23) Safety and tolerability as assessed by
a) Serious adverse events (SAEs), adverse events (AEs), adverse events of special interest (AESIs),
physical examination, vital signs, medical history, electrocardiogram (ECG)
b) Chemistry and hematology
c) Liver markers
d) Renal biomarkers (including urinalysis)
e) Other biochemical safety markers
f) Histology
24) PK assessed by GFT505 and GF1007 concentrations measurement in plasma
Additionally, apart from histology and PK assessments, the same endpoints as for the DB period will be
collected over the LTE period to assess the maintenance of efficacy and safety of the treatment.
Data Safety Monitoring Board (DSMB):

An independent DSMB will be established in order to review the progress of the study and to perform a
safety data review (including review of the adjudication reports issued from the clinical events committee
(CEC) on a regular basis during the study to protect patient welfare and preserve study integrity.
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist,
1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent from the conduct of
the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB.

Page 21
Clinical Event committee (CEC)
The CEC will conduct adjudication of the clinical outcomes (excluding the progression to histological cirrhosis
for non cirrhotic patients at baseline) and DILI (Drug Induced Liver Injury) events. The CEC assessment and
adjudication will occur in a blinded (during DB period) and consistent and unbiased manner throughout the
course of the study to determine whether the event meets the protocol specified criteria.
The CEC will be comprised of 3 hepatologists; all of them will be independent from the conduct of the study.
Statistical considerations:
Determination of the sample size
The assumptions used for the determination of the sample size are:
• an expected response rate in the placebo group slightly higher than that in the phase 3 pivotal study
supporting the regulatory approval of OCA (10%) [4],
• an expected response rate in the elafibranor group at least similar to OCA (47%).
The response rates from phase 3 pivotal study supporting the regulatory approval of OCA has been estimated
after imputation of missing data as non-response.
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power to
demonstrate a statistically significant between group difference of 35% (47% in elafibranor group vs 12% in
placebo group) in the response rate at week 52 of the primary efficacy endpoint with a two-sided alpha of
0.01 and using an exact Fisher test.
In addition, assuming 1/50 (2.0%) patient in the placebo group with ALP normalization at week 52 (key
secondary endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power to detect a
statistically significant between group difference of 20.0% at a two-sided 0.01 alpha level.
Assuming a pooled standard deviation(SD) of 3 points, 150 patients (100 Elafibranor vs 50 placebo) provide
at least 80% power to detect a statistically significant between group difference of 1.8 points in mean change
from baseline in PBC Worst Itch NRS score (second key secondary endpoint) at a two-sided 0.01 alpha level.
Analysis sets:
• Screened set: all patients who sign informed consent. This set will be used to summarize disposition.
• Intent-to-treat (ITT) set: All randomized subjects.
• Per-protocol (PP) set: All subjects from the ITT set without any major protocol deviation affecting
the primary efficacy endpoint.
• Safety set (SS): All subjects who were administered at least one dose of study drug.
• Pharmacokinetics set (PKS): All patients who were administered at least one dose of study drug
and have at least one post-dose PK sample. Moreover, patients of the PK set must have data for
time of dosing, time of sampling and amount of drug administered. Placebo patients will be
removed from the analysis population.
Efficacy analysis:
DB treatment period
The primary and secondary efficacy analyses will be performed primarily on the ITT set and secondarily on
the PP set. Each efficacy endpoint will be evaluated up to week 52. For patients who completed additional
visits during the DB period, descriptive statistics will be presented up to the end of the DB period.
• Primary efficacy endpoint

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The response rates (ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%) at week 52 will be compared
between the treatment groups using the exact Cochran-Mantel-Haentzel test stratified by the randomization
strata. Patients who stopped prematurely the study treatment will be considered as non-responders.
A sensitivity analysis to the statistical model will be performed using an exact logistic regression model with
treatment group and randomization strata as factors.
Three supplementary/sensitivity analyses will be assessed using relevant multiple imputation methods to
manage missing data. One will assume Missing At Random (MAR) and use multiple imputation to impute
values as if subjects would follow their initial treatment. A second one will impute values using the information
from the placebo group. The third one will be a tipping point analysis to explore a number of scenarios about
the missing outcomes.
A last supplementary analysis will use outcome value at week 52 regardless of treatment discontinuation or
use of rescue therapy.
• Key secondary endpoints
The response rates (proportion of patients with ALP normalization) at week 52 will be compared between the
treatment groups using the same method as for the primary efficacy endpoint, including sensitivity and
supplementary analyses.
The change from baseline in PBC Worst Itch NRS score until week 52 will be summarized by treatment group
and will be compared using a Mixed Model with Repeated Measurement (MMRM) with stratification factors as
fixed factors. A supplementary analysis based on treatment policy will use outcome values at week 52
regardless of treatment discontinuation or use of rescue therapy.
• Other secondary endpoints
The continuous endpoints will be compared between the treatment groups using the MMRM.
The categorical endpoints will be analyzed using the exact Cochran-Mantel-Haentzel test stratified by the
randomization strata. As for the primary endpoint, the subject who do not complete the study will be
considered as non-responders/treatment failures.
• Control of type I error rate
The fixed-sequence testing approach will be used to control the overall Type I error rate at a two-sided 0.01
level. If the primary endpoint is statistically significant at a two-sided 0.01 level, the first key secondary
endpoint (ALP normalization) will be tested at the same level. If the first key secondary endpoint is statistically
significant at a two-sided 0.01 level, the second key secondary endpoint (change in pruritus) will be tested at
the same level.
LTE period
All the efficacy endpoints (apart from histology and PK) considered for the DB period will be summarized using
descriptive statistics by DB treatment group and overall on both ITT and PP sets.
Safety analysis:
Descriptive statistics will be provided on the SS according to the treatment groups and an overall summary
will be produced. In addition, for AEs, exposure adjusted incidence rates (EAIR) will be compared between
treatment groups presenting estimates with their confidence intervals (CIs). No formal significance testing is
planned. Safety analyses will be performed for both DB treatment period and LTE period.
Pharmacokinetic analysis:
The PK analysis will be performed on the PKS using a PK pop model approach.

Page 23
PK parameters of elafibranor and GFT1007 will be calculated at steady state and summarized by geometric
mean, SD, coefficient of variation, minimum and maximum, and median.

Page 24
Table 1: Study General Assessment Schedule

Double Blind (DB) If
Study Period Screening Long-term Extension (LTE)
Common DB Variable DB applicable Safety contact in
variable DB & LTEa
SV SV SV
Visit number V1 V2 V3 V4 V5 V6 V7 V8 LVDBk EOT DBb LT1 LT2 to LTn EOT-LTEb
1 2 3
Safety DB period:
At max.
Follow- -Week 65 13 Safety Follow-
13 weeks LT2 13 weeks
up: -Week 91 weeks up: 16 to 30
after last after LT1
Weeks -12 to -2 0 4 13 26 39 52 78 104 16 to 30 LTE: after days after last
V6 for the then every 26
days after - 13 weeks after last DB study drug
last weeks
last drug LT2 then every 26 visit intake
patient
intake weeks
LT2: 91 days
Week 65: 456 days V6 or
after LT1
Days 1 29 92 183 274 365 547 729 NA NA then every NA
LTE: 91 d after LT2 LVDB +
182 days up
then every 182 d 91 d
to 2185
+/- +/- +/- +/- +/- +/-
Tolerances (Days) +/- 7 NA NA +/- 14 +/- 14 +/- 14 NA
14 14 14 14 14 14
STUDY PROCEDURES f
Obtain Informed Consent X

Medical and Disease History X
Inclusion/Exclusion Criteria X X
Physical Examination (Height at
X X X X X X X X X X X X X X
SV1 only)
Vital Signs and Weight X X X X X X X X X X X X X X
12-lead Electrocardiogram X X X X X X
PROc questionnaires
PBC Worst Itch NRS Xd
PBC Worst Itch NRS-Past Week X X X X X
PGIC X X X X X X X X X X
PGIS Xe X X X X X X X X X X X
5-D Itch X X X X X X X X X X X
PROMIS Fatigue Short Form
X X X X X X X X X X X
7a
ESS X X X X X X X X X X X
PBC-40 X X X X X X X X X X X
EQ-5D-5L X X X X X X X X X X X
Transient Elastography (TE) X X X X X X

Page 25
Clinical Trial GFT505B‐319‐1


Common DB Variable DB applicable Safety contact in
SV SV SV variable DB & LTEa
1 2 3
Safety DB period:
At max.
Follow- -Week 65 13 Safety Follow-
13 weeks LT2 13 weeks
up: -Week 91 weeks up: 16 to 30
after last after LT1
Weeks -12 to -2 0 4 13 26 39 52 78 104 16 to 30 LTE: after days after last
V6 for the then every 26
days after - 13 weeks after last DB study drug
last weeks
last drug LT2 then every 26 visit intake
patient
intake weeks
LT2: 91 days
after LT1
LTE: 91 d after LT2 LVDB +
182 days up
then every 182 d 91 d
to 2185
+/- +/- +/- +/- +/- +/-
14 14 14 14 14 14
Liver Biopsy Xh X
Ultrasound exam (liver &
X X X Xj
bladder)
PK Xi
Adverse Events (AEs) X X X X X X X X X X X X X X X
Clinical Outcomes X X X X X X X X X X X X X X
Concomitant Medications X X X X X X X X X X X X X X X
Randomization X
Treatment Assignmentl X
Dispense Study Drug X X X X X X X X Xg
Study Drug
Accountability/Compliance
EOS registration To be completed in study system(s) as applicable
Footnotes:
a. Safety contact by phone call every alternating 26 weeks starting 13 weeks after V6 in the DB period and starting after LT2 during LTE to check AEs and concomitant medications
b. If premature study drug discontinuation during DB period, end of treatment (EOT) DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue in the study until V8, or until the last
completed V6 whichever occurs first. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. If premature study drug discontinuation occurs during LTE
period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake

Page 26

c. Refer to Table 3 (Schedule of PRO Questionnaires) for details

d. During the screening period and DB period up to week 52 (V6), the PBC Worst Itch NRS score will be collected every evening via an eDiary. The mean score of the 14 days prior to randomization (V1) will be used for stratification.
Patients must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to V1, for a total of at least 8 values in the 14 days prior to V1
e. Patient Global Impression of Severity (PGIS) will be collected at SV1 only during the screening period
f. Procedures/assessments should be conducted in the following order during study visits: PROs (when completed at the study center), investigator assessments, safety and laboratory assessments, administration of study drug
g. Drug dispensation will be done up to LT10. There will be no drug dispensation at LT11
h. Liver biopsy at inclusion to be done at any SV as long as it is completed at the latest 4 weeks prior to randomization visit
i. PK assessment will include the following timepoints: predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h
j. Ultrasound exam to be performed every year
k. Last DB visit if prior to V8, is to be scheduled at the latest 13 weeks after the last V6 completed. It will allow switching the patients in a timely manner to LTE with open label elafibranor. In case the last visit double blind (LVDB)
visit occurs within the time window of the next scheduled visit, LVDB visit replaces the scheduled visit. The same procedures as for V8 will be performed for LVDB.
l. The switch to elafibranor treatment will happen when V8 completed by any patient, or will be triggered when the last V6 completed for all randomized patients will be completed.

Page 27
Table 2: Study Biological Assessment Schedule
Double Blind (DB)

Study Period Screening If applicable Long-term Extension (LTE)
Common DB Variable DB
Visit number SV1 SV2 SV3 V1 V2 V3 V4 V5 V6 V7 V8 LVDBk EOT DBb LT1 LT2 to LTn EOT-LTEb
Safety
At max. 13
Follow-up:
weeks after 13 weeks LT2 13 weeks after Safety Follow-up: 16
10 16 to 30
Weeks -12 to -2 0 4 13 26 39 52 78 last V6 for after last LT1 then every 26 to 30 days after last
4 days after
the last DB visit weeks study drug intake
last drug
patient
intake
V6 or V8 LT2: 91 days after
18 27 36 54 72
Days 1 29 92 NA NA or LVDB + LT1 then every 182 NA
3 4 5 7 9
91 d days up to 2185
+/- +/- +/- +/- +/- +/- +/-
Tolerances (Days) NA NA +/- 14 +/- 14 NA
7 14 14 14 14 14 14
Serum Hematology
Hemoglobin, hematocrit, WBC with differential, X X X X X X X X X X X X X X
platelet count, prothrombin time (PT) , INR,
reticulocytes/RBC
Screening Serum Chemistry
ALP, ALT, AST, GGT, CPK, total and conjugated X
bilirubin, albumin, creatinine, sodium, AFP, eGFR
(MDRD formula & CKD-EPI formula), MELD-Na
Serum Chemistry
Sodium, potassium, chloride, calcium, albumin,
BUN, creatinine, TB , conjugated bilirubin, AST, X X X X X X X X X X X X X
ALT, ALP, GGT, 5’ NT, total proteins, lipase,
amylase, TC, LDL-C, HDL-C, VLDL-C, TG, CPK ,
FPG, eGFR, MELD-Na
ALP fractionated X X
Serology
X
HIV Ab I/II, Anti- HAV IgM , HBs, HCV

Page 28
Safety
At max. 13
Follow-up:
10 16 to 30
4 days after
last drug
patient
intake
18 27 36 54 72
3 4 5 7 9
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Serum Bile Acids and Biomarkers of Bile
Acid Synthesis
Bile acids (cholic acid (CA), glycocholic acid
(GCA), taurocholic acid (TCA), chenodeoxycholic
acid (CDCA), glycochenodeoxycholic acid
(GCDCA), taurochenodeoxycholic acid (TCDCA), X X X X X X
deoxycholic acid (DCA), glycodeoxycholic acid
(GDCA), taurodeoxycholic acid (TDCA),
lithocholic acid (LCA), glycolithocholic acid
(GLCA), taurolithocholic acid (TLCA)), C4, FGF-
19
Biomarkers of Hepatic Fibrosis and/or

Inflammation
HsCRP, fibrinogen, haptoglobin, TNF-α , IL-6, X X X X X X
ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18
(M65 and M30), Pro-C3
Additional Safety Markers
Cystatin C, urine albumin to creatinine ratio X X X X X X
(urine ACR) , AFP
Immunoglobulins
X X X X X X
IgG, IgM
Urinalysis (dipstick)c,
Specific gravity, pH, protein, glucose, ketones, X X X X X X X X X X X X X X
bilirubin, urobilinogen, blood, nitrite, leukocytes

Page 29
Safety
At max. 13
Follow-up:
10 16 to 30
4 days after
last drug
patient
intake
18 27 36 54 72
3 4 5 7 9
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Urine-based β-human chorionic
X X X X X X X X X X X X
gonadotropin (hCG) Pregnancy Testd,e
urinary myoglobin, serum IgG and SMA f X X X X X X X X X X X X
Biobankg X X X X X X
Footnotes:
a. Repeated measured for AST, ALT, ALP and TB to collected (See 3.5.1)
b. If premature study drug discontinuation during DB period, EOT DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue in the study until V8. In case
the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. If premature study drug discontinuation occurs during LTE period, an EOT LTE
visit will be performed between 16 and 30 days after last drug intake
c. Microscopic evaluation will be performed if dipstick urinalysis indicated presence of any significant abnormality
d. Urine-based β-hCG pregnancy tests must be performed in all females of childbearing potential. If positive, a confirmatory pregnancy blood test must be performed at the site
e. A home pregnancy test to be performed every 4 weeks, starting at V1
f. Assessment of presence of myoglobin in urine to be done locally only in case of clinically significant CPK elevation; assessment of IgG and SMA to be done locally in case of suspicion of AIH
g. Additional blood samples will be will be collected from patients, who have given their consent, to be used to discover or validate biomarkers in PBC and related diseases

Page 30
Table 3: Schedule of Patient Reported Outcomes (PROs) Questionnaires

eDiary devices will be provided to patients at SV1 for daily completion throughout the study. eDiary devices will be collected at V6 (or EOT visit, whichever occurs earlier).
Platform Assessment Frequency and Duration of Assessment Time of Assessment
eDiary PBC Worst Itch NRS Once daily during screeninga and the Common DB periods (up to V6) Evening
eTablet PBC Worst Itch NRS-Past Week Throughout the Variable DB and LTE periods During study visitb
eTablet PGIC Throughout the DB period (starting at V2) and LTE periods During study visitb
eTablet PGIS Throughout the screening, DB, and LTE periods During study visitb
eTablet 5-D Itch Throughout the DB and LTE periods During study visitb
eTablet PROMIS Fatigue Short Form 7a Throughout the DB and LTE periods During study visitb
eTablet ESS Throughout the DB and LTE periods During study visitb
eTablet PBC-40 Throughout the DB and LTE periods During study visitb
eTablet EQ-5D-5L Throughout the DB and LTE periods During study visitb
Footnotes:
a. The mean PBC Worst Itch NRS score of the 14 days prior to randomization (V1) will be used for stratification. Patients must have at least 4
available values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to V1, for a total of at least 8 values in the 14
days prior to V1
b. Administered on-site

Page 31
TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ......................................................................... 2
CLINICAL STUDY PROTOCOL - INVESTIGATOR SIGNATURE PAGE .............................................. 6
STUDY CONTACTS ........................................................................................................................ 7
LIST OF ABBREVIATIONS.............................................................................................................. 9
CLINICAL STUDY SYNOPSIS........................................................................................................ 13
TABLE OF CONTENTS ................................................................................................................. 30
1 INTRODUCTION AND RATIONALE ...................................................................................... 35
1.1. BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY CHOLANGITIS ......................... 35
1.2. SUMMARY OF NON CLINICAL STUDIES ...................................................................................... 36
1.2.1. Nonclinical Pharmacology............................................................................................. 36
1.2.1.1. In Vitro Pharmacology .............................................................................................................. 36
1.2.1.1.1. Activity on Human and Murine PPAR isoforms ......................................................................... 36
1.2.1.1.2. Anti-fibrotic Activity ............................................................................................................ 37
1.2.1.2. In Vivo Pharmacology ............................................................................................................... 37
1.2.1.2.1. Rat Model of CCl4-induced Hepatic Fibrosis............................................................................. 37
1.2.1.3. Safety Pharmacology................................................................................................................. 37
1.2.1.4. Absorption/distribution/metabolism/excretion Studies (ADME)......................................................... 37
1.2.1.5. Toxicology .............................................................................................................................. 38
1.2.1.5.1. Mutagenicity and Genotoxicity ............................................................................................... 38
1.2.1.5.2. Acute Toxicity..................................................................................................................... 38
1.2.1.5.3. Repeated Dose Toxicity Studies .............................................................................................. 38
1.2.1.5.4. Phototoxicity Studies ............................................................................................................ 38
1.3. CLINICAL STUDIES ............................................................................................................... 39
1.3.1. Phase 1 Program ......................................................................................................... 39
1.3.2. Phase 2 Program ......................................................................................................... 39
1.4. CONCLUSION ...................................................................................................................... 39
1.5. RATIONALE FOR STUDY POPULATION ....................................................................................... 39
1.6. JUSTIFICATION OF THE SELECTED DOSE .................................................................................... 41
2 STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 42
2.1. OBJECTIVES ........................................................................................................................ 42
2.1.1. DB Period .................................................................................................................. 42
2.1.1.1. Primary Objective ..................................................................................................................... 42
2.1.1.2. Key Secondary Objectives.......................................................................................................... 42
2.1.1.3. Secondary Objectives ................................................................................................................ 42
2.1.2. LTE Period ................................................................................................................ 42
2.2. ENDPOINTS ......................................................................................................................... 42
2.2.1. DB Period .................................................................................................................. 42
2.2.1.1. Primary Endpoint ..................................................................................................................... 42
2.2.1.2. Secondary Endpoints ................................................................................................................. 43
2.2.2. LTE Period ................................................................................................................ 44
3 STUDY DESIGN .................................................................................................................... 45
3.1. NUMBER OF PATIENTS .......................................................................................................... 47
3.2. TREATMENT GROUPS ............................................................................................................ 47
3.3. DOSE ADJUSTMENT CRITERIA ................................................................................................. 47
3.4. DURATION OF STUDY PARTICIPATION....................................................................................... 47
3.5. STUDY PERIODS AND SCHEDULE OF ASSESSMENTS ..................................................................... 47
3.5.1. Screening Period ......................................................................................................... 48

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3.5.2. DB period (Week 0 to max Week 104) .............................................................................. 48
3.5.3. LTE period ................................................................................................................. 49
3.5.4. Safety Follow up .......................................................................................................... 50
3.5.5. Optional Visits ............................................................................................................ 50
3.5.5.1. Retesting and/or additional screening visits.................................................................................... 50
3.5.5.2. Unscheduled visits .................................................................................................................... 50
3.5.6. Off-site study procedures in case of crisis situation ............................................................. 50
4 PATIENT SELECTION .......................................................................................................... 51
4.1 INCLUSION CRITERIA ............................................................................................................ 51
4.2 EXCLUSION CRITERIA ........................................................................................................... 52
5 STUDY PROCEDURES .......................................................................................................... 54
5.1. SCREEN FAILURES ................................................................................................................ 54
5.2. PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ................................... 54
5.2.1. Permanent discontinuation of study drug/withdrawal from study ............................................ 54
5.2.2. Patients Lost to Follow-up ............................................................................................. 55
5.2.3. Replacement ............................................................................................................... 55
5.2.4. Premature Discontinuation of the Study ............................................................................ 55
6 ASSESSMENTS ..................................................................................................................... 56
6.1. EFFICACY AND SAFETY ASSESSMENT ....................................................................................... 56
6.1.1. Biological assessment ................................................................................................... 56
6.1.1.1. Laboratory Assessments ............................................................................................................ 56
6.1.1.2. Urinary Pregnancy Tests ............................................................................................................ 56
6.1.1.3. Serology ................................................................................................................................. 56
6.1.1.4. Other Parameters ...................................................................................................................... 57
6.1.2. Constitution of biobank ................................................................................................. 57
6.1.3. Histological assessment ................................................................................................ 57
6.1.3.1. Recommendations related to liver biopsy ...................................................................................... 57
6.1.3.2. Liver biopsy reading ................................................................................................................. 58
6.1.4. Pharmacokinetic assessment .......................................................................................... 58
6.1.4.1. Pharmacokinetic blood sampling timepoints .................................................................................. 58
6.1.4.2. Pharmacokinetic blood handling procedures .................................................................................. 58
6.1.4.3. Bioanalytical analysis ................................................................................................................ 59
6.1.4.4. Description of pharmacokinetic evaluation parameters ..................................................................... 59
6.2. OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING ............................................... 59
6.2.1. Physical Examination ................................................................................................... 59
6.2.2. Vital Sign and Weight ................................................................................................... 59
6.2.3. 12 Lead ECG .............................................................................................................. 59
6.2.4. Liver stiffness by transient elastography (FibroScan®) ......................................................... 60
6.2.5. Patient Reported Outcomes Questionnaires ....................................................................... 60
6.3. IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES .............. 61
6.3.1. Creatine Phosphokinase ................................................................................................ 61
6.3.2. Liver Function Monitoring............................................................................................. 61
6.3.2.1. Treatment discontinuation rule for elevated Aminotransferase (AT) values regardless of baseline values ... 62
6.3.2.2. Treatment discontinuation rules for elevated Aminotransferase (AT) values according to baseline values .. 62
6.3.2.2.1. Monitoring of patients with normal baseline AT values ............................................................... 62
6.3.2.2.2. Monitoring of patients with abnormal baseline AT values ............................................................ 63
6.3.2.2.3. Monitoring of patients with abnormal TB baseline values ............................................................ 63
6.3.3. Auto-immune hepatitis monitoring ................................................................................... 63
6.3.4. Acute Pancreatitis Monitoring ........................................................................................ 64
6.3.4.1. Treatment discontinuation rule for suspected acute pancreatitis ......................................................... 64
6.3.5. Monitoring of hepatocellular and bladder cancer ............................................................... 64
6.3.5.1. Liver monitoring ...................................................................................................................... 64
6.3.5.2. Bladder & urinary tract monitoring .............................................................................................. 64
6.3.6. Safety Review.............................................................................................................. 64
6.3.7. Clinical event committee ............................................................................................... 64

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6.4. GUIDANCE FOR INVESTIGATORS .............................................................................................. 64
6.4.1. Summary of safety data ................................................................................................. 64
6.4.2. Benefit/risk assessment ................................................................................................. 65
7 TREATMENTS ...................................................................................................................... 67
7.1. DESCRIPTION OF STUDY MEDICATIONS ..................................................................................... 67
7.2. PACKAGING AND LABELING ................................................................................................... 67
7.2.1. Packaging .................................................................................................................. 67
7.2.2. Labeling .................................................................................................................... 67
7.3. DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO .................................................. 67
7.4. METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ............................................................. 67
7.5. STORAGE CONDITIONS .......................................................................................................... 68
7.6. DISPENSING OF TREATMENT................................................................................................... 68
7.7. TREATMENT REPLACEMENT ................................................................................................... 68
7.8. PROCEDURE FOR BLINDING .................................................................................................... 68
7.9. PROCEDURE FOR UNBLINDING ................................................................................................ 68
7.10. STUDY DRUG COMPLIANCE .................................................................................................... 69
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION ..................................................... 69
7.12. OTHER MEDICATION ............................................................................................................. 69
7.12.1. Handling of Concomitant Medication ............................................................................... 69
7.12.2. Non-permitted Medication ............................................................................................. 69
7.12.3. Permitted Medication Under Conditions ........................................................................... 70
7.12.4. Permitted Medication ................................................................................................... 70
8 ADVERSE EVENT AND TOXICITY MANAGEMENT ............................................................... 71
8.1. DEFINITIONS ....................................................................................................................... 71
8.1.1. Adverse Events (AEs) ................................................................................................... 71
8.1.2. Adverse events of special interest (AESIs) ......................................................................... 71
8.1.3. Serious Adverse Event .................................................................................................. 72
8.1.4. Clarification on Serious Adverse Events ........................................................................... 73
8.1.5. Adverse Drug Reaction ................................................................................................. 73
8.1.6. Unexpected Adverse Event ............................................................................................. 73
8.2. ASSESSMENTS ..................................................................................................................... 73
8.2.1. Intensity Assessment ..................................................................................................... 73
8.2.2. Relation to the Study Treatment ...................................................................................... 74
8.2.3. Action Taken and Outcome ............................................................................................ 74
8.3. REPORTING......................................................................................................................... 75
8.3.1. Reporting an AE .......................................................................................................... 75
8.3.2. Reporting a SAE or an AESI........................................................................................... 75
8.3.3. Follow-up .................................................................................................................. 76
8.4. POST STUDY REPORTING REQUIREMENTS .................................................................................. 76
8.5. CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES OR SAES ....... 76
8.6. SPECIAL SITUATION REPORTS ................................................................................................. 77
8.6.1. Pregnancy .................................................................................................................. 77
8.6.2. Medication Error ......................................................................................................... 77
8.6.3. Misuse....................................................................................................................... 77
8.6.4. Overdose ................................................................................................................... 77
8.6.5. Abuse ........................................................................................................................ 77
9 STATISTICAL METHODS AND DATA ANALYSIS ................................................................... 78
9.1. ESTIMANDS CONSIDERATIONS................................................................................................. 78
9.2. RANDOMIZATION AND TREATMENT ASSIGNMENT ....................................................................... 80
9.3. ENDPOINTS ......................................................................................................................... 80
9.3.1. Primary Endpoint ........................................................................................................ 80
9.3.2. Secondary Endpoints .................................................................................................... 80
9.4. ANALYSIS SETS ................................................................................................................... 82

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9.5. ANALYSIS OF PRIMARY ENDPOINT ........................................................................................... 82
9.6. OTHER STATISTICAL ANALYSIS ............................................................................................... 84
9.6.1. Key secondary endpoints ............................................................................................... 84
9.6.2. Other secondary endpoints ............................................................................................ 84
9.6.3. Subgroup analyses ....................................................................................................... 84
9.7. STRATEGIES TO CONTROL TYPE I ERROR................................................................................... 85
9.8. SAMPLE SIZE CALCULATION ................................................................................................... 85
9.8.1. Reduction in ALP and TB .............................................................................................. 85
9.8.2. Normalization in ALP ................................................................................................... 86
9.9. SAFETY ANALYSIS ............................................................................................................... 86
10 DATA HANDLING AND RECORD KEEPING........................................................................... 87
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ......................................................................... 87
10.2. RETENTION OF RECORDS ....................................................................................................... 87
11 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 88
11.1. QUALITY CONTROL & MONITORING PROCEDURES ....................................................................... 88
11.2. ETHICAL PRINCIPLES ............................................................................................................ 88
11.3. QUALITY ASSURANCE ........................................................................................................... 88
12 ETHICS AND REGULATORY ................................................................................................ 90
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................................ 90
12.2. COMPETENT AUTHORITY ....................................................................................................... 90
12.3. PATIENT INFORMATION AND CONSENT ..................................................................................... 90
12.4. PATIENT CONFIDENTIALITY .................................................................................................... 91
12.5. DEFINITION OF THE END OF THE RESEARCH .............................................................................. 91
13 FINANCING AND INSURANCE .............................................................................................. 92
13.1. FINANCIAL ISSUES ................................................................................................................ 92
13.2. INSURANCE AND PATIENT INJURY............................................................................................ 92
14 STUDY RESULTS AND PUBLICATION POLICY ..................................................................... 93
14.1. STUDY REPORT ................................................................................................................... 93
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND PUBLICATION ........... 93
15 REFERENCES LIST .............................................................................................................. 95
16 APPENDICES:....................................................................................................................... 97
16.1. APPENDIX 1: BARC CENTRAL LABORATORY REFERENCE RANGES FOR ALP, AST, ALT, GGT, DIRECT AND
INDIRECT BILIRUBIN, AND TOTAL BILIRUBIN .......................................................................................... 97
16.2. APPENDIX 2: ALCOHOL COMPARISON TABLE .............................................................................. 99
16.3. APPENDIX 3: PERMITTED/NON-PERMITTED MEDICATION ............................................................ 100
16.4. APPENDIX 4: PRODUCT CARTON AND WALLET LABELING ........................................................... 102
16.5. APPENDIX 5: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES: ......................................... 103
16.5.1. PBC-40 ................................................................................................................... 103
16.5.2. Epworth Sleepiness Scale (ESS) .................................................................................... 107
16.5.3. 5-D Itch Scale ........................................................................................................... 108
16.5.4. PROMIS Fatigue Short Form 7a ................................................................................... 109
16.5.5. The Patient Global Impression of Change (PGIC) ............................................................ 110
16.5.6. The Patient Global Impression of Severity (PGIS) ............................................................. 111
16.5.7. PBC Worst Itch NRS .................................................................................................. 112
16.5.8. EuroQoL EQ-5D-5L ................................................................................................... 113

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LIST OF TABLES
Table 1: Study General Assessment Schedule ....................................................................................................... 23
Table 2: Study Biological Assessment Schedule ..................................................................................................... 26
Table 3: Schedule of Patient Reported Outcomes (PROs) Questionnaires .................................................................. 29
LIST OF FIGURES
Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN) ................................................................... 41
LIST OF SCHEMA
Schema 1: GFT505B-319-1 Study Design ............................................................................................................. 13
Schema 1: GFT505B-319-1 Study Design ............................................................................................................. 46

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1 INTRODUCTION AND RATIONALE
1.1. BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY CHOLANGITIS
Characterization of the disease

PBC is a rare, chronic, progressive liver disease of autoimmune etiology, characterized by injury of the
intrahepatic bile ducts that, in untreated patients or non-responders to existing therapies, may progress to
hepatic fibrosis, cirrhosis, hepatic decompensation, and death unless they receive a liver transplant [5, 6].
PBC disproportionately affects women versus men (approximately 10:1) and is typically diagnosed in patients
between 40 years to 60 years of age. The incidence and prevalence rates for PBC in Europe, North America,
Asia, and Australia are reported as ranging from 0.33 to 5.8 per 100,000 inhabitants and 1.91 to 40.2 per
100,000 inhabitants, respectively [7]. Kim et al estimated that there were 47,000 prevalent cases of PBC in
the United States white population and that approximately 3500 new cases are diagnosed each year [8]. Over
60% of the newly diagnosed cases are asymptomatic. The majority of asymptomatic patients become
symptomatic within 10 years and the estimates for developing symptoms at 5 and 20 years are 50% and
95%, respectively [6]. Patients with PBC progress at varying rates, some experiencing liver decompensation
over a period of several years while others over decades [9, 10]. PBC is one of the leading indications for
liver transplantation. Despite its rarity, PBC remains an important cause of morbidity in the Western world.
PBC has also been identified as an important risk factor for hepatocellular carcinoma [11].
PBC is characterized by cholestasis caused by autoimmune destruction of biliary ductules with progressive
impairment of bile flow in the liver. This results in increased hepatocellular bile acid concentrations which are
toxic to the liver. Such hepatocellular injury is associated with a local inflammatory response resulting early
on in an abnormal elevation of serum ALP levels, a hallmark of the disease. Antimitochondrial antibody and
IgM are specific immunological hallmarks of PBC, and antimitochondrial antibody is a diagnostic marker of
the disease in approximately 90% of patients [12]. Liver biopsy, while confirmatory, is no longer the standard
of care.
ALP is also routinely used to clinically monitor the disease and serves as a leading indicator of disease
progression. ALP increases with disease progression as bilirubin starts to decline in more advanced disease
(as the excretory function starts to decline), and both have been shown to be highly predictive of long-term
clinical outcomes (e.g., transplant-free survival) [13-15]. Two large clinical PBC databases, the PBC Study
Group (> 6100 patients) and the UK-PBC Research Cohort (> 5900 patients) have confirmed a near log-linear
correlation of both elevated ALP and bilirubin after 1 year of follow up with long-term liver transplant-free
survival [15].
As PBC advances, the transaminases ALT and AST may also be elevated due to hepatocellular damage
secondary to cholestasis. While GGT lacks specificity, elevation of this enzyme in the presence of elevated
ALP is confirmatory of a cholestatic condition such as PBC [16].
The most common symptoms of PBC are fatigue and pruritus [17]. The mechanisms underlying these
symptoms are not well elucidated and neither correlates with disease stage or clinical outcomes.
Current Treatment Options

UDCA, an epimer of the primary human bile acid UDCA, was the only medicine currently approved to treat
PBC until May 2016. UDCA has been shown to improve ALP and bilirubin, and to delay histological progression,
thereby increasing liver transplant-free survival [18]. Accordingly, UDCA treatment has been recommended
as first line therapy for patients with PBC in the treatment guidelines of the American Association for the
Study of Liver Diseases [19] and the European Association for the Study of the Liver (EASL) [20]. While UDCA

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has had a marked impact on clinical outcomes in PBC, a large proportion of patients have an inadequate
response. It is estimated [11] that up to 40% of UDCA-treated patients have a suboptimal response to UDCA.
Lammers et al. found that ALP remains elevated in up to 70% of patients who are currently being treated or
are intolerant to UDCA [15]. Such patients remain at risk of disease progression and longer term adverse
clinical outcomes.
Ocaliva (OCA), at doses from 5 to 10 mg, was approved as a second line therapy by the Food and Drug
Administration (FDA) in May 2016 under the accelerated approval regulations based on achieving a primary
endpoint. The primary endpoint was defined as a composite endpoint of an ALP level of less than 1.67 times
the ULN range, with a reduction of at least 15% from baseline, and a TB level at or below the ULN range at
12 months. On a background of standard of care, the rate of the primary endpoint was higher in the 5-10 mg
group (46%) and in the 10 mg group (47%) compared to the placebo group at month 12 (p<0.001 for both
comparisons). Pruritus was the most common AE across all groups, with a higher incidence reported in the
5-10 mg group (56%) and the 10 mg group (68%) than in the placebo group (38%) [4].
A 24-month, DB, placebo-controlled, phase 3 study of bezafibrate, a pan-peroxisome proliferator-activated
receptor (PPAR) agonist, demonstrated efficacy in patients who had an inadequate response to UDCA. In this
study the primary outcome was the percentage of patients with a complete biochemical response, which was
defined as normal serum levels of ALP, AST, ALT, total bilirumin and albumin, as well as a normal prothrombin
index at 24 months. The result was the primary outcome occurred in 31% of the patients assigned to
bezafibrate and in 0% assigned to placebo (p<0.001). Results regarding changes in pruritus, fatigue, and
noninvasive measures of liver fibrosis, including liver stiffness and ELF score, were consistent with the results
of the primary outcome [21].
Rationale for Evaluation of Elafibranor in PBC

Elafibranor is being developed by Genfit for the treatment of PBC, based on its pharmacological properties as
a PPARα/δ agonist. Activation of PPARα receptors leads to a decrease in bile acid synthesis, increase in bile
acid uptake, and increased detoxification of bile acids through the increased uptake in micelles. PPARα and
PPARδ receptor activation also has anti-inflammatory effects by acting on different pathways of inflammation
(nuclear factor kappa B [NF-κB] and B-cell lymphoma 6 [BCL6] pathways).
Ligand-activated PPARα contributes to a range of actions, including cholesterol and bile acid homeostasis.
PPARα primarily downregulates bile acid synthesis. PPARα also interferes with pro-inflammatory transcription
factor pathways leading to the hypothesis that fibrates may exert their beneficial effect on cholestatic liver
function by also regulating anti-inflammatory pathways. Fenofibrate may also ameliorate cholestatic liver
disease through its transcriptional activation of multidrug resistance protein type 3 (MDR3) [22].
1.2. SUMMARY OF NON CLINICAL STUDIES
1.2.1. Nonclinical Pharmacology
1.2.1.1. In Vitro Pharmacology
1.2.1.1.1. Activity on Human and Murine PPAR isoforms
In Gal4- PPAR reporter gene assays, elafibranor (GFT505) and its main metabolite GFT1007 are PPAR agonists
with a similar selectivity profile on both the human and murine PPAR isoforms. Both (GFT505) and GFT1007
activate the PPARα subtype with a 5-fold selectivity over PPARδ.
In human hepatocytes, elafibranor and GFT1007 induce the expression of mitochondrial genes (pyruvate
dehydrogenase kinase [PDK]4, carnitine palmitoyltransferase [CPT]1a) but not peroxisomal PPAR target
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genes (acylCoA-oxidase [ACOX]1, enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase [EHHADH]), likely
via PPARδ activation.
In stimulated human monocytes, elafibranor decreases the secretion of inflammatory markers (monocyte
chemotactic protein (MCP)-1 and tumor necrosis factor [TNF-α]) through combined PPARα and PPARδ
activation and parallel PPAR-independent mechanisms.
1.2.1.1.2. Anti-fibrotic Activity
Anti-fibrotic properties of (GFT505) were demonstrated in primary human hepatic stellate cells (hHSC).
(GFT505) inhibits hHSC proliferation induced by either fetal calf serum or platelet-derived growth factor
(PDGF)-BB. Moreover, (GFT505) specifically inhibited PDGF-BB-induced PDGF receptor β phosphorylation in
vitro. (GFT505) also inhibited hHSC activation (gene expression of fibrosis markers: α-smooth muscle actin
[αSMA], collagen [Col] 1α1 and Col4α1) induced by TGF β1.
1.2.1.2. In Vivo Pharmacology
1.2.1.2.1. Rat Model of CCl4-induced Hepatic Fibrosis
The liver-protective effects of (GFT505) have also been demonstrated in a rat model of carbon tetrachloride
(CCl4)-induced hepatic fibrosis. When administered concomitantly with CCl4, (GFT505) totally prevented the
development of liver fibrosis evaluated by macroscopic and microscopic examination. In addition, (GFT505)
significantly reduced CCl4-induced macro- and micro- steatosis and liver inflammation. (GFT505) treatment
prevented the CCl4-induced increase in liver expression of genes involved in the inflammatory ( [IL]-1β,
RANTES) and pro-fibrotic (collagens [Col1α1, Col1α2], TGFβ1, TIMP-2, αSMA) response.
1.2.1.3. Safety Pharmacology
Any potential effects on the cardiovascular, respiratory, and central nervous system have been assessed and
no safety issue was identified.
1.2.1.4. Absorption/distribution/metabolism/excretion Studies (ADME)
In animal studies, elafibranor (GFT505) was well and rapidly absorbed although absolute bioavailability was
moderate (about 20% to 40%). (GFT505) is extensively metabolized and the activity is mainly carried by the
active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both (GFT505)
and GFT1007 linearly increase with the dose after single or repeated administrations. (GFT505) and its
metabolites are rapidly cleared from the plasma and they are totally excreted by both fecal and renal route
within 48 hours. In the rat, (GFT505) and/or its metabolites are rapidly excreted into the bile and undergo
an extensive entero-hepatic cycle giving support for liver targeting of (GFT505) and/or GFT1007. The
distribution study in the rat supports the liver targeting of (GFT505) and/or its metabolites.
In vitro, (GFT505) does not inhibit cytochrome p450 (CYP) 1A2, CYP3A4, and CYP2D6, with moderate
inhibition of CYP2C9, and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. Thus,
the risk of drug-drug interaction (DDI) due to an inhibition of the main cytochromes involved in drug
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed
through a clinical study (GFT505-112-8) designed to evaluate potential PK interaction of (GFT505) 120 mg
administered for 14 days alone or with a single administration of warfarin. This study demonstrated that
(GFT505) administration did not affect the PK profile of warfarin (R-warfarin and S-warfarin). A protein binding
study showed that (GFT505) and GFT1007 were highly bound to human serum albumin. The risk of DDI due
to albumin binding should be limited since this binding is not saturable.

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In vitro studies have been performed to determine whether GFT505 and its principal metabolite GFT1007 are
substrates and/or inhibitors of major drug transporters, in order to assess the potential for DDI. Based on the
results of the OATP1B3 (organic anion transporting polypeptide 1B3) transporter inhibition assay, GFT505
has recently been assessed in a follow-up clinical DDI study with the OATP1B3-sensitive substrate,
atorvastatin.
For the other drug transporters studied, the interaction observed does not require follow-up studies based on
current regulatory guidance.
The metabolic stability and metabolism pathways of GFT505 have been studied on liver microsomes and in
primary hepatocytes from rat, dog, mouse, monkey, and human. There was no evidence of the formation of
unique human metabolites or metabolites formed at disproportionately higher levels in human hepatocytes
than in any other species.
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig,
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute
bioavailability was moderate (about 20% to 40%).
1.2.1.5. Toxicology
1.2.1.5.1. Mutagenicity and Genotoxicity
The toxicology program performed according to the International Conference on Harmonisation (ICH)
guidelines demonstrates that (GFT505) has no genotoxic or mutagenicity potential.
1.2.1.5.2. Acute Toxicity
According to acute toxicity study results, it can be concluded that (GFT505) is extremely safe when
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of
1000 mg/kg.
1.2.1.5.3. Repeated Dose Toxicity Studies
The safety of (GFT505) has been assessed in multiple preclinical toxicology studies with repeated-dose oral
administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year repeated-dose
carcinogenicity studies in mice and rats have been completed.
The only consistent safety concern raised by these studies is the expected PPARα-associated hepatomegaly,
hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). However, it is well known
that, compared to nonhuman primates and humans, rodents are highly sensitive to PPARα agonist induced
peroxisome proliferation and associated liver side effects. Thus, available information on this class of drug
which includes marketed fibrates together with the lack of any liver side effects in monkeys treated with high
doses of (GFT505) for 1 year support the non-relevance to human [23]. Overall, these studies did not reveal
any other safety issues up to the highest doses tested. Notably, (GFT505) did not have any of the known
PPARγ-related concerns such as excess weight gain, hemodilution, edema, cardiomegaly, adiponectin
induction, or urinary bladder carcinoma. Importantly, the non-clinical studies have demonstrated a reduced
plasma ALP activity in monkeys treated for 3 or 12 months with (GFT505).
1.2.1.5.4. Phototoxicity Studies
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 Neutral Red Uptake (NRU)
phototoxicity test and the UV-Local Lymph Node Assay (UV-LLNA) test in mice. GFT505, but not its major
metabolite GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice
with oral dosing for 3 days at up to 800 mg/kg/day (GFT505). Although a very conservative No Observed
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Adverse Effect Level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is
considered that data are more in favor of an absence of phototoxic effect, given the tissue distribution of
GFT505, and absence of phototoxicity signal in the clinical studies.
Additional information can be found in the Investigator’s Brochure (IB).
1.3. CLINICAL STUDIES
1.3.1. Phase 1 Program
A Phase 1 program to assess the safety and the tolerability, as well as the PK profile, of elafibranor currently
comprises 13 completed and 4 ongoing clinical studies. As of 31 July 2019 (the date of the most recent
Development Safety Update Reports (DSUR) update (Development Safety Update Reports, 2019), 659
volunteers had been randomized in these studies, including 561 healthy and lean subjects, 60 overweight or
obese but otherwise healthy subjects, 12 subjects with type 2 diabetes, 6 with end stage renal disease and
20 with hepatic impairment (Child-Pugh class A, B or C). Elafibranor daily doses ranged between 5 mg and
360 mg, with a maximum treatment duration of 14 to 16 days.
Additional information can be found in the IB.
One phase 2 study with elafibranor was completed in PBC patients. Study GFT-505B-216-1 was a 12-week,
DB, randomized, parallel group, placebo-controlled, proof-of-concept study in PBC. A total of 45 adult patients
were randomized to one of 3 treatments arms in a 1:1:1 ratio: elafibranor 80 mg, elafibranor 120 mg, or
placebo. In both elafibranor-treated groups, a significant decrease in mean ALP was achieved: -48% for the
80 mg dose and -41% for 120 mg dose, compared to a mean 3% increase in ALP for subjects receiving
placebo. This resulted in a highly significant treatment effect versus placebo: -52% (95% CI: [-62.5;-41.5])
(p<0.001) for 80 mg and -43.9% (95% CI: [-55.7;-32.1]) (p< 0.001) for 120 mg elafibranor. There was no
apparent difference in the magnitude of improvement between the 2 elafibranor doses suggesting a plateau
of the dose exposure-response. The effect was observed from the first visit following baseline (Visit 2 [Week
2]) and was maintained and reinforced up to the end of the active treatment period. A composite endpoint
composed of ALP <1.67xULN and ALP decrease >15% and TB <ULN, was achieved in 66.7% subjects at 80
mg and 78.6% of subjects at the 120 mg elafibranor dose (p= 0.002 and p< 0.001, respectively) as compared
to 6.7% subjects on placebo.
1.4. CONCLUSION
In summary, elafibranor may provide an effective therapeutic option for patients with PBC who are
inadequately responding to or unable to tolerate UDCA. As a result, elafibranor will be further evaluated in
this larger Phase 3 study with an open-label extension.
1.5. RATIONALE FOR STUDY POPULATION
Partial or suboptimal responders constitute up to 40% of UDCA-treated PBC patients [11]. This group of
patients along with patients intolerant to UCDA treatment will be randomized in this study.
This study targets patients with mild and moderately advanced disease and excludes patients with advanced
cirrhosis. ALP reduction is not a good predictive marker of long term benefit in the advanced disease
population[15]. Patients with moderately advanced disease are identified per Rotterdam Criteria (TB > ULN or
Albumin < LLN).
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In addition, a recent publication has shown that in UDCA-treated and untreated patients with TB levels
≤1×ULN at baseline or 1 year, the TB threshold with the highest ability to predict LT or death at 1 year was
0.6×ULN. The risk for LT or death was stable below TB levels of 0.6×ULN and yet increased beyond this
threshold [24] and Fig1.
To ensure adequate representation of moderately advanced disease patients and of patients at risk of
progression to clinical outcomes, at least 10% of randomized patients will be moderately advanced per
Rotterdam Criteria and at least 20% will have a TB > 0.6 x ULN (patients at risk of progression)

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Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN)
1.6. JUSTIFICATION OF THE SELECTED DOSE
There was no apparent difference in the magnitude of improvement of cholestatic paramaters (ALP, GGT and
5’ NT) between the two elafibranor doses (80 and 120 mg) in Study GFT-505B-216-1 suggesting a plateau of
the dose-exposure-response. In addition, both doses were generally well-tolerated. As a result, elafibranor
80 mg was selected for this study.

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2 STUDY OBJECTIVES AND ENDPOINTS
2.1. OBJECTIVES
2.1.1. DB Period
2.1.1.1. Primary Objective
To evaluate the effect of elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint over
52 weeks of treatment compared to placebo.
2.1.1.2. Key Secondary Objectives
To evaluate the effect of elafibranor (80mg/day) over 52 weeks of treatment compared to placebo on:
- Normalization of ALP
- Pruritus based on change from baseline through week 52 in PBC Worst Itch NRS score
2.1.1.3. Secondary Objectives
To evaluate the effect of elafibranor (80 mg/day) over 52 weeks of treatment compared to placebo on:
c) Lipid parameters
d) Bile acids
e) liver histology
h) HRQoL
i) Health utility
j) Safety and tolerability
To determine the PK parameters of elafibranor and its active metabolite GFT1007, at steady state
following daily oral administration at 80 mg) in PBC patients.Of note, and in order to further collect safety
and clinical outcomes data in a DB manner, placebo controlled treatment will be maintained until the last
completed week 52 visitor until a maximum of 104 weeks, whichever occurs first. When this time point is
reached, every patient will be switched to open-label Elafibranor 80 mg.
2.1.2. LTE Period
To evaluate the effect of elafibranor (80 mg/day) during the LTE period on:
2.2. ENDPOINTS
2.2.1. DB Period
2.2.1.1. Primary Endpoint

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2.2.1.2. Secondary Endpoints
Key Secondary Endpoint

Response to treatment based on ALP normalization at week 52.
Change in pruritis from baseline through week 52 based on PBC Worst Itch NRS score.
Other Secondary Endpoints

a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b) ALP < 3 x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris II)
f) TB ≤ 0.6 x ULN
g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1]
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline of more
4) PBC risk scores at week 52: UK PBC score [2] and GLOBE score [3]
5) Response based on the normalization of bilirubin at week 52
6) Response based on the normalization of albumin at week 52
GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
8) Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, fibrinogen,
haptoglobin and TNF-α
9) Change from baseline to week 52 in immune response as measured by IgG and IgM
as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver stiffness
measured by TE (continuous)
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated
VLDL-C and triglycerides (TG)
12) Change from baseline to week 52 in FPG
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by
bile acids, C4 and FGF-19
14) Response in PBC Worst Itch NRS defined as at least 30% reduction from baseline of NRS at week 52 in
patients with a baseline NRS ≥ 4
15) Proportion of patients with no worsening of pruritus from baseline to week 52 as measured by the PBC
Worst Itch NRS
17) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a
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18) Change from baseline to week 52 in ESS
a) MELD-Na >14 for patients with baseline MELD-Na ≤12
b) Progression to histological cirrhosis for non cirrhotic patients at baseline
c) Liver transplant
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven score of 2 or more
f) Death
a) fibrosis stage according to Nakanuma scoring
b) Bile duct scores
f) Other exploratory scores such as Fibrosis (per modified Ishak scoring), Portal inflammation, ductular
reaction, Cholestasis andconcentric periductal fibrosis
23) Safety and tolerability as assessed by:
a) SAE, AE, AESI, physical examination, vital signs, medical history, ECG
c) Liver markers
f) Histology
24) PK assessments by GFT505 and GF1007 concentrations measurement in plasma
2.2.2. LTE Period
Additionally, apart from histology and PK assessments, the same endpoints as for the DB period will be
collected over the LTE period to assess the maintenance of efficacy and safety of the treatment. The endpoints
will be described using descriptive statistics by DB treatment group and overall on both ITT and PP sets.

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3 STUDY DESIGN
This is a phase 3, randomized, DB, placebo-controlled, parallel group study followed by an open-label LTE
that evaluates the efficacy and safety of elafibranor in patients with PBC and inadequate response or
intolerance to UDCA.
In the DB period, approximately 150 patients will be randomized in a 2:1 ratio to receive elafibranor 80 mg
or placebo, once daily, for maximum 104 weeks or until the last completed week 52 visit (V6), whichever
happens first. Placebo control will be maintained after week 52 notably to further collect safety and clinical
outcome data in a DB manner. At the end of the DB period, all patients will receive elafibranor 80 mg, once
daily, for up to 5 years or until the patient’s total treatment duration is 6 years, whichever occurs first. When
applicable, patients should continue their pre-study dose of UDCA throughout the study participation.

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Footnotes:
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last completed V6 (W52), whichever occurs first
c. The LTE duration is 5 years after end of the DB period or until the patient’s total treatment duration is 6 years, whichever occurs first

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3.1. NUMBER OF PATIENTS
The study is projected to randomize approximately 150 patients including a minimum of 15 patients (10%
of the total randomized patients) with a TB above ULN or albumin below LLN and a minimum of 30 patients
(20% of the total randomized patients) with a TB above 0.6 x ULN.
3.2. TREATMENT GROUPS
The treatment groups will be allocated, in a 2:1 ratio, to receive either elafibranor 80 mg or placebo during
the DB period.
3.3. DOSE ADJUSTMENT CRITERIA
N/A
3.4. DURATION OF STUDY PARTICIPATION
Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the screening period, 52 to 104 weeks for
the DB period, 208 to 260 weeks for the LTE period, and 4 weeks for safety follow-up). The full treatment
period for each patient will last 312 weeks, with a variable number of weeks in the DB Period and in the
LTE Period depending the time point of the visit V8 or LVDB completed.
3.5. STUDY PERIODS AND SCHEDULE OF ASSESSMENTS
The study will be comprised of 3 periods: a screening period, a DB period and a LTE period.
A schedule of assessments by visit is presented in Table 1 and Table 2.

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3.5.1. Screening Period
Screening visits (SV1, SV2 or SV3) should be performed within 2 to 12 weeks of randomization. At the SV1,
preliminary eligibility criteria will be reviewed. Eligible patients will be asked if they agree to participate in the
study and sign the Informed Consent Form (ICF). Each patient who has signed the ICF will perform procedures
listed on Table 1 and
Table 2.
For the purpose of establishing relevant baseline chemistries for suspected DILI repeated measures of AST,
ALT and TB will be collected (see Appendix 1 for Lab reference ranges) ONLY if the first measure (M1)
collected at SV1 is > ULN. M1 and another value either a historical value (M0), collected at least 4 weeks and
up to 12 weeks apart before SV1, or a second measure (M2) will be collected at SV2 (4 to 6 weeks after SV1).
This applies to only the analyte above ULN.
• If variability between M1 and either M0 or M2 is ≤ 40% the patient is eligible
• If variability between M1 and either M0 or M2 is > 40% a third measure (M3) will collected at SV3 (4
to 6 weeks after SV1 (if M0 compared) or SV2 (if M2 compared)):
o If variability between M1 and M3 is ≤ 40% the patient is eligible
o If variability between M1 and M3 is > 40% the patient is ineligible for the study
To assess the ALP eligibility criterion, two ALP values will be required. One value is the M1 collected at SV1,
and the other value is M0 collected at least 4 weeks and up to 12 weeks apart before SV1 or M2 collected at
SV2 (4 to 6 weeks after SV1).
• If M1 is < 1.67 x ULN, the patient will be excluded and no further assessment will be performed
• If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is ≥ 1.67 x ULN, and variability is ≤
40% the patient is eligible
• If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is < 1.67 x ULN or variability is >
40%, M3 collected at SV3 (4 to 6 weeks after SV1 (if M0 compared) or SV2 (if M2 compared)) will be
required:
o If the mean of M1 and M3 is ≥ 1.67 x ULN and variability is ≤ 40%, the patient is eligible
o If the mean of M1 and M3 is < 1.67 x ULN or variability is > 40%, the patient is ineligible for
the study
NOTE: M2 and M3 values for AST, ALT, TB and ALP can be obtained at local laboratory. Comparison between
M1 and local value(s) will be done on normalized values according to ULN.
In absence of valid historical liver biopsy, the Liver biopsy can be performed at any visits as long as it is
completed at the latest 4 weeks prior to the planned randomization visit.
Screening is a minimum duration of 2 weeks to help ensure the stability of the PBC Worst Itch NRS daily
scores for the calculation of the baseline score.
In case of ineligibility, the patient should be contacted as soon as possible.
3.5.2. DB period (Week 0 to max Week 104)
At the Randomization visit 1 (week 0), all eligibility criteria will be evaluated for inclusion including lab
assessments obtained during the screening period.
Randomization in IXRS will be stratified based on central lab assessments obtained for ALP & TB at SV1, as
well as on the mean PBC Worst Itch NRS Score over the 14 days preceding the visit 1.

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At least 4 values of the PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to
randomization (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to
randomization (V1) are required for randomizing the patients. In case this number is not achieved, the
screening period may be extended in order to obtain the expected number of NRS values.
To ensure adequate representation of moderately advanced disease or patients at risk of progression to
clinical outcomes, at least 10% of randomized patients will be moderately advanced per Rotterdam Criteria
(TB> ULN or Albumin < LLN) and at least 20% will have a TB > 0.6 x ULN (patients at risk of progression).
The DB period will last until the last completed week 52 (V6) visit or until a maximum of 104 weeks DB period,
whatever happens first.
During the DB period the patients will return to the site every 13 weeks (±2 weeks) from Visit V1 up to Visit
V6 (week 52) except for the Visit V2 (4 weeks after V1) and if applicable post visit V6, every 26 weeks up to
visit V8; Between V6 and V8, safety contacts will be performed by phone call between on site visits, every
alternating 26 weeks (+/-14 days), to collect information related to AEs, concomitant medications, pregnancy,
and study drug compliance. The first phone safety contact will start 13 weeks after V6 as applicable.
Any patient completing V8 will be automatically switched to open LTE. The last visit V6 completed for all
randomized patients will trigger the switch to open LTE for all patients still in DB. The switch will be operated
either at V6 for this last patient or at an additional onsite visit (LVDB) to be scheduled within 13 weeks of this
timepoint to allow switching all patients in a timely manner. In case the LVDB visit occurs within the time
window of the next scheduled visit, LVDB visit replaces the scheduled visit. The same procedures as for V8
will be performed for LVDB.
In case of premature study drug discontinuation prior to visit 8 during DB period, EOT DB visit should be
performed between 16 and 30 days after last drug intake. The patients will continue in the study until V8, or
until the last completed V6 whichever occurs first, and will complete all visit procedures except liver biopsy
and PK (if not done prior to study drug discontinuation). In case the EOT DB visit occurs within the time
window of the next scheduled visit, EOT DB visit replaces the scheduled visit. For any EOT patients, their EOS
status will be registered in relevant study system(s) as applicable.
Patients will be contacted at least 1 week before each onsite visit to be reminded of procedures and study
drug return.
The study scheduled assessments will be performed as per Table_1 and Table 2.
3.5.3. LTE period
After the last DB visit, patients will continue to the LTE period (open label). During the LTE period, all patients
will receive elafibranor 80 mg for up to 5 years after he DB period or until the patient’s total treatment
duration is 6 years, whichever occurs first.
Apart for the first 2 visits in this LTE period which will occur of 13 weeks interval starting after V8 or the last
DB visit, patients will return to the site every 26 weeks (+/-14 days) for procedures listed on Table 1 and
Table 2, and safety contacts by phone call will be performed, every alternating 26 weeks (+/-14 days) after
LT2, to collect information related to AEs, concomitant medications, pregnancy, and study drug compliance.
The Investigator may subsequently decide to perform an unscheduled visit (see Section 3.5.5.2).
If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between
16 and 30 days after last drug intake.
For any patients in the LTE, their EOS status will be registered in relevant study system(s) as applicable.

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3.5.4. Safety Follow up
An EOT DB or EOT LTE visit will be performed between 16 to 30 days after the last drug intake for any
subjects who received the study drug. The study procedures will be assessed as per the Table 1 and Table
2.
3.5.5. Optional Visits
3.5.5.1. Retesting and/or additional screening visits
• If CPK value is >2xULN at SV1, it can be repeated within 1 to 2 weeks, but prior to V1
If HCV Ab test is positive at SV1, a patient’s HCV infection status needs to confirmed by HCV RNA testing
prior to V1Any other retest deemed necessary by the Investigator should be discussed with the Study Medical
Monitor.
3.5.5.2. Unscheduled visits
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for safety
reasons or when repeat measurements are required out of the screening period (either to confirm a
measurement or in case of errors, measuring device failure, etc.).
3.5.6. Off-site study procedures in case of crisis situation
In cases of emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient safety
and minimize risks to study integrity, certain study procedures may be completed remotely (e.g., not on-site)
for patients already randomized in the study. Any temporary changes to study conduct will be defined based
on a risk assessment specific to the crisis, and regulatory agencies and ethics committees will be informed in
accordance with local laws and regulations.
The temporary study conduct changes might include:
• Study visits conducted with the patient via phone
• Laboratory testing performed in the patient’s local lab
• Study drug shipped from the site or supplier to the patient, or delivered by the site study staff to the
patient
Certain changes may be applied on a case-by-case basis depending on the investigator’s judgment.
The investigator will confirm a patient's agreement before implementing any temporary study conduct
changes.

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4 PATIENT SELECTION
A patient will be eligible for the study only if all of the following criteria apply:
4.1 INCLUSION CRITERIA
1) Must have provided written informed consent and agree to comply with the study protocol
2) Males or females age of 18 to 75 years inclusive at SV1
3) Definite or probable PBC diagnosis as demonstrated by the presence of ≥ 2 of the following
3 diagnostic criteria:
b. Positive AMA titers (> 1/40 on immunofluorescence or M2 positive by ELISA or positive
PBC-specific ANA
4) Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to
have:
a. 1 liver biopsy during the Screening Period (if no historical biopsy within 12 months
before screening is available)
5) ALP ≥ 1.67 x ULN
6) TB ≤ 2 x ULN
To ensure adequate representation of moderately advanced disease or at risk of progression
to clinical outcomes, at least 10% of randomized patients will be moderately advanced per
Rotterdam Criteria (TB > ULN or Albumin < LLN) and at least 20% will have a TB > 0.6 x
ULN (patients at risk of progression)
7) Must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day
intervals in the 14 days prior to randomization (V1), for a total of at least 8 values for PBC
Worst Itch NRS in the last 14 days prior to randomization (V1)
8) UDCA for at least 12 months (stable dose ≥ 3 months) prior to randomization, or unable to
tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to randomization (per country
9) If on colchicine must be on a stable dose for ≥ 3 months prior to randomization
10) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or
sertraline) must be on a stable dose for ≥ 3 months prior to randomization
randomization
12) Females participating in this study must be of non-child bearing potential or must be using
highly efficient contraception for the full duration of the study and for 1 month after the
last drug intake:
• Non-child bearing potential: Cessation of menses for at least 12 months due to ovarian
failure or surgical sterilization such as bilateral oophorectomy, hysterectomy, or
medically documented ovarian failure for > 6 months prior to randomization
• If required by local IRB regulations and/or National laws, sexual abstinence may be
considered adequate (the reliability of sexual abstinence needs to be evaluated in

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relation to the duration of the clinical study and the preferred and usual lifestyle of the
patient)
• Using a highly effective non-hormonal medical contraception (bilateral tubal occlusion,
vasectomized partner or intra-uterine device) for ≥ 3 months prior to screening
• Highly effective contraception with barrier or highly effective hormonal method of
contraception (oral, intravaginal or transdermal combined estrogen and progestogen
hormonal contraception associated with inhibition of ovulation, oral, injectable or
implantable progestogen-only hormonal contraception associated with inhibition of
ovulation or intrauterine hormone-releasing system). The hormonal contraception must
be started at ≥ one month prior to screening
4.2 EXCLUSION CRITERIA
Patients presenting any of the following exclusion criteria will not be included in the study:
a) Positive anti-HAV IgM antibodies or positive HBsAg or positive HCV RNA (tested for in case
of known cured HCV infection or positive HCV Ab at screening)
b) PSC
c) ALD
d) AIH or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence of
overlap AIH features, that cannot be explained alone by insufficient response to UDCA
e) NASH
a) History of liver transplantation, current placement on a liver transplant list, current MELD-
Na score ≥ 12 linked to hepatic impairment
b) Patients with cirrhosis/portal hypertension complications, including known esophageal
varices, ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal
bands or TIPS, and hepatic encephalopathy, history or presence of spontaneous bacterial
peritonitis, hepatocellular carcinoma
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease) or which
may diminish life expectancy to < 2years, including known cancers
4) Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have tested
positive for HIV
5) Evidence of any other unstable or untreated clinically significant immunological, endocrine,
hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the
investigator
6) Other clinically significant medical conditions that are not well controlled or for which
medication needs are anticipated to change during the study
7) History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for
men, and more than 20 g pure alcohol per day for women, or other substance abuse within 1
year prior to screening visit (SV1)

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8) For female patients: known pregnancy, or has a positive urine pregnancy test (confirmed by a
positive serum pregnancy test), or lactating
a) 2 months prior to randomization and throughout the study (up to the last study visit):
fibrates and glitazones
b) 3 months prior to randomization and throughout the study (up to the last study visit): OCA,
azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and
other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa,
sodium valproic acid isoniazid, or nitrofurantoin)
c) 12 months prior to randomization and throughout the study (up to the last study visit):
antibodies or immunotherapy directed against ILs or other cytokines or chemokines
10) Patients who are currently participating in, plan to participate in, or have participated in an
investigational drug study or medical device study containing active substance within 30 days
or five half-lives, whichever is longer, prior to screening; patients with previous exposure to
seladelpar are excluded
12) SV value ALT and/or AST > 5 x ULN
13) SV value albumin<3.0 g/dl
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < LLN)
15) SV value INR > 1.3 due to altered hepatic function
16) SV value CPK > 2 x ULN
17) Screening serum creatinine > 1.5 mg/dl
18) Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as
patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2) calculated by
MDRD
19) Platelet count < 150 x 103/µL
20) AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer

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5 STUDY PROCEDURES
The procedures performed at each visit are summarized in the study schedules (Table 1 and Table 2 and
Table 3) and in Section 3.5.
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of the day for
each patient. A patient may be seen at any time for reasons of safety.
During each visit, vital signs will be measured, and the patient will be queried in the form of an open question
regarding new or continuing events.
During any study visit during which PROs are performed, it is recommended to be completed by the patient
prior to the site performing any invasive procedures.
Procedures for premature discontinuation after randomization are described in Section 5.2.
5.1. SCREEN FAILURES
Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently
randomized. A minimal set of screen failure information is required to ensure transparent reporting of screen
failure subjects. Minimal information includes demography, screen failure details, eligibility criteria, and any
SAE.
Individuals who screen failure because of a specified modifiable factor may be rescreened.
5.2. PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES
5.2.1. Permanent discontinuation of study drug/withdrawal from study
Patients will be informed that they have the right to discontinue the study at any time, for any reason, without
affecting future management and treatment.
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient may
be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for safety,
behavioral, or administrative reasons.
The reason for permanent discontinuation of study drug should be documented in the electronic case report
form (eCRF) and the Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event
should be documented in the eCRF.
Some possible reasons that may lead to permanent early study drug discontinuation include:
• Any AE, AESI, SAE (described in Section 8.1.1 and 8.1.2), or significant change in a laboratory value
in the opinion of the Investigator. Investigators are advised to call the Medical Monitor prior to making
such a decision
• Non-permitted concomitant medication (described in Section 7.12 and Section 16.3 - appendix 3A)
• Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to
use a reliable method of birth control during the study
• Non-compliance with the study treatment
• Uncooperative patient
• The patient requests to stop study drug permanently.
Patients permanently discontinued from study drug during the DB period will perform an EOT DB visit within
16-30 days after the last drug intake and will continue to attend all scheduled visits until the visit 8 (without

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undergoing histology or PK assessment, if applicable), or until the last completed V6 whichever occurs first.
Patients permanently discontinuing study drug during the LTE period will attend the EOT LTE Visit within 16
to 30 days after the last administration of study drug (as described in Section 3.5.4).
5.2.2. Patients Lost to Follow-up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and
is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to contact
patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the site.
5.2.3. Replacement
No patient replacements are permitted in this study.
5.2.4. Premature Discontinuation of the Study
Premature termination of this clinical study may occur because of a Regulatory Authority decision, change in
opinion of the institutional review board/independent ethics committee (IRB/IEC), drug safety problems, or
at the discretion of the Sponsor. In addition, the Sponsor retains the right to discontinue development of the
study treatment at any time.
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended number of patients,
but intends only to exercise this right for valid scientific or administrative reasons. After such a decision, the
Investigator must contact all participating patients within a reasonable period of time. As directed by the
Sponsor, all study materials must be collected and all case report forms (CRFs) completed to the greatest
extent possible.
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the Investigator
must notify the Sponsor immediately of his/her decision and give the reason in writing.
In all cases IRB/IEC and Health Authorities should be informed.
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study
materials must be returned to the Sponsor.

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6 ASSESSMENTS
6.1. EFFICACY AND SAFETY ASSESSMENT
6.1.1. Biological assessment
All blood samples for efficacy and/or for safety assessment will be returned and centralized by the central
laboratory (Cerba Research/BARC: Ghent – Belgium, New York – USA, or Johannesburg – South Africa).
A Laboratory Manual will be provided to each site.
The Manual will outline the collection process and shipping requirements for the specific central laboratory.
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and
shipped as outlined in the Laboratory Manual. Refer to the Laboratory Manual for exact amounts of blood
required for each test.
For all visits, reportable laboratory results (except serology) will be available at sites approximately 24-48
hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed,
signed and dated by the Investigator as soon as received. The Investigator should comment upon out of
range parameters and assess clinical significance.
In order to maintain the blind, ALP, GGT and 5’ NT obtained from blood samples from V2 to V8 / LVDB/or
last V6 whichever occurs first (up to end of DB period) will be kept in blinded condition during the treatment
period for each patient. The Investigator will not be informed of these values until the database lock at the
end of the DB period.
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to
be performed at Retesting and/or additional SVs) is limited to CPK, and HCV RNA (in case of positive HCV Ab
at SV) as described Section 3.5.5 and in Table 2.
At visits for which blood samples will be drawn, patients must be fasting for at least 12 hours. These visits
should be scheduled in the morning.
Both blood and urine dipstick samples will be transported to the central laboratory for testing and analysis
except for urinary myoglobin that may be tested at local laboratory when applicable.
Local laboratory assessments are allowed for repetition of assessment of ALT, AST, TB and ALP during the
screening period as well as for any required retest for liver function monitoring and assessment of urinary
myoglobin, when applicable.
Local laboratory results will be entered in eCRF including corresponding normal ranges.
6.1.1.1. Laboratory Assessments
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at
every visit as described in Table 2.
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine dipstick samples will
be transported to the central laboratory for testing and analysis.
6.1.1.2. Urinary Pregnancy Tests
For WOCBP, urinary pregnancy tests will be administered at each visit. Monthly urine home pregnancy test
kits will be provided during scheduled visits for use during non-visit months.
6.1.1.3. Serology
Screening for hepatitis and HIV will be performed during screening and will include:
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• HIV Ab I/II
• Anti-HAV IgM
• HBsAg
• HCV Ab (If positive, a HCV RNA test will be performed to determine infection status)
6.1.1.4. Other Parameters
All other parameters will be measured according to the schedule described on Table 1.
6.1.2. Constitution of biobank
In order to be able to test other specific parameters which could be of interest regarding the elafibranor
development program or regarding diagnosis, prevention, or treatment of PBC or other related diseases, an
additional amount of blood will be sampled from patients who have given their consent for these additional
analyses by signature of the biobank ICF.
These samples will be destroyed 3 years after final study results at the latest.
6.1.3. Histological assessment
A liver biopsy (see Section 6.1.3.1 for recommendations) will be performed:

• At baseline
• At 52 weeks of treatment
A Laboratory Manual will be provided to each study site. The manual will outline the collection process,
and shipping requirements for the specific central laboratory.
6.1.3.1. Recommendations related to liver biopsy
The patient’s platelet count and PT should be checked according to local hospital standards before the date
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 4
seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available.
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in liver
disease.
The recommended biopsy procedure to be applied is:
• Needle core biopsy
• Biopsy obtained with a 16 or lower gauge needle
• A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length
• Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe biopsy
should be used for future biopsies.
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours
after the procedure.
The biopsies will be sent to the central laboratory and then stained and digitalized, before being transfered
for central reading. Biopsy slides will be blinded for patient and visit identification prior to central reading.
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other
available slides or new slides to be prepared from an available block of tissue may be requested to the site.

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6.1.3.2. Liver biopsy reading
Histological changes from baseline to Week 52 will be evaluated.

Liver biopsy samples will be sent to the central laboratory where they will be stained and digitalized.
Liver biopsy slides will be assessed and scored by at least two pathologists. Scores for fibrosis, bile duct,
cholangitis activity, interface hepatitis activity, will be evaluated and agreed. A liver biopsy management plan
will detail the process of management of the liver biopsy samples from collection to final assessment. A liver
biopsy assessment protocol will detail the reading methodology to be implemented.
6.1.4. Pharmacokinetic assessment
Elafibranor (GFT505) and GFT1007 plasma concentrations PopPK analysis is to be done at steady-state. Thus
the PK blood collection will be at steady state after repeated administration of elafibranor in order to assess
its PK and the one of its main active metabolites, GFT1007, in PBC patients. GFT505 and GFT1007 will both
be included in the PopPK analysis.
6.1.4.1. Pharmacokinetic blood sampling timepoints
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at steady-state
after 4 weeks of treatment (V2).
The collection of PK blood samples is to be performed at the first visit post randomization (V2) in order to
limit as much as possible treatment compliance issues. Prior to sampling the patient, the investigator will
have to check the patient compliance over the preceding 16 days.
All patients (including patients under placebo in order to maintain the blind of the study) will be sampled with
6 sampling timepoints: predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h.
The following restrictions should be applied to patients for the visit V2 where PK sampling are planned:
• Study treatment will be taken at site under fasting conditions after the blood sampling for biological
assessment (see section 6.1.1) and predose PK sampling and before further PK samplings, in this
strict order.
• The time of study drug intake (T0) should be at least 24h after the previous dosing.
• The date and time of study drug intake the day before the visit (V2) has to be recorded as well as
the day of the visit (V2).
• The predose PK sampling has to be collected as close as possible to the study drug intake (T0) (within
max 1h prior to T0).
Samples should be collected as close as possible to the therotical timepoints. Exact time of
sampling will be recorded in the eCRF.
6.1.4.2. Pharmacokinetic blood handling procedures
At each time point (predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h), 1 tube of 6 mL blood sample should
be drawn into lithium heparin Vacutainer® tube protected from light with foil. Plasma will be separated, stored
and shipped as described in the laboratory manual, first to the central laboratory Cerba Research / BARC (as
for all the other blood samples collected) where they will be stored until shipped to EUROFINS ADME
BIOANALYSE to be submitted to analysis.

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The exact time of sample collection will be recorded in the source documents and reported in the eCRF.
6.1.4.3. Bioanalytical analysis
The bioanalysis part will be conducted at EUROFINS ADME BIOANALYSES (75, Chemin de Sommières - 30310
Vergèze - France) in compliance with the Standard Operating Procedures (SOPs) in use at ADME
BIOANALYSES.
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method
previously developed and validated by EUROFINS ADME BIOANALYSES as detailed in the Bioanalytical Study
Plan.
The popPK analyses will be performed at Phinc Development.
6.1.4.4. Description of pharmacokinetic evaluation parameters
PK parameters (AUCss, clearance, volumes of distribution, etc.) will be determined from elafibranor and
GFT1007 plasma concentrations using a popPK model. A dedicated software for nonlinear mixed models will
be used for the analysis.
The popPK analyses will be performed at Phinc Development.
PK parameters of elafibranor and GFT1007 will be summarized by geometric mean, SD, coefficient of
variation, minimum and maximum, and median.
6.2. OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING
6.2.1. Physical Examination
A physical examination including neurological exam will be performed at the time points specified in the study
general assessment schedule of events (Table 1). Height will be measured at the SV only. The physical
examination will include the following: General appearance, weight, hair and skin, lymph nodes, head,
eyes/ears/nose, throat, neck, respiratory system, cardiovascular system, abdominal region, musculoskeletal
system, mental status and neurological system.
6.2.2. Vital Sign and Weight
Blood pressure (BP), heart rate, respiratory rate and temperature will be measured [25]. Weight will be
measured in pounds or kilograms. All measurements will be recorded in eCRF.
6.2.3. 12 Lead ECG
ECGs will be analyzed by the Investigator or designee. Patients are to be supine position for at least 5 minutes
prior to ECG assessments. A minimum of 3 cycles will be recorded per lead. Any potential clinical significance
of ECG changes will be determined by the Investigator with relation to the patient’s medical history, physical
examination, and concomitant medications and recorded in eCRF.

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6.2.4. Liver stiffness by transient elastography (FibroScan®)
FibroScan® TE device (Echosens, Paris, France) is a non-invasive technique used to measure liver stiffness,
which correlates with fibrosis. This assessment will be performed on all patients as illustrated by the Study
General Assessment Schedule (Table 1). All sites must have designated staff trained in the use of the device.
This assessment will be done the day of the visit. Failing this, it can be performed within 7 days of the visit.
To ensure reliability of the assessments patients must be in a fasted state for at least 2 hours before the
examination. Additional instructions will be provided in a separate manual.
6.2.5. Patient Reported Outcomes Questionnaires
The following PROs will be assessed:
a) The PBC Worst Itch NRS (Appendix 16.5.7) is a simple, self-administered PRO questionnaire that
measures itch intensity. It uses 24-hour and 7-day recall periods and asks patients to rate the intensity
of their Worst Itch on an 11-point scale ranging from 0 (no itch) to 10 (Worst Itch imaginable).
Patients will record their scores once daily (24-hour recall) using the eDiary during the screening and
Common DB periods and during study visits (7-day recall; PBC Worst Itch NRS-Past Week) during
the Variable DB and LTE periods as outlined in Table 3. At randomization, the patient’s daily scores
(24-hour recall) over the previous 14 days will be averaged to determine the baseline score for
stratification and analysis; at least 4 available values for PBC Worst Itch NRS during each of the 7
day intervals in the 14 days prior to randomization (for a total of at least 8 values for PBC Worst Itch
NRS in the last 14 days prior to randomization) are required for the baseline score to be calculated.
b) The 5-D Itch scale (Appendix 16.5.3) is a questionnaire that has been validated in several different
diseases. It assesses symptoms in terms of 5 domains: degree, duration, direction, disability and
distribution [26]. Patients rate their symptoms over the preceding 2-week period on a 1 to 5 scale,
with 5 being the most affected. Patients will complete the 5-D Itch scale as outlined in Table 3.
c) The PBC-40 (Appendix 16.5.1) is a validated, PBC-specific, HRQoL 40 question questionnaire that
assesses symptoms across six domains: fatigue, emotional and social, cognitive function, general
symptoms and itch [27]. Patients respond on a verbal response scale, depending on the section
options range from ‘never’ / ‘not at all’ / ‘strongly disagree’ to ‘always’ / ‘very much’ / ‘strongly agree’.
Five items (3/3 in the itch domain and 2/10 in the social domain) also include a ‘does not apply’
option. A score for each domain is provided (but a total score is not calculated), with each verbal
response scale correlating to a score of 1-5 per item (0-5 on items with a ‘does not apply’ option)
with 5 being the most affected. The PBC-40 has a 4-week recall period (Appendix 16.5.1). Patients
will complete the PBC-40 as outlined in Table 3.
d) The Euro quality of life (EuroQol) EQ-5D-5L (Appendix 16.5.8) is a 6-item, standardized questionnaire
that assesses mobility, self-care, usual activities, pain / discomfort, anxiety / depression, and overall
health state.
e) The ESS [28, 29] (Appendix 16.5.2) is a short, self-administered questionnaire that consists of eight
questions asking to rate how likely it is to fall asleep in everyday situations (each question can be
scored from 0 to 3 points; ‘0’ indicates no sleepiness, ‘3’ indicates significant sleepiness). It provides
a total score which has been shown to relate to the patient’s level of daytime sleepiness (total score
range 0–24 points). Patients will be asked to complete the ESS with regard to the level of sleepiness
they experienced over approximately the past 7 days as outlined in Table 3.
f) The PROMIS Fatigue Short Form 7a (Appendix 16.5.4) consists of seven items that measure both the
experience of fatigue and the interference of fatigue on daily activities over the past week (National
Institute of Health, 2007). Patients will complete the PROMIS Fatigue Short Form 7a as outlined in
Table 3.

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g) The Patient Global Impression of Change (PGIC) (Appendix 16.5.5) is a single item 5 point scale
designed to assess the change in overall itch intensity since the baseline visit. PGIC-Itch scores will
be captured as outlined in Table 3.
h) The PGIS (Appendix 16.5.6) is a 1-item 5-point scale designed to assess patient’s impression of itch
severity. The PGIS-Itch scores will be captured as outlined in Table 3.
Of note, PGIC and PGIS are collected as anchors to facilitate the derivation of a clinically meaningful
threshold but will not be used to measure any treatment effect.
In order to avoid bias in the patients' responses to the questionnaires, it is recommended that site based
assessments be completed before any other evaluations or study procedures on the day of the study visit
and prior to discussions with the investigator or study site staff. Site procedures and assessments should
be conducted in the following order: PROs, investigator assessments, safety and laboratory assessments,
administration of study drug.
6.3. IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION

RULES
6.3.1. Creatine Phosphokinase
If at any visit during the treatment period, a patient experiences diffuse myalgia, muscle tenderness, and
marked increase in muscle CPK values between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), an additional visit
and test must be performed within 48 to 72 hours, and an assessment of myoglobinuria may be done locally.
If, during that visit, the patient still experiences diffuse myalgia, muscle tenderness and/or marked increase
in muscle CPK values between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), myopathy must be considered and
the patient must be discontinued from study treatment immediately and followed up as described in Section
5.2.1.
If at any visit during the treatment period, a patient experiences marked increase in muscle CPK values >5 x
ULN, the patient must be discontinued from study treatment immediately and followed up as described in
Section 5.2.1.
6.3.2. Liver Function Monitoring
Patients will be closely monitored and evaluated for other causes of liver injury and for the potential of DILI.
Relevant assessment for suspected DILI includes:
• Establishing baseline values (by at least two samples obtained at least 4 weeks and no more than 12
weeks apart)
• Obtaining a more detailed history of symptoms and prior or concurrent disease
• Obtaining a history of concomitant drug use (including nonprescription medications and herbal and
dietary supplement preparations), alcohol use, recreational drug use, and special diets
• Ruling out acute viral hepatitis types A, B, C, D and E; autoimmune or alcoholic hepatitis; NASH;
hypoxic/ischemic hepatotoxicity; and biliary tract disease
• Obtaining a history of exposure to environmental chemical agents
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin)
• Considering gastroenterology or hepatology consultations
In addition, guidelines for management of any sign of liver function deterioration are given in the several
subsequent sections below.

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For any of the cases below, if a patient lives in a remote area from the site, laboratory testing can be
performed in a local lab. The results should be promptly communicated to the investigator site.
Liver function monitoring will be done with respect to Liver Function Tests baseline values. Of note, in the
absence of large prospective comparative data, there is little evidence to support one threshold over another
[30] therefore the IQ-DILI best practice recommendations have been adopted for this protocol. The
International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium), a
science-focused, not-for-profit organization launched the IQ-DILI Initiative in 2016, reached consensus, and
proposed the following best practices related to DILI with respect to patients with elevated ALT at baseline:
- If ALT ≥ 3 x baseline and there is no change in TB or liver-related symptoms, repeat measures and
initiate close observation [31]
- If ALT ≥ 3 x baseline, TB is normal or elevated and liver-related symptoms (i.e., severe fatigue,
nausea, vomiting, right upper quadrant pain), interrupt study drug and initiate close observation [31]
In addition to management guideliens, the criteria used for reporting a potential DILI for adjudication are
given below and correspond to the criteria leading to permanent study drug discontinuation.
6.3.2.1. Treatment discontinuation rule for elevated Aminotransferase (AT) values

regardless of baseline values
In all cases, whether baseline Aminotransferase (AT) values are normal or elevated, an increase of AT >10 x
ULN will lead to permanent discontinuation of the patient from study drug, and scheduling of EOT DB/EOT
LTE visit.
6.3.2.2. Treatment discontinuation rules for elevated Aminotransferase (AT) values

according to baseline values
6.3.2.2.1. Monitoring of patients with normal baseline AT values
For patients with normal baseline AT values at V1 who at any visit from V2 onwards during the treatment
periods exhibit:
• Increase in AT to ≤ 3 x ULN: no additional action required, schedule next visit as per assessment
schedule.
• Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours.
If during the following retest:
o AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (twice a
week). Frequency of repeated testing can decrease to once a week or less if abnormalities
stabilize or the study drug has been discontinued and the patient is asymptomatic
o AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule
EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT >5 x ULN: retest after 48 to 72 hours.
o AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT
DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4)
o AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (twice a week).
Frequency of repeated testing can decrease to once a week or less if abnormalities stabilize
or the study drug has been discontinued and the patient is asymptomatic.
• Increase in AT >3 x ULN andincrease in TB > 2 ULN: permanently discontinue patient from study
drug and schedule EOT DB /EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT >3 x ULN and increase in INR>1.5 (in the absence of anti-coagulant therapy):
permanently discontinue patient from study drug and schedule EOT Visit (see Section 5.2.1 and
Section 3.5.4).

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• Increase in AT >3 x ULN and fatigue, nausea, vomiting, right upper quadrant pain or tenderness,
fever, rash: permanently discontinue patient from study drug and schedule EOT DB/EOT LTE Visit
(see Section 5.2.1 and Section 3.5.4).
• Increase in AT >3 x ULN and eosinophilia (> 5%) with total count > ULN: permanently discontinue
patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
6.3.2.2.2. Monitoring of patients with abnormal baseline AT values
For patients with abnormal AT baseline values at V1 who at any visit post V1 onwards during the treatment
periods exhibit:
• Increase in AT to ≤ 3 x baseline value: no additional action required, schedule next visit as per
assessment schedule.
• Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours:
o If baseline value < 2 x ULN:
 AT increase ≤ 5 x baseline: continue the drug with close serial monitoring (twice a
week)
 AT increase > 5 x baseline: permanently discontinue patient from study drug and
schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section 3.5.4)
o If baseline value > or equal 2 x ULN but < 5 x ULN:
 AT increase ≤ 3 x baseline: no additional action required, schedule next visit as per
assessment schedule
 AT increase remains > 3 x baseline: permanently discontinue patient from study drug
and schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section 3.5.4)
• Increase in AT >3 x baseline value and increase in TB > 2 x baseline: permanently discontinue patient
from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT > 3 x baseline value and increase in INR by above > 0.2 compared to baseline INR
(in the absence of anti-coagulant therapy): permanently discontinue patient from study drug and
schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT > 3 x baseline value and fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT/EOS
Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT > 3 x ULN and eosinophilia (> 5%) with total count > ULN: permanently discontinue
patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
6.3.2.2.3. Monitoring of patients with abnormal TB baseline values
For patients with abnormal TB values at V1 who at any visit post V1 onwards during the treatment periods
exhibit:
• Increase in TB to > 1.5 x baseline value: retest after 48 to 72 hours
o TB remains >1.5 x baseline value: continue study drug and implementation of close
observation (testing and physical examination 2-3 times per week). Discontinuation of study
should be considered.
6.3.3. Auto-immune hepatitis monitoring
For patients who at any visit post V1 onwards during the treatment periods, exhibits ALT>5 X ULN, IgG serum
or smooth muscle autoantibody should be tested (these tests can be done locally);
if IgG is >2XULN or smooth muscle autoantibody positive, a liver biopsy should be performed at an
unscheduled visit; if moderate or severe interface hepatitis is detected on histology, AIH will be confirmed
and patient should be discontinued from study drug (if not already discontinued according to discontinuation
rules described in Section 6.3.2).

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6.3.4. Acute Pancreatitis Monitoring
6.3.4.1. Treatment discontinuation rule for suspected acute pancreatitis
If at any visit during the treatment period, a patient experiences serum amylase and lipase ≥ 3 x ULN,
associated with abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe,
epigastric pain often radiating to the back), an ultrasound exam or CT scan will be performed for the diagnosis
of pancreatitis. If confirmed, the patient must be discontinued from the study drug immediately and followed
up as described in Section 5.2.1.
6.3.5. Monitoring of hepatocellular and bladder cancer
6.3.5.1. Liver monitoring
Ultrasonography of liver and analysis of AFP will be performed at visit V1, & then every year (V6, V8, LT3,
LT5 , LT7, and LT9 if applicable).
6.3.5.2. Bladder & urinary tract monitoring
Ultrasonography of bladder and urinary tract will be performed at visit V1, & then every year (V6, V8, LT3,
LT5 , LT7, and LT9 if applicable).
6.3.6. Safety Review
Safety oversight will be implemented under the direction of a DSMB composed of five experienced
physicians (an endocrinologist, cardiologist, oncologist, hepatologist and nephrologist) and one
independent statistician, all independent from the conduct of the study. Members of the DSMB should be
free of conflicts of interest. The members of DSMB will review the progress of the study and perform a
safety data review (including review of the adjudication reports issued from the CEC) on a regular basis
(at least every six months) to ensure patient safety and preserve study integrity.
A DSMB charter will define the roles, responsibilities, rules and tasks of the DSMB.
6.3.7. Clinical event committee
The CEC will conduct adjudication of the clinical outcomes (excluding progression to histological cirrhosis for
non cirrhotic patients at baseline) and DILI events. The CEC assessment and adjudication will occur in a
blinded (during DB period) and consistent and unbiased manner throughout the course of the study to
determine whether the endpoint meets the protocol specified criteria.
The CEC will be comprised of 3 hepatologists, all of them will be independent from the conduct of the study.
6.4. GUIDANCE FOR INVESTIGATORS
6.4.1. Summary of safety data
The safety and tolerability of elafibranor were confirmed in Phase 1 to Phase 3 studies.
A Phase 1 program has been conducted to assess the safety and tolerability, as well as the PK profile, of
elafibranor. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up to 16
days. Importantly a PK study in hepatic impaired subjects was recently conducted and concluded that no
dose adjustment is required in cirrhotic patients, unless there is a safety concern.

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A Phase 2 program has been conducted to assess the safety and efficacy profile of elafibranor in patients
suffering from cardiometabolic disorders and NASH.
A Phase 2 study (GFT505B-216-1) in PBC was also completed and included forty five (45) patients with PBC
and inadequate response to UCDA. This study evaluated the efficacy and safety of elafibranor at daily doses
of 80 mg and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor daily doses ranged
between 30 mg and 120 mg, with a maximum treatment duration of 12 months.
A Phase 3 study in subjects with NASH and fibrosis (Study GFT505-315-1) is ongoing. In this study, subjects
are receiving 120 mg/day elafibranor or placebo for up to 72 weeks during the first treatment period, followed
by a long-term treatment period to assess efficacy on progression to cirrhosis, all-cause mortality and liver-
related clinical outcomes as measured by the onset of any of the listed adjudicated events of portal
hypertension/cirrhosis related events.
Based on the cumulative experience gathered to date, gastro-intestinal disorders (such as nausea , diarrhea
and decreased appetite) and fatigue/asthenia are considered common and non-serious adverse reactions
reasonably associated with elafibranor; most of them are of mild to moderate severity. Of note, these AEs
are to be monitored as AESIs (see Section 8.1.2) as well as other AESIs which could be considered as class
effect AEs.
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical studies,
given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is monitored in
clinical studies. For this reason, it is recommended that investigators review these lab results in the course of
clinical studies.
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our clinical
studies, in a range of 1-10%. This increase was reversible at EOT. This should also be monitored in clinical
studies.
Liver enzymes will also be monitored in clinical studies, with specific attention paid to DILI.
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical studies [32].
As such, all clinical studies with elafibranor including WOCBP request a negative pregnancy test before
Randomization, effective contraceptive measures throughout the study and mandatory study discontinuation
upon becoming pregnant. It is recommended to maintain the contraception up to 1 month after the last drug
intake. Pregnancy tests should be repeated as stated in the Table 2.
For further details, refer to the IB.
6.4.2. Benefit/risk assessment
Clinical studies completed to date have not raised any major safety concerns associated with elafibranor
treatment, thus providing a favorable efficacy/safety profile for the drug candidate.
A Phase 2 study in PBC subjects who had an inadequate response to UDCA demonstrated improvement in
GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels was observed, resulting
in significant treatment effects versus placebo on the primary endpoint, whilst also meeting the composite
endpoint used for drug registration (i.e. serum ALP <1 .67 x ULN, an ALP decrease > 15%, and TB < ULN).
Plasma concentrations and PK parameters measured for GFT505 and GFT1007 in subjects with PBC were
similar with that measured in healthy volunteers in previous studies with comparable dose regimen. The
results obtained in this study suggest that the PK of GFT505 and its active metabolite (GFT1007) are not
modified in subjects with PBC.

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Despite this favorable benefit-risk profile, an independent DSMB will be established in order to review the
safety of the treatment during the study in an unblinded manner, to protect patient welfare and preserve
study integrity (Section 6.3.4).
In conclusion, the safety data collected so far and the current knowledge on GFT505 confirm the favorable
balance between risks and anticipated efficacy/benefits.

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7 TREATMENTS
7.1. DESCRIPTION OF STUDY MEDICATIONS
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-

methylpropanoic acid) will be supplied as 80 mg white to off-white round coated tablets with no printed
inscription. The tablet contains elafibranor and inactive ingredients (microcrystalline cellulose, povidone,
croscarmellose, anhydrous colloidal silica, magnesium stearate, Opadry II HP 85F18422).
Placebo tablets to match elafibranor 80 mg will be provided as a white to off-white round coated tablet with
no printed inscription.
7.2. PACKAGING AND LABELING
7.2.1. Packaging
Elafibranor/placebo:
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil blisters.
This has been shown to be a suitable primary packaging for tablets.
Blisters, containing 7 tablets each, will be packed in child proof wallets.
Each childproof wallet will contain 5 blisters (covering approximately one month of treatment). Three wallets
(covering the period between each visit) will be packaged inside a period box.
7.2.2. Labeling
All labels for study drugs will meet all applicable requirements of the US FDA and the EU annex 13 of Good
Manufacturing Practices: Manufacture of Investigational Medicinal Products (February 2010) and /or other
local regulations, as applicable.
Distribution of study drug will be performed according to the Good Distribution Practices.
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by
national and regional guidelines/regulations. The label will contain the statements “For clinical study use only”
or other similar/appropriate statements as well as the following instructions “Please return empty packaging
and unused products to your doctor at your next visit.” Details of period boxes and wallet labels are given in
Appendix 4.
7.3. DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO
Patients will be informed to take 1 tablet per day of elafibranor 80 mg or placebo orally before breakfast with
a glass of water each morning.
7.4. METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP
If the patient fulfills all criteria to enter the DB treatment period, the Investigator will register the patient in
the IXRS system to randomize him/her.
The Investigator will log into the system using his identification number and access code. The IXRS will then
allocate the patient to a treatment group (placebo or elafibranor 80 mg) through a treatment number.
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A specific IXRS manual will be provided to the pharmacy and investigator site.
The randomization list will be generated by the Clinical Research Organization (CRO) for data management
& statistics, and will be kept under blinded condition to the study patients, investigator site, sponsor and
sponsor representative until the database lock and the Sponsor authorization to unblind the study.
7.5. STORAGE CONDITIONS
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions
are specified on the label.
7.6. DISPENSING OF TREATMENT
The Investigator will confirm each study drug dispensation in the IXRS.
At every visit from V1 up to visit V6 (apart from visit V2), every randomized patient will be delivered with one
period box.
From visit V6, two period boxes will be delivered at each site visit.
7.7. TREATMENT REPLACEMENT
Treatment replacement, if needed, will be explained in a specific IXRS procedure manual.
7.8. PROCEDURE FOR BLINDING
The Investigator, patient, and study personnel will be blinded to the treatment. Both elafibranor and placebo
tablets and packaging are indistinguishable.
Identification numbers will be assigned to a patient at the SV. The number will also be reported in the eCRF.
Upon completion of the SV, eligible patients will be randomly assigned to elafibranor 80 mg or placebo at the
randomization visit.
7.9. PROCEDURE FOR UNBLINDING
The randomization code may be broken by the Investigator when urgent action is required for the clinical
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be
stored in the IXRS. The Investigator will be able to unblind any treatment period box that was dispensed to
the patient by connecting to the IXRS (24-hour and 7-day access) and entering their identification number
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered
treatment period box number and the screen will then display the treatment group. When completed, a
blinded confirmatory email will be sent to the Investigator and the Sponsor. The reason for unblinding should
be clearly and fully documented by the Investigator.
Unblinding of treatment arm will occur after the database lock of the DB period and the Sponsor authorization.

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7.10. STUDY DRUG COMPLIANCE
From Visit 1 and at every subsequent visit while the patient is being treated with study drug, the patient will
be directed to bring back all used and unused period box/wallets. Compliance will be checked by the
Investigator during those visits and recorded in the eCRF.
The compliance will be collected within the 16 days prior the Visit V2 for further PK assessment.
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be
documented.
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION
The Investigator, pharmacist or designee will acknowledge receipt for each study treatment on the day of
receipt. A study drug accountability record should be maintained by the person responsible for dispensing the
study drug to the patient.
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of the
study.
Upon Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or
unused) and will proceed to their destruction only after the Sponsor provides written authorization.
If the site has an appropriate SOP for study drug destruction, the site may destroy used and unused study
drugs in accordance with the site SOP and always after the drug accountability has been performed by the
monitor.
If study drug is destroyed at the site, the Investigator must maintain accurate records for treatment cartons
destroyed recording:
• Treatment carton (kit) number (see Appendix 4)
• Quantity destroyed
• Method of destruction
• Person who disposed of the study drug
7.12. OTHER MEDICATION
7.12.1. Handling of Concomitant Medication
In a general manner, patients should be discouraged from starting any new medication without consulting
the Investigator unless the new medication is required for emergency purpose. Similarly, any qualitative or
quantitative change in concomitant therapy should be avoided, when possible (see Non-permitted medication
and condition, Appendix 3). In the event such a change becomes necessary during the study, it should be
recorded by the Investigator in the eCRF (including concomitant medications taken within 30 days prior to
Screening) and information should be communicated to the Medical Monitor in order to evaluate the risk of
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis.
7.12.2. Non-permitted Medication
Some medications are not allowed within the timeframe given in Appendix 3.

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If it is identified after Randomization that these non-permitted drugs have been administered to a patient
within the excluded timeframes, the decision to permanently discontinue the patient will be discussed with
the medical monitor (see Section 5.2).
7.12.3. Permitted Medication Under Conditions
The following medications are permitted under the condition of steady dosage prior to Screening:
• UDCA if taken for at least 12 months (and stable dose for ≥ 6 months) prior to SV
• Statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to randomization
• Colchicine provided the dosage is kept stable for at least 3 months prior to Randomization.
7.12.4. Permitted Medication
Any medications other than those listed above are permitted. However, the dosage of a current medication
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown
DDIs.
In the event that additional concomitant therapy becomes necessary during the study, it should be recorded
by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an “as-needed” basis.
Patients should be discouraged from starting any new medication without consulting the Investigator unless
the new medication is required for emergency purpose.

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8 ADVERSE EVENT AND TOXICITY MANAGEMENT
8.1. DEFINITIONS
8.1.1. Adverse Events (AEs)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical
(investigational) product and which does not necessarily have a causal relationship with this treatment will
be considered as an AE. The term AE is synonymous with the term “adverse experience” as used by the FDA.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or,
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or
not considered related to the medicinal product.
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and
termination of pregnancy.
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero and breastfeeding.
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as
follows:
• Test result is associated with accompanying symptoms
• Test result requires additional diagnostic testing or medical/surgical intervention
• Test result leads to a change in study dosing or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy
• Test result is considered to be an AE by the Investigator or Sponsor.
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any
abnormal test result that is determined to be an error does not require reporting as an AE.
An AE does not include the following:
• Medical or surgical procedures performed; the condition that leads to the procedure may be an AE if
applicable
• Pre-existing disease, condition or laboratory abnormalities present or detected before the SV that do
not worsen
• Any medical condition or clinically significant laboratory abnormality with an onset before the consent
form is signed. Such a medical condition is considered to be pre-existing and should be documented
on the medical history of the eCRF.
The questions concerning whether the condition existed before the start of the active phase of the study and
whether it has increased in severity and/or frequency will be used to determine whether an event is a
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the active
phase of the study begins and is not a chronic condition that is part of the patient’s medical history, or (2) it
is present at the start of the active phase of the study or as part of the patient’s medical history, but the
severity or frequency increases during the active phase. The active phase of the study begins at the time of
the first dose of the study drug. The active phase of the study ends at the last study visit.
8.1.2. Adverse events of special interest (AESIs)
AESIs are treatment emergent AEs corresponding to the conceptual definition of:
• CPK elevations of severe intensity or leading to permanent study drug discontinuation

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• Muscle injury symptoms of severe intensity corresponding to:
o Muscle pain or Myalgia
o Muscle spasms or Tremor
o Muscle weakness
• Transaminases elevations from baseline of severe intensity or leading to permanent study drug
discontinuation
• Autoimmune hepatitis
• Liver injury events of severe intensity corresponding to:
o Hepatic impairment
o Hepatic failure
• Gastrointestinal symptoms of severe intensity corresponding to:
o Abdominal pain
o Constipation
o Diarrhea
o Nausea
o Decreased appetite
o Vomiting
o Acute cholecystis
o Acute pancreatitis
• Fatigue and Asthenia of severe intensity
• Serum creatinine elevations of severe intensity or leading to permanent study drug discontinuation
• Renal injury events of moderate or severe intensity corresponding to:
o Renal failure
o Renal impairment
o Renal colic
• Neurological abnormalities of moderate to severe intensity corresponding to:
o Tremor
o Ataxia
o Fasciculations
• Parkinson’s Disease
• Peripheral edema of moderate to severe intensity
• Weight gain of more than 5% from baseline
• Major Adverse Cardiovascular Events corresponding to:
o Non-fatal myocardial infarction/unstable angina
o Non-fatal stroke
o Unstable Angina
o Hospitalization for Heart Failure
o Coronary Revascularization (bypass or percutaneous coronary intervention )
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are described
in the Section 8.6.1.
8.1.3. Serious Adverse Event
A SAE is any untoward medical occurrence that at any dose:

• Results in death
• Is life-threatening
• Requires in-patient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity
or
• Is a congenital anomaly/birth defect.

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8.1.4. Clarification on Serious Adverse Events
• Death is an outcome of an AE, not an AE in itself.

• A SAE may occur even if the patient was not being treated with the study drug at the occurrence of
the event.
• Life-threatening means that patient is at immediate risk of death.
• Complications that occur during hospitalizations are AEs. If a complication prolongs the
hospitalization, it is a SAE.
• Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. Of
note, a procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported
as SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be
reported as SAE.
• Only a persistent or significant or incapacitating disability is implied. This item refers to a substantial
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to
include experiences of relatively minor medical significance such as headache, nausea, vomiting,
diarrhea, influenza, and accidental trauma.
• Congenital anomaly/birth defect includes foetal malformations associated with spontaneous
abortions or elective abortions.
• Medical and scientific judgment should be exercised in deciding whether expedited reporting is
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require
intervention to prevent one of the other outcomes listed in the definition above. These should also
usually be considered serious.
• Any illnesses reported before starting active treatment or AE meeting the criteria of seriousness (as
defined above) and considered to be possibly related (according to the Investigator) to any study-
specific procedure (e.g. wash-out period, laboratory testing procedure, etc…) must be reported as
SAE.
8.1.5. Adverse Drug Reaction
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and
unintended at any dose and that is considered causally related to an investigational medicinal product. A
serious ADR (SADR) is an ADR which meets the seriousness criteria.
8.1.6. Unexpected Adverse Event
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of
severity or specificity that is not consistent with the applicable IB or that is symptomatically and
pathophysiologically related to a known toxicity but differs because of a greater severity or specificity.
“Unexpected” refers to an ADR that has not been previously reported rather than an event that has not been
anticipated based on the properties of the drug.
8.2. ASSESSMENTS
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent.
The patient will be questioned in a general manner to determine specific symptoms without offering the
patient any suggestion.
8.2.1. Intensity Assessment
The intensity of the AE will be graded as follows:

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• Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation;
signs and symptoms are transient.
• Moderate: Events introduce a low level of inconvenience or concern to the subject and may interfere
with daily activities, but are usually improved by simple therapeutic measures; moderate experiences
may cause some interference with functioning.
• Severe: Events interrupt the subject’s normal daily activities and generally require systemic drug
therapy or other treatment; they are usually incapacitating.
8.2.2. Relation to the Study Treatment
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related to
study treatment. The Investigator will evaluate any changes in laboratory values, make a determination as
to whether or not the change is clinically important, and whether or not the changes were related to study
drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or clinically
significant laboratory abnormality must be recorded in the CRF.
The Investigator will record the relation to the study treatment according to the following causality terms:
• Related: the AE or laboratory test abnormality follows a reasonable temporal sequence from the
time of drug administration and it cannot be explained by the patient's clinical state or the study
procedures/conditions or other drugs. The AE abates upon discontinuation of the study drug and
reappears when the study drug is introduced.
• Possibly related: the AE follows a reasonable temporal sequence from the time of drug
administration, but could have been produced by the patient's clinical state or the study
procedures/conditions.
• Unlikely related: the temporal association between the AE and the study drug is such that the
study drug is not likely to have any reasonable association with the AE. The relationship is not likely
because of other plausible explanations.
• Not related: the AE must definitely be caused by the patient's clinical state or the study
procedure/conditions. A reasonable explanation must be given, e.g., no study drug taken,
preplanned elective medical intervention, or incompatible temporal relationship.
• Not assessable: the report suggesting an adverse reaction cannot be judged because information
is insufficient or contradictory and data cannot be supplemented or verified.
8.2.3. Action Taken and Outcome
The Investigator will record the action taken with drug and outcome of the event for each AE according to
the following:
Action taken with study drug
• Drug withdrawn – in case a patient is permanently withdrawn from the study drug
• Drug interrupted – in case the study drug is temporarily withdrawn
• Dose not changed – in case no action is taken regarding the study drug
• Unknown
• Not applicable – an AE started before initiation of treatment with study drug, the treatment had been
completed prior to reaction/event, or the patient has died
Outcome
• Recovered/resolved
• Recovering/resolving
• Not recovered/not resolved
• Recovered/resolved with sequelae
• Fatal
• Unknown

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Note: In case of irreversible congenital anomalies, the choice not recovered/not resolved should be used.
“Fatal” should be used when death is possibly related to the reaction/event.
8.3. REPORTING
8.3.1. Reporting an AE
All AEs regardless of seriousness or relationship to study drug, including those occurring during the Screening
Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s medical record from
the ICF signature until the last study visit of the patient. Whenever possible, symptoms should be grouped
as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal intensity, action
taken with respect to study drug, corrective therapy given, outcome, and his/her opinion as to whether there
is a reasonable possibility that the AE was caused by the study drug.
AE reporting begins from signature of the patient ICF at the first SV and ends at the last study visit.
8.3.2. Reporting a SAE or an AESI
SAE reporting begins from signature of the patient ICF and ends at the last study visit.
AESI reporting starts from first study drug intake and ends at study end for each patient.
Investigators must notify, by fax, or email, the Sponsor designed representative SGS Life Science Services
Medical Affairs (SGS) of all SAEs or AESIs IMMEDIATELY (within 24 hours of the Investigator
becoming aware of the event) regardless of the causality. The Investigator will be requested to supply
as much detailed information regarding the event that is available at the time of the initial contact (such as
examinations carried out and laboratory results).

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ANY SERIOUS ADVERSE EVENTS, OR ADVERSE EVENTS OF SPECIAL INTEREST, WHETHER

RELATED OR NOT TO THE STUDY DRUG, MUST BE REPORTED IMMEDIATELY (WITHIN 24
HOURS) TO SGS AT THE FOLLOWING FAX NUMBER:
FAX num bers: +32 (0)15 29 93 94 or 1-800-746-6618
Contact P erson: SGS LSS M edical Affairs Departm ent
E-m ail: be.life.saefax -m a@sgs.com
The Investigator is also required to submit follow-up reports to Sponsor or its representative within 24
hours of becoming aware of additional information such as diagnosis, outcome, causality assessment,
results of specific investigations and any new significant information that has not been previously reported.
Copies of additional laboratory tests, consultation reports, post mortem reports, hospital case reports, autopsy
reports, and other documents should be sent when requested and applicable.
In case of death, a comprehensive narrative report of the case should be prepared by the Investigator and
sent to SGS with the SAE/AESI form, retaining a copy on site with the CRF. If an autopsy is performed, copy
of autopsy report should be actively sought by the Investigator and sent to SGS as soon as available, retaining
a copy on site with the CRF.
Initial and follow-up report will be completed by the Investigator using appropriate template provided to him
by the Sponsor.
The expected / unexpected status of the serious and related AE will be judged by the Sponsor or its designated
Representative with regards to the reference documents (IB).
The Sponsor or its designated Representative will report all the relevant safety information to the concerned
IRB/IEC concerned according to the country specific requirements.
The Investigator must also fulfill his/her obligation regarding AE reporting according to the law in force in
his/her country.
8.3.3. Follow-up
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she
should follow-up the outcome of any AE until the return to normal or until consolidation of the patient
condition.
The patient must be followed-up until clinical recovery is complete and laboratory results have returned to
normal, or until progression has been stabilized. This may imply that follow-up will continue after the patient
has left the study and that additional investigations may be requested by the Sponsor, notably for the potential
related AEs, and that additional investigations may be requested by the Sponsor . This information should be
documented in the patient’s medical records.
8.4. POST STUDY REPORTING REQUIREMENTS
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality,
should be reported.
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and which
is considered by him/her to be caused by the study drug within a reasonable possibility, should be reported.
8.5. CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES

OR SAES
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities that
are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable.

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Reporting timelines for AEs and SAEs/AESIs are described respectively in Section 8.3.1and Section 8.3.2
8.6. SPECIAL SITUATION REPORTS
8.6.1. Pregnancy
In case of pregnancy a communication will be sent by the Investigator to SGS by faxing a completed
pregnancy form within 24 hours of his/her knowledge of the pregnancy.
Pregnancies of females partners of male patients exposed to study drug should also be reported to SGS using
the corresponding pregnancy form, provided that females partners sign the corresponding and separate ICF.
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator as
soon as possible once they are aware of being pregnant or suspect that they are pregnant during the study
or within 30 days of the last dose of the study drug.
Female patients will be requested, as part of the general ICF, to provide informed consent to allow reasonable
attempts to be made to obtain information on any possible study drug exposure to an embryo or fetus and
to follow up on the outcome of the pregnancy.
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic abortion,
stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the procedure for
reporting SAEs/AESIs as detailed in Section 8.3.2.
8.6.2. Medication Error
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a

medicinal product while in the control of the healthcare professional, patient, or consumer. All medication
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be reported
as appropriate.
8.6.3. Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used not in
accordance with the protocol. All misuse will be documented in the eCRF and, in case of any potential risk to
patient safety, would be reported as appropriate.
8.6.4. Overdose
This refers to the administration of a quantity of a medicinal product given per administration or cumulatively,
which is above the maximum recommended dose. Clinical judgment should always be applied.
8.6.5. Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is
accompanied by harmful physical or psychological effects.

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9 STATISTICAL METHODS AND DATA ANALYSIS
This section is an overview of the key elements of the statistical analysis for this study. Further details on
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP may
be revised during the study only to accommodate protocol amendments and to make changes to adapt to
unexpected issues in study execution and data collection that could affect planned analyses. In all
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first
approved version of the SAP should be available within 3 months of first patient randomized and before the
first DSMB data review meeting.
Descriptive summary statistics for continuous variables will include the number of patients, mean, SD, median,
and range. Descriptive summary statistics for categorical variables will include frequency counts and
percentages. Unless stated otherwise, the denominator for percentage calculations will be the number of
patients with non-missing data.
9.1. ESTIMANDS CONSIDERATIONS
The primary objective of the study is to evaluate the effect of elafibranor (80 mg/day) on cholestasis over 52
weeks of treatment compared to placebo.
The cholestasis is predominantly characterized by elevation of serum ALP. In the Phase 2 study, a significant
effect of elafibranor on ALP serum levels was observed from the first visit following baseline and was
reinforced up to the end of the active treatment period. Thus, a rapid decrease of the ALP serum levels in
elafibranor group and no change in placebo group can be expected.
To limit the occurrence of intercurrent events (ICEs) such as study treatment discontinuations due to lack of
efficacy and/or use of rescue medication such as OCA, the patients and the investigators will remain blinded
of the ALP, GGT and 5’ NT results until the dabase lock and the Sponsor authorization to unblind the study.
Thus, no between group imbalance in the occurrence of these events that might bias the treatment effect
estimate in favor of elafibranor is expected.
As detailed below, in line with ICH E9 (R1) addendum; five attributes (treatment condition ,population,
endpoint, ICEs and population level summary) have been specified to translate the primary objective into
treatment effect that is to be estimated (estimands):
• Primary estimand
The composite strategy imputing non response for patients who experienced ICEsprior to week 52 will be
applied.
- A. Treatment condition: Administration of Elafibranor or Placebo on top of UDCA or in subjects
intolerant to UDCA,
- B. Population: Randomized patients with PBC and Inadequate Response or Intolerance to UCDA,
- C. Endpoint: Response to treatment (binary variable) indicating a successful response at week 52 for
a subject with ALP <1.67 x ULN, TB ≤ ULN and ALP decrease ≥ 15%, and who does not stop
prematurely the study treatment nor use any rescue therapy,
- D. Intercurrent events: To be considered as non response irrespective of data after the study
treatment discontinuation or use of rescue therapy being missing or not,
- E. Population-level summary: Between treatment group difference in response proportions.
The primary estimand can be defined as the between treatment group difference in proportions of patients,
from all randomized patients, achieving response at week 52, defined as ALP < 1.67 x ULN, TB ≤ ULN and
ALP decrease ≥ 15%, and not stopping prematurely the study treatment nor using rescue therapy.
In addition, two strategies will be explored as supplementary analysis:
- The hypothetical strategy will be investigated comparing the potential outcomes that would
have been observed at week 52 between the treatment arms as if:
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o The patients who experienced an ICE would follow their initial randomized treatment
o The patients who experienced an ICE from both arms would continue on placebo
In addition, a tipping point analysis will explore various scenarios among the hypothetical
strategy where missing outcomes experienced after an ICE vary independently from
Elafibranor and placebo groups
- The treatment policy strategy will be investigated where patients are classified as responders
based on their outcome value at week 52 regardless of treatment discontinuation or use of
rescue therapy.
• Key secondary estimands

Key-secondary endpoint: Response to treatment based on ALP normalization at week 52.
The composite strategy imputing non response for patients who experienced ICEs prior to week 52 will be
applied.
intolerant to UDCA,
- C. Endpoint: Response to treatment (binary variable) indicating a successful normalization of ALP at
week 52 without stopping prematurely the study treatment not using any rescue therapy,
The key secondary estimand can be defined as the between treatment groups difference in proportions of
patients, from all randomized patients, who successfully normalized their ALP at week 52 and who do not
prematurely stop the study treatment nor use any rescue therapy.
The same hypothetical and treatment policy strategies as for the primary estimand will be applied as
supplementary and sensitivity analyses.
Key-secondary endpoint: Change in pruritus from baseline through week 52 based on PBC Worst Itch NRS
score.
The hypothetical strategy assuming that patients who experienced an ICE would have continued within their
treatment arm will be applied.
intolerant to UDCA,
- C. Endpoint: Change from baseline through week 52 in PBC Worst Itch NRS score,
- D. Intercurrent events: Any outcome value collected after a treatment discontinuation or use of rescue
therapy will be considered as missing,
- E. Population-level summary: Between treatment group difference in mean changes from baseline.
The key secondary estimand can be defined as the between treatment groups difference in PBC Worst Itch
NRS mean change from baseline from all randomized patients through week 52 assuming they continued the
assigned treatment after they experienced an ICE.
As for the key binary endpoints, a tipping point analysis point analysis will be performed to explore several
scenarios where missing outcomes experienced after an ICE vary independently from Elafibranor and placebo
groups.
In addition, the treatment policy strategy will be investigated where all outcome values until week 52 will be
used regardless of treatment discontinuation or use of rescue therapy.
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9.2. RANDOMIZATION AND TREATMENT ASSIGNMENT
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis and
stratified by the following factors:
1) ALP > 3 x ULN or TB > ULN: Yes/No
2) PBC Worst Itch NRS score (averaged over the 14 days preceding randomization) ≥ 4: Yes/No
During the LTE period, all patients will receive elafibranor 80 mg.
9.3. ENDPOINTS
9.3.1. Primary Endpoint
9.3.2. Secondary Endpoints
Key Secondary Endpoints

1-Response to treatment based on ALP normalization at week 52.
2-Change in pruritus from baseline through week 52 in PBC Worst Itch NRS score.

b) ALP < 3 x ULN, AST <2 x ULN and TB ≤ 1 mg/dL (Paris I)
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5 x ULN and TB ≤ 1mg/dL (Paris II)
f) TB ≤ 0.6 x ULN
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline of more
4) PBC risk scores at week 52: UK PBC score and GLOBE score
GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
8) Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, fibrinogen,
haptoglobin and TNF-α

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as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and TE
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated VLDL-
C and TG
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile
acids, C4 and FGF-19
14) Proportion of patients with no worsening of pruritus at week 52 based on PBC Worst Itch NRS
15) Response in Worst Itch NRS defined as 30% reduction from baseline of NRS at week 52 in patients with
a baseline NRS ≥ 4
20) Change from baseline to week 52 in health utility as measured by EQ-5D-5L
a) MELD-Na > 14 for patients with baseline MED-Na ≤12
b) Progression to histological cirrhosis for non cirrhotic patients at baseline
c) Liver transplant
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven/Conn of 2 or more
f) Death
22) Change from baseline in: the histological scores
a) fibrosis stage according to Nakanuma scoring
b) Bile duct scores
f) Other exploratory scores (Fibrosis according to modified Ishak (adapted to PBC) scoring, portal
inflammation, ductular reaction, cholestasis and concentric periductal fibrosis)
c) Liver markers

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f) Histology
24) PK assessed by GFT505 and GFT2007 concentrations measurement in plasma
Additionally, the same endpoints as for the DB period (except histology and PK assessment) will be collected
over the LTE period to assess the maintenance of efficacy and safety of the treatment. The endpoints will be
described using descriptive statistics by DB treatment group and overall on both ITT and PP sets.
9.4. ANALYSIS SETS
The following analysis sets will be used in this study:
• Screened set: all patients who signed ICF. This set will be used to summarize disposition.
• ITT) set: all randomized subjects. This set will be used to summarize efficacy.
• PP set: all subjects from the ITT set without any major protocol deviation affecting the primary
efficacy endpoint.
• SS: all subjects who were administered at least one dose of study drug. This set will be used to
summarize safety.
• PKS: All patients who were administered at least one dose of study drug and have at least one post-
dose PK sample. Moreover, patients of the PK set must have data for time of dosing, time of sampling
and amount of study drug administered. Placebo patients will be removed from the analysis
population.
Patients in the ITT and PP sets will be analyzed based on randomized treatment. Patients in the SS will
be analyzed based on actual treatment received.
9.5. ANALYSIS OF PRIMARY ENDPOINT
The null hypothesis for response to treatment based on the primary endpoint is that there is no difference in
response rates between elafibranor and placebo groups. The alternative hypothesis is that there is a difference
in response rates between both groups. The null hypothesis will be tested at a two-sided alpha of 0.01 (see
Section 9.6). The efficacy analysis will be performed at the end of the common DB period (week 52) only,
but descriptive statistics will be provided over the entire DB period (up to week 104).
The number and percentage of patients with favorable response to treatment will be summarized by
treatment group at the end of the 52 weeks of the common DB treatment period as well as at the end of the
overall DB period (either V6/V8/LVDB). The response rates (ALP < 1.67 x ULN and TB ≤ ULN and ALP
decrease ≥ 15%) at week 52 will be compared between the treatment groups using the exact Cochran-
Mantel-Haentzel test stratified by the randomization strata. The estimate of the odds ratio, its 99% CI and
the corresponding p-value will be provided. The main analysis will be based on the ITT. To assess the
robustness of the results, the same analysis will be replicated on the PP set.
A sensitivity analysis to the statistical model will be performed on both ITT and PP sets, using an exact logistic
regression model with treatment group and randomization strata as factors.
Subjects who stopped prematurely the study treatment will be considered as non-responders.
Three supplementary/sensitivity analyses imputing outcome experienced after an ICE at Week 52 will be
applied using relevant multiple imputation methods. The imputations will be based on patients completing
the week 52 treatment period and relevant baseline covariates:
1) Outcomes will be imputed assuming that patients would follow their initial treatment (rather than
switching to placebo after discontinuation). Therefore, the treatment arm will be included in the
imputation model as a covariate or separate models will be fitted by treatment arm.

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2) Outcomes will be imputed for both placebo and treatment dropouts as if they would continue on
placebo (using placebo-based multiple imputation (PBI)).
3) A tipping point analysis will be performed where outcomes will be imputed assuming that the missing
outcomes on the two arms vary independently.
A last supplementary analysis will use outcome value at week 52 regardless of treatment discontinuation or
use of rescue therapy.
Further details will be provided in the SAP.

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9.6. OTHER STATISTICAL ANALYSIS
9.6.1. Key secondary endpoints
The number and percentage of patients with favorable response to treatment (according to ALP
normalization) will be described at the end of the common DB treatment period and at the end of the overall
DB period (either V6/V8/LVDB), and the same statistical methods as for the primary endpoint will be applied
to evaluate the treatment effect at week 52.
The change from baseline in PBC Worst Itch NRS score through week 52 will be summarized by treatment
group using monthly scores computed every 28 days and will be compared using a MMRM with stratification
factors as fixed factors. The statistical model will be used to calculate the mean treatment difference
(elafibranor - placebo), 99% CI and the corresponding p-value. The main analysis assumes that patients who
experienced an ICE would have continued within their treatment arm. A tipping point sensitivity analysis will
evaluate the impact on imputing outcomes in both treatment arms independently. A supplementary analysis
based on treatment policy will use outcome values at week 52 regardless of treatment discontinuation or use
of rescue therapy. Additionnally, the PBC Worst Itch NRS-Past week score obtained during the variable DB
period will be described.
Both key secondary endpoints will be analysed on ITT and PP sets.
9.6.2. Other secondary endpoints
During the DB period

The continuous endpoints will be described all along the DB period. At week 52, they will be compared
between treatment groups using the MMRM with stratification factors as fixed factors. The statistical model
will be used to estimate the mean treatment difference and its 95% CI. As for the key secondary endpoint,
patients who will experience an ICE will be analyzed as if they would have continued within their treatment
arm.
The categorical endpoints will be described at week 52 and at the end of the DB period, and will be analyzed
using the exact Cochran-Mantel-Haentzel test stratified by the randomization strata. The statistical model will
be used to estimate the odds ratios and its 95% CI. As for the primary endpoint, subjects with missing data
will be considered as non-responders.
All the analyses of other secondary endpoints will be performed based on the ITT and additionally, on the
PP.
PK assessment are described in Section 6.1.4. The statistical considerations applicable to the popPK modeling
will be fully described in a dedicated Analysis Plan (popPK SAP).
During the LTE period

All the endpoints defined as primary or secondary endpoints (apart from histology and PK endpoints) will be
assessed during the LTE period at the appropriate timepoint to assess the maintenance of efficacy of the
treatment. The endpoints will be summarized by treatment group using descriptive statistics based on both
ITT and PP.
9.6.3. Subgroup analyses
Exploratory analyses of the primary and key secondary endpoints will be done for the following subgroups:
• Age (< or > 60 years)

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• Gender
• Race
• UDCA treatment at baseline (Yes/No)
• Prior OCA treatment (Yes/No)
• ALP level at baseline (≤ or > 3 x ULN)
• TB at baseline (≤ or > 1 x ULN)
• TB at baseline > ULN or albumin at baseline < LLN (Yes/No)
• TB > 0.6 x ULN (Yes/No)
• Geographic region
• PBC Worst Itch NRS score ≥ 4 (Yes/No)
• ALP > 3 x ULN or TB > ULN (Yes/No)
Forest plots will be generated for each endpoint for patients in the ITT population. Further details will be
provided in the SAP.
9.7. STRATEGIES TO CONTROL TYPE I ERROR
The overall type I error for the primary and key secondary endpoints is two-sided α=0.01.
The fixed-sequence testing approach will be used to control the overall type I error rate at a two-sided 0.01
level. If the primary endpoint is statistically significant at a two-sided 0.01 level, the first key secondary
endpoint (ALP normalization) will be tested at the same level. If the first key secondary endpoint is statistically
significant at a two-sided 0.01 level, the second key secondary endpoint (change in pruritus) will be tested
at the same level.
Statistical testing for other secondary endpoints will be of exploratory nature.
9.8. SAMPLE SIZE CALCULATION
All sample size calculations were done in East® 6.5.
9.8.1. Reduction in ALP and TB
• An expected response rate in the placebo group slightly higher than that in the phase 3 pivotal study
supporting the regulatory approval of OCA (10%) [4]
• An expected response rates in the Elafibranor group at least similar to OCA (47%)
The response rates from phase 3 pivotal study supporting the regulatory approval of OCA has been estimated
after imputation of missing or non reliable data as non response.
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power to
demonstrate a statistically significant between group difference of 35% (47% in elafibranor group vs 12% in

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9.8.2. Normalization in ALP
Assuming 1/50 (2.0%) patient in the placebo arm with ALP normalization at week 52 (key secondary
endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power to detect a statistically
significant between group difference of 20.0% at a two-sided 0.01 alpha level.
9.8.3. Change in pruritus
Assuming a pooled SD of 3 points, 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power
to detect a statistically significant between group difference of 1.8 points in mean change from baseline in
PBC Worst Itch NRS score at a two-sided 0.01 alpha level.
9.9. SAFETY ANALYSIS
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will be summarized by treatment
group and overall using descriptive statistics after both DB period and LTE period. The main summaries of
safety will be based on the SS.
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
Descriptive statistics will be presented giving the number and percentage of patients reporting at least one
AE, the number of events and the EAIR. In addition, comparison of treatment arms will be performed giving
EAIR estimates and their CIs. An overall summary of AEs will be provided. AEs will also be presented by
MedDRA System Organ Class and Preferred Term. The AEs will be summarized by worst severity and
relationship to study drug. SAEs, AESIs, and AEs leading to discontinuation will also be summarized. Narratives
will be written for all SAEs, AESIs, and AEs leading to discontinuation.
Clinical laboratory values (hematology, chemistry, and urinalysis) recorded at each timepoint and change
from baseline will be summarized by treatment group and overall using descriptive statistics. Clinical
laboratory values for each parameter will be assigned a classification according to whether the value is lower
than, within, or higher than the reference range for that parameter. The values will then be summarized using
shift tables to evaluate categorical changes from baseline to end of the 52 weeks treatment period and end
of DB period with respect to reference ranges. The number and percentage of patients reporting markedly
abnormal clinical laboratory values will also be summarized by treatment group and overall.
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group and
overall using descriptive statistics.

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10 DATA HANDLING AND RECORD KEEPING
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS
An eCRF is required and should be completed for each screened patient. The completed eCRFs are the sole
property of the Sponsor and should not be made available in any form to third parties, except for authorized
Sponsor’s representatives or appropriate regulatory authorities, without written permission from the Sponsor.
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform
to source documents, in accordance with specific instructions accompanying the eCRFs designed specifically
for this study. The CRF being used for this study is an electronic CRF that has been fully certified as being
compliant with the ICH Good Clinical Practice (GCP) guidance requirements.
All study required patient data generated during the study will be recorded in the eCRF, with the exception
of SAE forms which will be collected in paper. PRO data will be transferred from electronic (source data) in
the clinical database. Patients will not be identified by name in the eCRF or on any study documents to be
collected by the Sponsor (or designee), but will be identified by a unique patient number.
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as
attestation of the Investigator’s responsibility for ensuring that all data entered in the eCRF are complete,
accurate, and authentic.
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized person
and explained (if necessary). All corrected data will be tracked through an audit trail.
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates,
administration of study drug, AEs [start and stop dates] and all concomitant medications [start and stop
dates]). All data recorded in the eCRF will be documented by source data.
10.2. RETENTION OF RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully
documented and the study data to be subsequently verified.
The Investigator will be provided with a study file, which should be used to file the IB, protocol/amendments,
drug accountability records, sample informed consent, staff curriculum vitae, and correspondence with the
IRB/IEC, Sponsor, and other study-related documents.
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs,
source documents, and detailed records of treatment disposition.
The Investigator must retain the study documentation until at least 2 years after the last approval of a
marketing application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of
the study drug. However, these documents should be retained for a longer period if required by the applicable
regulatory requirements or by an agreement with the Sponsor. All hospital records will be archived according
to local regulation.
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the
study. The study records must be transferred to an acceptable designee, such as another Investigator,
another institution, or to the Sponsor.

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11 QUALITY CONTROL AND QUALITY ASSURANCE
11.1. QUALITY CONTROL & MONITORING PROCEDURES
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the
protocol, GCP (ICH topic E6 R2), applicable regulatory requirements, and the current Declaration of Helsinki
and that valid data are entered into the eCRFs.
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the
Sponsor in the maintenance of attributable, legible, and contemporaneously recorded, original or a true copy,
accurate (ALCOA), well-organized, and easily retrievable data.
Before screening any patients in this study, the Study Monitor will review the protocol, the IB, the eCRFs and
instructions for their completion and return, the procedure for obtaining informed consent, and all other study
procedures (e.g. the laboratory manual, electronic patient-reported outcomes [ePRO] manual, IXRS manual,
etc) including the reporting AEs and SAEs with the Investigator. In addition, the Study Monitor will explain
the Investigator’s reporting responsibilities and all applicable regulations concerning the clinical evaluation of
the study drug.
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the Sponsor
deems is necessary to determine that data recording and protocol adherence are satisfactory. A Study Monitor
from the CRO will be responsible for monitoring this clinical study. To this end, the Study Monitor will visit
the study site at suitable intervals and be in frequent contact through verbal and written communication. The
eCRFs and related source documents, as well as drug accountability will be reviewed in detail by the monitor,
in accordance with relevant SOPs and GCP (ICH topic E6 R2) regulations. This includes results of tests
performed as a requirement for participation in this study and any other medical records required to confirm
information contained in the eCRFs, such as past medical history.
Further details can be found in the monitoring plan.
It is essential that the Study Monitor has access to all documents (related to the study and the individual
subjects) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to
cooperate with the Study Monitor, to be available during a portion of the monitoring visit to answer questions,
and to provide any missing information.
All monitoring activities will be reported and archived in the Trial Master File.
11.2. ETHICAL PRINCIPLES
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and
all applicable amendments laid down by the World Medical Assemblies and the GCP guidelines.
This study also complies with applicable local regulatory requirements and laws of each country in which the
study is performed, as well as any applicable guidelines.
11.3. QUALITY ASSURANCE
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study
records for review, being understood that these personnel will adhere to all requirements for patient
confidentiality, and as such will not disclose any personal identity or personal medical information.
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As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the Sponsor
and authorize the Sponsor to participate to this inspection if permitted by the Authorities.
The confidentiality of the data verified and the anonymity of the patients should be respected during these
inspections.
The clinical study protocol, each step of the data capture procedure, and the handling of the data, including
the final clinical study report, will be subject to independent Quality Assurance activities. Audits may be
conducted at any time during or after the study to ensure the validity and integrity of the study data.

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12 ETHICS AND REGULATORY
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
The GCP guidelines and the US Code of Federal Regulations (CFR) Title 21 Section 56 (21 CFR 56) require
that approval must be obtained from an IRB/IEC prior to participation of human patients in research studies.
Prior to the study onset, the protocol, ICF, advertisements to be used for patient recruitment, and any other
written information regarding this study to be provided to the patient or the patient’s legally acceptable
representative must be approved by the IRB/IEC. The Sponsor will supply relevant material for the
Investigator to submit to the IRB/IEC for the protocol’s review and approval. Verification of the IRB/IEC’s
unconditional approval of the protocol and the written ICF statement will be transmitted to the Investigator.
Documentation of the relevant IRB/IEC approval and of the IRB/IEC compliance with GCP guideline will be
maintained by the site and will be available for review by the Sponsor or its designee or by the authorized
members of regulatory agencies.
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the
clinical research before the start of the study.
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC.
If any alterations, other than changes of administrative nature only, are made to the study protocol, a formal
protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent protocol
amendments and of suspected unexpected serious adverse reactions (SUSARs). Approval for protocol
amendments will be transmitted in writing to the Investigator.
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to the
IRB/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required time
frame.
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing direct
access to source data/documents.
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one
year) and a Study Progress Report following the completion, termination, or discontinuation of the
Investigator’s participation in the study.
12.2. COMPETENT AUTHORITY
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from
Competent Authorities should be granted before the beginning of the study. If applicable, Amendments will
also be submitted to CA for approval.
12.3. PATIENT INFORMATION AND CONSENT
Written ICF for the study will be obtained from each patient before protocol-specific procedures are carried
out. The ICF used by the Investigator for obtaining the patient's informed consent must be reviewed and
approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC). The ICF will be
approved (along with the protocol) by the IRB/IEC.
The Investigator or a person designated by the Investigator (according to applicable regulatory

requirements), will explain the nature of the study and the action of the study drug. The patients will be
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informed that participation is voluntary and that they can withdraw from the study at any time. In accordance
with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF approved by
the designated IRB/IEC and will be signed and personally dated by the patient or by the patient’s legally
acceptable representative and by the person who conducted the informed consent discussion prior to
protocol-specific procedures being performed. A separate consent form will be obtained for optional biomarker
samples to be stored in the blood bank.
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given
to the patient.
12.4. PATIENT CONFIDENTIALITY
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by protocol
number and patient number.
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall not
be published or disclosed to a third party without the prior written consent of the Sponsor.
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the
Investigators who has/have contributed significantly to the study will be asked to endorse the final report.
The endorsement is required by some regulatory agencies.
The Investigator shall not make a patent application based on the results of this study and shall not assist
any third party in making such an application without the written authorization of the Sponsor unless
otherwise specified in the Clinical Trial Agreement (CTA).
12.5. DEFINITION OF THE END OF THE RESEARCH
The end of the study is defined as completion of the last visit or procedure of the last patient participating in
the study (last EOT DB/EOT LTE visit).

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13 FINANCING AND INSURANCE
13.1. FINANCIAL ISSUES
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of
the study.
13.2. INSURANCE AND PATIENT INJURY
The patients taking part in the study will be covered by the insurance taken by the Sponsor for this study, if
they were to suffer any prejudice as a result of taking part in the study.
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable and
necessary medical treatment for the injury, to the extent the expenses are not covered by the patient’s
medical insurance, a government program, or other responsible third party. If laws or regulations of the
locality in which the study is taking place require additional payment of expenses, the Sponsor shall comply
with such law or regulation.
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil
liability and that of everyone involved in the research, and notably that of the Investigators and their
colleagues with regard to any accidents or damage concerning the administration of the drug or paraclinical
examinations directly linked to the performance of the study.

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14 STUDY RESULTS AND PUBLICATION POLICY
14.1. STUDY REPORT
The final report will be written in English upon completion of study and statistical analysis according to ICH
E3 guideline. The report or part of it must be submitted to relevant authorities if applicable.
The CRO will prepare an integrated Clinical Study Report (CSR). Prior to issuing the final CSR, the CRO will
prepare a draft report for approval by the Sponsor. The draft report will be submitted for Quality Control, the
findings of which will be incorporated into the final version.
An electronic copy of the final CSR will be made available to the Sponsor. The CSR will be provided in PDF
and MS Word formats unless agreed otherwise by the CRO. Reports requiring specialized Sponsor
formats/alternative computer software packages may be possible on request from the Sponsor but may
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final
report.
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s
comments.
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND
PUBLICATION
All materials, information (oral or written), and unpublished documentation provided to the Investigators (or
any company/institution acting on their behalf), including this protocol, the patient CRFs, and the IB, are the
exclusive property of the Sponsor and may not be published, given, or disclosed, either in part or in whole,
by the Investigator or by any person under his/her authority to any third party without the prior express
consent of the Sponsor.
However, the submission of this protocol and other necessary documentation to IRB/IEC and the Competent
Authority is expressly permitted, their members having the same obligation of confidentiality.
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior
written consent.
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the
present study, either in the form of CRFs (or copies of these), or in the form of a report, with or without
comments and with or without analysis, in order to submit them to the Health Authorities of any country.
Investigators who has/have contributed significantly to the study will be asked to endorse the CSR. The
endorsement is required by some regulatory agencies.
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such results,
which will be filed by the Sponsor or its designees in its own name and at its expense.
Clinical study will be registered on the open access website https://www.clinicaltrials.gov before the screening
of the first patient in the study.

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It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their studies,
using only clean, checked, and validated data in order to ensure the accuracy of the results.
The publication of study results will be agreed between the Sponsor and the Investigators.
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the manuscript
or abstract for review by the Sponsor, and, if necessary, delay publication or communication for a limited
time in order to protect the confidentiality or proprietary nature of any information contained therein. The
Sponsor may also request that the Sponsor’s name and/or names of one or several of its employees appear
or not appear in such publication.

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15 REFERENCES LIST
1. Lammers, W.J., K.V. Kowdley, and H.R. van Buuren, Predicting outcome in primary biliary
cirrhosis. Ann Hepatol, 2014. 13(4): p. 316-26.
2. Carbone, M., et al., The UK-PBC risk scores: Derivation and validation of a scoring system
for long-term prediction of end-stage liver disease in primary biliary cholangitis.
Hepatology, 2016. 63(3): p. 930-50.
3. Lammers, W.J., et al., Development and Validation of a Scoring System to Predict Outcomes
of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy.
Gastroenterology, 2015. 149(7): p. 1804-1812 e4.
4. Nevens, F., et al., A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary
Cholangitis. New England Journal of Medicine, 2016. 375(7): p. 631-643.
5. Kuiper, E.M., et al., Relatively high risk for hepatocellular carcinoma in patients with
primary biliary cirrhosis not responding to ursodeoxycholic acid. Eur J Gastroenterol
Hepatol, 2010. 22(12): p. 1495-502.
6. Kumagi, T. and E.J. Heathcote, Primary biliary cirrhosis. Orphanet J Rare Dis, 2008. 3: p.
1.
7. Boonstra, K., U. Beuers, and C.Y. Ponsioen, Epidemiology of primary sclerosing cholangitis
and primary biliary cirrhosis: a systematic review. J Hepatol, 2012. 56(5): p. 1181-8.
8. Kim, W.R., et al., Epidemiology and natural history of primary biliary cirrhosis in a US
community. Gastroenterology, 2000. 119(6): p. 1631-6.
9. Al-Harthy, N. and T. Kumagi, Natural history and management of primary biliary cirrhosis.
Hepat Med, 2012. 4: p. 61-71.
10. Selmi, C., et al., Environmental pathways to autoimmune diseases: the cases of primary
biliary cirrhosis and multiple sclerosis. Arch Med Sci, 2011. 7(3): p. 368-80.
11. Ali, A., T. Byrne, and K. Lindor, Orphan drugs in development for primary biliary cirrhosis:
challenges and progress. 2015. 5: p. 83-97.
12. Hirschfield, G.M. and M.E. Gershwin, The immunobiology and pathophysiology of primary
biliary cirrhosis. Annu Rev Pathol, 2013. 8: p. 303-30.
13. Beuers, U. and K.D. Lindor, A major step towards effective treatment evaluation in primary
biliary cirrhosis. J Hepatol, 2011. 55(6): p. 1178-80.
14. Carbone, M., et al., Sex and age are determinants of the clinical phenotype of primary biliary
cirrhosis and response to ursodeoxycholic acid. Gastroenterology, 2013. 144(3): p. 560-569
e7; quiz e13-4.
15. Lammers, W.J., et al., Levels of alkaline phosphatase and bilirubin are surrogate end points
of outcomes of patients with primary biliary cirrhosis: an international follow-up study.
Gastroenterology, 2014. 147(6): p. 1338-49 e5; quiz e15.
16. Giannini, E.G., R. Testa, and V. Savarino, Liver enzyme alteration: a guide for clinicians.
CMAJ, 2005. 172(3): p. 367-79.
17. Crosignani, A., et al., Clinical features and management of primary biliary cirrhosis. World
J Gastroenterol, 2008. 14(21): p. 3313-27.
18. Corpechot, C., et al., Biochemical response to ursodeoxycholic acid and long-term prognosis
in primary biliary cirrhosis. Hepatology, 2008. 48(3): p. 871-7.
19. Lindor, K.D., et al., Primary biliary cirrhosis. Hepatology, 2009. 50(1): p. 291-308.
20. EASL, EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J
Hepatol, 2009. 51(2): p. 237-67.
21. Corpechot, C., et al., A Placebo-Controlled Trial of Bezafibrate in Primary Biliary
Cholangitis. New England Journal of Medicine, 2018. 378(23): p. 2171-2181.

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22. Ghonem, N.S., D.N. Assis, and J.L. Boyer, Fibrates and cholestasis. Hepatology, 2015.
62(2): p. 635-43.
23. Cattley, R., et al., Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic
Hazard to Humans? Regulatory Toxicology and Pharmacology, 1998. 27(1): p. 47-60.
24. Murillo Perez, C.F., et al., Goals of Treatment for Improved Survival in Primary Biliary
Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and
Normalization of Alkaline Phosphatase. Am J Gastroenterol, 2020.
25. Pickering, T.G., et al., Recommendations for blood pressure measurement in humans and
experimental animals: part 1: blood pressure measurement in humans: a statement for
professionals from the Subcommittee of Professional and Public Education of the American
Heart Association Council on High Blood Pressure Research. Circulation, 2005. 111(5): p.
697-716.
26. Elman, S., et al., The 5-D itch scale: a new measure of pruritus. Br J Dermatol, 2010. 162(3):
p. 587-93.
27. Jacoby, A., et al., Development, validation, and evaluation of the PBC-40, a disease specific
health related quality of life measure for primary biliary cirrhosis. Gut, 2005. 54(11): p.
1622-9.
28. Broderick, J.E., et al., Pittsburgh and Epworth sleep scale items: accuracy of ratings across
different reporting periods. Behav Sleep Med, 2013. 11(3): p. 173-88.
29. Johns, M.W., A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
Sleep, 1991. 14(6): p. 540-5.
30. Chalasani, N. and A. Regev, Drug-Induced Liver Injury in Patients With Preexisting Chronic
Liver Disease in Drug Development: How to Identify and Manage? Gastroenterology, 2016.
151(6): p. 1046-1051.
31. Regev, A., et al., Consensus: guidelines: best practices for detection, assessment and
management of suspected acute drug-induced liver injury during clinical trials in patients
with nonalcoholic steatohepatitis. Aliment Pharmacol Ther, 2019. 49(6): p. 702-713.
32. CTFG, Recommendations related to contraception and pregnancy testing in clinical trials.
Available at: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 2014.
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16 APPENDICES:
16.1. APPENDIX 1: BARC CENTRAL LABORATORY REFERENCE RANGES FOR ALP, AST, ALT,
GGT, DIRECT AND INDIRECT BILIRUBIN, AND TOTAL BILIRUBIN

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16.2. APPENDIX 2: ALCOHOL COMPARISON TABLE
Alcohol Alcohol by Volume Amount of alcohol

type volume (ABV) Fluid ounce mL Units Grams
Beer 3.5% 12 350 0.7 9.8
Beer 5% 12 350 1 14
Cider 7% 12 350 1.4 19.6
Distilled
spirits or 40% 1.5 45 1 14
liquor
Wine 12% 5 150 1 14
Footnote:
1. e.g., gin, rum, vodka, whiskey.
2. Units calculated using the Cleave Books calculator for units of drink, using the US definition of 1 unit of alcohol as 17.7 mL
(14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm)

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16.3. APPENDIX 3: PERMITTED/NON-PERMITTED MEDICATION
A. NON-PERMITTED MEDICATION AND CONDITION
Medications When
Same pharmacological class (PPAR agonists)
Thiazoledinediones (glitazones 3pioglitazone and From 2 months prior to randomization and
rosiglitazone]) throughout the study
Fibrates
Other Medications
OCA
Budesonide and other systemic Corticosteroids
Azathioprine
Cyclosporine
Methotrexate
Mycophenolate
From 3 months prior to randomization and
Pentoxyfilline throughout the study
Alpha-methyl-dopa
Sodium valproic acid
Isoniazide
Nitrofurantoin
Amiodarone
Tamoxifen
Antibodies or immunotherapy directed against ILs or From 12 months prior to randomization and
other cytokines or chemokines throughout the study

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B. PERMITTED MEDICATION AND CONDITION
Medications When
Therapies for treatment of PBC
Taken for at least 12 months prior to the SV with
Dose stability required from at least 3 months prior to
UCDA Randomization and throughout the study.
Therapies for treatment of pruritus
Cholestyramine
Dose stability required for at least 3 months prior to
Rifampin
Randomization and up to the end of the Double Blind period.
Naltrexone
Sertraline
Other Medications
Colchicine
Lipid lowering therapy
Statins Dose stability required from at least 2 months prior to
Ezetimibe randomization

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16.4. APPENDIX 4: PRODUCT CARTON AND WALLET LABELING
Carton Wallet
Protocol number X X
Sponsor details X X
Site number X -
Subject ID X X
Kit number X X
Visit number X -
Lot number X X
Expiry date X X
Contents X X
Route of administration X X
Administration instructions X X
“For Clinical Trial Use only.” X X
“Keep out of reach of Children.” X X
Storage details X X
Instructions for product and package
X X
return at next visit

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16.5. APPENDIX 5: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES:
16.5.1. PBC-40

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16.5.2. Epworth Sleepiness Scale (ESS)

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16.5.3. 5-D Itch Scale

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16.5.4. PROMIS Fatigue Short Form 7a

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16.5.5. The Patient Global Impression of Change (PGIC)

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16.5.6. The Patient Global Impression of Severity (PGIS)

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16.5.7. PBC Worst Itch NRS
PBC Worst Itch NRS
PBC Worst Itch NRS-Past Week

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16.5.8. EuroQoL EQ-5D-5L

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Page 116
Protocol version 5.0 20 December 2022
CLINICAL PROTOCOL – PHASE 3
Protocol N° GFT505B-319-1
EudraCT N°2019-004941-34
IND number: 132202
Version 5.0 – 20 December 2022
A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to

International PPD MD Elson S. Floyd College of Medicine

Coordinating Director, Liver Institute Washington State University
Investigator Northwest 3216 NE 45th Place, Suite 212
Committee Seattle, WA, USA 98105
Clinical Professor
Phone: +1 206-459-8479
Email P
P
D
PPD MD
Director, Metabolic Liver University Medical Center Mainz
Research Program Langenbeckstraße,1
55131 Mainz, Germany
Phone: +49 6131 176074
Email: PPD
Sponsor IPSEN PHARMA SAS 65 Quai Georges Gorse

92100 Boulogne-Billancourt, France
Represented by: PPD MD, Phone: +1 857-600-8195

MSc Email P
Senior Medical P
Development Director D
CONFIDENTIAL - This document is the property of the Sponsor and may not - in full or part - be passed on, reproduced,
published or used by authorities or other applicants for approval or registration purposes without express permission of the
Sponsor.
IPSEN PHARMA SAS CONFIDENTIAL Page 1 of 133

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PPD
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Principal Investigator Signature Page
I have read and agree to Protocol N° GFT505B-319-1 Version 5.0 entitled ‘A Double-blind, Randomized,
Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of
Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response or Intolerance
to Ursodeoxycholic Acid’. I am aware of my responsibilities as an investigator under the guidelines of
Good Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I agree to conduct
the study according to these guidelines and to appropriately direct and assist the staff under my control,
who will be involved in the study.
NAME:
TITLE: [PRINCIPAL] SIGNATURE:
INVESTIGATOR
DATE:
OFFICE: []
[]
[]
[]
[]

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STUDY CONTACTS
Protocol N°: GFT505B-319-1 / EudraCT N° 2019-004941-34 / IND n° 132202

International PPD MD Elson S. Floyd College of Medicine
Coordinating Director, Liver Institute Washington State University
Investigator Northwest 3216 NE 45th Place, Suite 212
Committee Seattle, WA, USA 98105
Clinical Professor
Phone: +1 206-459-8479
Email: PPD
PPD Department of Medicine

University Medical Center Mainz
MD
Langenbeckstraße,1
Director Metabolic Liver 55131 Mainz, Germany
Research Program
Phone: +49 6131 176074
Email PPD
Sponsor IPSEN Pharma SAS

65 Quai Georges Gorse
Represented by: PPD MD, Phone: +1 857-600-8195
MSc Email: PPD
Senior Medical
Development Director

Page 120
PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document Version Date Status
Amendment 4 5.0 20 December 2022 Effective
Amendment 3 4.0 20 September 2022 Superseded, Replaced by V5.0
Amendment 2 3.0 18 March 2022 Superseded, Replaced by V4.0
Amendment 1 2.0 11 December 2020 Superseded, Replaced by V3.0
Original Protocol 1.0 22 July 2020 -
Amendment 4 (20 December 2022)
This amendment is considered to be substantial based on the criteria set forth in applicable regulations.
Overall Rationale for the Amendment:
The protocol was amended to transfer the sponsorship from Genfit to Ipsen Pharma SAS.
Other minor changes were included to comply with the Ipsen Protocol Template for Interventional
Studies.
Summary change table from previous version of the protocol
Any new or amended text in the protocol is indicated in bold (IS column). Deletions are marked in
strikeout text (WAS column). Minor formatting and editing are not included.

Page 121
Section Was (Version 4.0, 20 September 2022) Is (Version 5.0, 20 December Rationale
2022)
All pages (header) Protocol version 4.0 20 September 2022 Protocol version 5.0 20 December
2022
All pages (footer) GENFIT IPSEN PHARMA SAS Transfer of sponsorship

from Genfit to Ipsen
Title page Sponsor Sponsor Transfer of sponsorship

GENFIT IPSEN PHARMA SAS from Genfit to Ipsen
45 Prospect Street, Suite 214 Cambridge, MA, USA 02139 65 Quai Georges Gorse
92100 Boulogne-Billancourt,
Represented by: France
Carol Addy, MD MMSc
CMO Represented by:
Phone: +1 617-953-6469 PPD MD, MSc
Email: PPD Senior Medical Development
Director
Phone: +1 857-600-8195
Email: PPD
Clinical study Pages deleted and replaced by the To comply with Ipsen
protocol signature corresponding ‘Sponsor signatory’ page Protocol template
page of the Ipsen Protocol Template
Clinical study Page deleted and replaced by the To comply with Ipsen
protocol – corresponding ‘Principal investigator Protocol template
Investigator signature’ page of the Ipsen Protocol
signature page Template

Page 122
Study contacts Sponsor Sponsor Transfer of sponsorship

45 Prospect Street – Suite 214, 2nd floor Cambridge, MA, USA IPSEN PHARMA SAS from Genfit to Ipsen
02139 65 Quai Georges Gorse, 92100
Boulogne-Billancourt, France
Represented by: Represented by:

PPD , MD MMSc PPD MD, MSc
CMO Senior Medical Development
Phone: +1 617-953-6469 Director
Email: PPD Phone: +1 857-600-8195
Email: PPD
CRO for project Labcorp Labcorp To comply with Ipsen

management, (formerly Clinical Protocol template which
regulatory Covance Development doesn't require vendor
activities, site Limited) SARL names/details to be
data monitoring (Labcorp) mentioned
and medical Immeuble
monitoring and Ariane
Clinical Study 2 rue
Report Jacques
Daguerre
92565 Rueil-
Malmaison
cedex -
France,

management & 39 rue
statistics d’Aboukir
75002 Paris ,
France
Pharmacovigilance SGS Life SGS
Science Generaal De
Services Wittelaan
19A bus 5

Page 123
Medical 2800
Affairs Mechelen –
Belgium
Study drug ALMAC ALMAC
supplier Clinical
Services
9
Charlestown
Road,
Seagoe
Industrial
Estate
Craigavon
BT63 5PW,
UK
9 Plaça de
Catalunya,
Floor 5
Barcelona,
Spain, 08002
Central laboratory Cerba 3,

Research Industriepark
Zwijnaarde
B-9052
Ghent,
Belgium
BARC USA
Inc
5 Delaware
Drive
Lake Success

Page 124
2022)
NY 11042-
1114, United
States
Bioanalysis Eurofins 75a, avenue
ADME de Pascalet
30310
Vergèze –
France
PK assessments PhinC Immeuble
Development Genavenir 8
5, rue Henri
Desbruères
91030 Evry –
France
ePRO Clario Clario
(formerly 1818 Market
ERT) Street, Suite
2600,
Philadelphia,
Pennsylvania
19103, USA
Partner IPSEN IPSEN
65, quai
Georges
Gorse
92100
Boulogne-
Billancourt
(France)
Protocol Added section To comply with Ipsen
amendment Protocol template
summary of
changes

Page 125
2022)
Clinical study Sponsor: Sponsor: Transfer of sponsorship
synopsis GENFIT IPSEN PHARMA SAS from Genfit to Ipsen
The DSMB will consist of at least 5 experienced physicians (1 The DSMB will consist of at least 5
endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, experienced physicians (1
and 1 nephrologist) and 1 statistician, all of whom will be endocrinologist, 1 cardiologist, 1
independent from the conduct of the study. The DSMB hepatologist, 1 oncologist, and 1
Charter will define the role, responsibilities, rules, and tasks nephrologist) and 1 statistician, all of
of the DSMB. whom will be independent from the
conduct of the study. The DSMB To be aligned with the
Charter will define the membership, DSMB charter
role, responsibilities, rules, and tasks of
the DSMB.
1. Introduction Elafibranor is being developed by Genfit for the treatment of Elafibranor has been developed by Transfer of sponsorship
and rationale PBC. In December 2021, Genfit and IPSEN (“the partner”) Genfit for the treatment of PBC. In from Genfit to Ipsen
entered into an exclusive licensing agreement for elafibranor, December 2021, Genfit and IPSEN
which gives the partner, the exclusive worldwide license for (“the partner”) entered into an
the future development of elafibranor in PBC, with the exclusive licensing agreement for
exception of China, Taiwan, Hong-Kong and Macau. Genfit elafibranor, which gives the partner,
remains the sponsor of this study until transfer of sponsorship the exclusive worldwide license for the
to the partner which is anticipated to take place within future development of elafibranor in
approximately 30 days of top line results for the double-blind PBC, with the exception of China,
portion of the study (part A). Taiwan, Hong-Kong and Macau. The
transfer of sponsorship from Genfit to
Ipsen is anticipated to take place
within approximately 30 days of top
line results for the double-blind portion
of the study (part A).

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1.1. Background Rationale for Evaluation of Elafibranor in PBC Rationale for Evaluation of Transfer of sponsorship
and rationale for Elafibranor is being developed by Genfit for the treatment of Elafibranor in PBC from Genfit to Ipsen
elafibranor in PBC, based on its pharmacological properties as a PPARα/δ Elafibranor is being developed by
primary biliary agonist. Activation of PPARα receptors leads to a decrease in Ipsen for the treatment of PBC, based
cholangitis bile acid synthesis, increase in bile acid uptake, and increased on its pharmacological properties as a
detoxification of bile acids through the increased uptake in PPARα/δ agonist. Activation of PPARα
micelles. receptors leads to a decrease in bile
acid synthesis, increase in bile acid
uptake, and increased detoxification of
bile acids through the increased uptake
in micelles.
6.1.1.Biological All blood samples for efficacy and/or for safety assessment All blood samples for efficacy and/or To comply with Ipsen
assessment will be returned and centralized by the central laboratory for safety assessment will be returned Protocol template which
(Cerba Research: Ghent – Belgium, New York – USA, or and centralized by the central doesn't require vendor
Johannesburg – South Africa). laboratory. names/details to be
mentioned
6.1.5.2. Plasma will be separated, stored and shipped as described in Plasma will be separated, stored and To comply with Ipsen
Pharmacokinetic the laboratory manual, first to the central laboratory Cerba shipped as described in the laboratory Protocol template which
blood handling Research (as for all the other blood samples collected) where manual, first to the central laboratory doesn't require vendor
procedures they will be stored until shipped to a specialized laboratory (as for all the other blood samples names/details to be
for analysis. collected) where they will be stored mentioned
until shipped to a specialized laboratory
for analysis.
6.1.5.3. The bioanalysis part will be conducted at a specialized The bioanalysis part will be conducted To comply with Ipsen
Bioanalytical laboratory in compliance with the Standard Operating at a specialized laboratory in Protocol template which
analysis Procedures (SOPs) in use at ADME BIOANALYSES. compliance with its Standard Operating doesn't require vendor
Procedures (SOPs) in use. names/details to be
mentioned

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6.3.6. Safety Safety oversight will be implemented under the direction of a Safety oversight will be implemented Insertion for consistency
review DSMB composed of five experienced physicians (an under the direction of a DSMB across the document
endocrinologist, cardiologist, oncologist, hepatologist and composed of at least five experienced
nephrologist) and one independent statistician, all physicians (an endocrinologist,
independent from the conduct of the study. cardiologist, oncologist, hepatologist
and nephrologist) and one independent
A DSMB charter will define the roles, responsibilities, rules statistician, all independent from the
and tasks of the DSMB. conduct of the study.
To be aligned with the
A DSMB charter will define the DSMB charter
membership, roles, responsibilities,
rules and tasks of the DSMB.
7.2.2. Labeling … … As a result of Appendix 4

Details of period boxes and wallet labels are given in deletion.
Appendix 4.

Page 128
2022)
8.3.2. Reporting Investigators must notify, by fax, or email, the Sponsor Investigators must notify by email, or To comply with Ipsen
an SAE or an AESI designed representative SGS Life Science Services Medical fax the Sponsor of all SAEs or AESIs Protocol template which
Affairs (SGS) of all SAEs or AESIs IMMEDIATELY (within IMMEDIATELY (within 24 hours of doesn't require vendor
24 hours of the Investigator becoming aware of the the Investigator becoming aware names/details to be
event) regardless of the causality. of the event) regardless of the mentioned
causality.
ANY SERIOUS ADVERSE EVENTS, OR ADVERSE To be consistent with Ipsen
EVENTS OF SPECIAL INTEREST, WHETHER RELATED processes, (report of SAEs
OR NOT TO THE STUDY DRUG, MUST BE REPORTED and AESIs in the first
IMMEDIATELY (WITHIN 24 HOURS) TO SGS AT THE instance by email and in
FOLLOWING FAX NUMBER: instances where
FAX numbers: +32 (0)15 29 93 94 or 1-800-746-6618 investigators/sites
Contact Person: SGS LSS Medical Affairs Department encounter any issues with
E-mail: be.life.saefax-ma@sgs.com sending the report via
email, by fax)
In case of death, a comprehensive narrative report of the
case should be prepared by the Investigator and sent to SGS
with the SAE/AESI form, retaining a copy on site with the
CRF. If an autopsy is performed, copy of autopsy report
should be actively sought by the Investigator and sent to SGS
as soon as available, retaining a copy on site with the CRF.
In case of death, a comprehensive

narrative report of the case should be
prepared by the Investigator and sent
to the Sponsor with the SAE/AESI
form, retaining a copy on site with the
CRF. If an autopsy is performed, copy
of autopsy report should be actively
sought by the Investigator and sent to
the Sponsor as soon as available,
retaining a copy on site with the CRF.

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2022)
8.6.1. Pregnancy In case of pregnancy a communication will be sent by the In case of pregnancy a communication To comply with Ipsen
Investigator to SGS by faxing a completed pregnancy form will be sent by the Investigator to the Protocol template which
within 24 hours of his/her knowledge of the pregnancy. Sponsor by emailing a completed doesn't require vendor
Pregnancies of females partners of male patients exposed to pregnancy form within 24 hours of names/details to be
study drug should also be reported to SGS using the his/her knowledge of the pregnancy. mentioned
corresponding pregnancy form, provided that females Pregnancies of females partners of
partners sign the corresponding and separate ICF. male patients exposed to study drug To be consistent with Ipsen
should also be reported to the processes (report of
Sponsor using the corresponding pregnancy by email)
pregnancy form, provided that females
partners sign the corresponding and
separate ICF.

Page 130
2022)
10.1. Data The contract between the sponsor and their vendors, its The contract between the sponsor and Transfer of sponsorship
protection partner and study sites specifies the responsibilities of the their vendors, and study sites specifies from Genfit to Ipsen
parties related to data protection, including handling of data the responsibilities of the parties
security breaches and respective communication and related to data protection, including
cooperation of the parties. handling of data security breaches and
respective communication and
cooperation of the parties.
In the event of a potential data To comply with Ipsen

security breach concerning Protocol template and
personal data processed on behalf procedure
of the sponsor, the data protection
officer must be informed without
undue delay and no later than 24
hours from the discovery of the
event. The data protection officer
will evaluate the event and notify
the Data Protection Authorities
within 72 hours, if required.
Corrective actions and preventive
actions will be implemented to
mitigate the possible adverse
effects. Affected study
participants will be informed
accordingly. Ipsen Data Protection
Officer can be contacted by email:
dataprivacy@ipsen.com.

Page 131
12.3. Patient A separate consent form will be obtained for optional A separate consent form will be
information and biomarker samples to be collected and to be stored in the obtained for optional biomarker
consent blood bank. samples to be collected and to be
stored in the blood bank.
Participants to the optional To comply with Ipsen
research biobanking programme Protocol template
have the right to withdraw their
consent at any time and for any
reason during the study or during
the period of sample storage (i.e.
the entire 15 years during which
samples are kept).
If a participant wishes to
withdraw their consent for
optional biobanking and the
samples are still at the
investigator site or at the central
laboratory at the time, the
investigator must inform the study
monitor in writing of the
participant’s decision and destroy
the samples.
If the samples are at the sponsor’s
repository (biobanking vendor),
the investigator must inform the
sponsor directly using the e-mail
address:
IpsenBiobanking@ipsen.com,
mentioning only the participant ID
in this e-mail. The sponsor will
ensure destruction of the samples
and all corresponding aliquots and
issue confirmation of the
destruction, which will be
forwarded to the investigator.
Analyses conducted before the
withdrawal will not be affected.

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12.5. Definition of The end of the study is defined as completion of the last visit The end of the study is defined as To comply with Ipsen
the end of the or procedure of the last patient participating in the study (last completion of the last visit or procedure Protocol template
research EOT DB/EOT LTE visit). of the last patient participating in the
study globally (last EOT DB/EOT LTE
visit).
13.1. Financial Investigators and sub- To comply with Ipsen
issues investigators will provide the Protocol template and
Sponsor with sufficient, accurate procedure
financial information as requested
to allow the Sponsor to submit
complete and accurate financial
certification or disclosure
statements to the appropriate
regulatory authorities.
Investigators are responsible for
providing information on financial
interests during the course of the
study and for one year after
completion of the study.
14.1. Study report The partner will prepare an integrated Clinical Study Report The Sponsor will prepare an Transfer of sponsorship
(CSR). Prior to issuing the final CSR, the CRO will prepare a integrated Clinical Study Report (CSR). from Genfit to Ipsen
draft report for approval by the Sponsor and by the study Prior to issuing the final CSR, the CRO
Steering Committee. The draft report will be submitted for will prepare a draft report for approval
Quality Control, the findings of which will be incorporated into by the Sponsor and by the study
the final version. Steering Committee. The draft report
will be submitted for Quality Control,
the findings of which will be
incorporated into the final version.

Page 133
14.2. Clinical study will be registered on the open access website Protocol information and To comply with Ipsen
Confidentiality and https://www.clinicaltrials.gov before the screening of the first (final/interim) study results will Protocol template and
ownership of data, patient in the study. be made publicly available on the procedure
use of the study US website
results and (www.clinicaltrials.gov) and on
publication the EU Clinical Trials Register
(www.clinicaltrialsregister.eu) or
EU Clinical Trials Portal
(https://euclinicaltrials.eu/home).
The sponsor also provides clinical
trial information to other national
clinical trial registries or
databases according to local
requirements/legislation. A lay
summary of the study will be
made available on the EU Clinical
Trials Portal
(https://euclinicaltrials.eu/home)
and/or Sponsor website.
It is the policy of the Sponsor to encourage the presentation It is the policy of the Sponsor to
and/or publication of the results of their studies, using only encourage the presentation and/or
clean, checked, and validated data in order to ensure the publication of the results of their
accuracy of the results. studies, using only clean, checked, and
validated data in order to ensure the
accuracy of the results.
The publication of study results will be agreed between the
Sponsor and the Investigators. The study results may be published
At least 45 days in advance of proposed submission, the or presented at scientific meetings
Investigator should forward a copy of the manuscript or after agreement between the
abstract for review by the Sponsor, and, if necessary, delay Sponsor and the Investigators.
publication or communication for a limited time in order to If this is foreseen, the investigator
protect the confidentiality or proprietary nature of any should discuss specific publication
information contained therein. The Sponsor may also request concepts, including data to be
that the Sponsor’s name and/or names of one or several of covered, target congress/journal
its employees appear or not appear in such publication. and proposed authors, with the
Sponsor for agreement before

Page 134
2022)
initiation. The Sponsor may also
request that the Sponsor’s name
and/or names of one or several of its
employees appear or not appear in
such publication. The investigator
agrees to submit all manuscripts
or abstracts to the Sponsor before
submission. This allows the
Sponsor to protect proprietary
information and to provide
comments.
16.1. 16.1. Appendix 1: Page deleted To comply with Ipsen
BARC Central Protocol template which
Laboratory doesn't require central
Reference Ranges laboratory reference ranges
for ALP, AST, ALT, to be mentioned in the
GGT, Direct and protocol. Reference to this
Indirect Bilirubin, appendix is replaced by
and Total reference to the Laboratory
Bilirubin, Albumin, Manual
platelets, CPK and
serum creatinine
16.2. 16.4. Appendix 4: Page deleted To comply with Ipsen

Product carton Protocol template which
and wallet labeling doesn’t require such
information in the protocol

Page 135
Amendments to be implemented in the following documents
Informed consent form Yes No

Case report form (CRF) Yes No
Statistical analysis plan (SAP) Yes No

Page 136
LIST OF ABBREVIATIONS
Ab Antibody
ABV alcohol by volume
ADR adverse drug reaction
AE adverse event
AESI adverse event of special interest
AIH autoimmune hepatitis
ALCOA attributable, legible, contemporaneous, original and accurate
ALD alcoholic liver disease
ALP alkaline phosphatase
ALT alanine aminotransferase
AMA anti-mitochondrial antibodies
ANA antinuclear antibodies
AST aspartate aminotransferase
AT aminotransferase
AUCss Area Under Curve steady state
BP blood pressure
BUN blood urea nitrogen
C4 serum 7α-hydroxy-4-cholesten-3-one
CA cholic acid
CCl4 carbon tetrachloride
CDCA chenodeoxycholic acid
CEC clinical events committee
CFR Code of Federal Regulations
CI confidence interval
CK-18 cytokeratin-18
CKD-EPI Chronic Kidney Disease - Epidemiology Collaboration
CRF case report form
CRO clinical research organization
CSR clinical study report
CT computed tomography
CTA Clinical Trial Agreement
CTFG Clinical Trial Facilitation Group
CYP cytochrome P450
DB double blind
DCA deoxycholic acid
DDI drug-drug interaction
DEXA dual-energy X-ray absorptiometry
DILI drug-induced liver injury
DSMB data safety monitoring board
DSUR development safety update report
EAIR exposure adjusted incidence rates
EASL European Association for the Study of the Liver

Page 137
ECG electrocardiogram
ELF enhanced liver fibrosis
ELISA enzyme-linked immunosorbent assay
EOS end of study
EOT end of treatment
ePRO electronic patient-reported outcomes
FGF19 fibroblast growth factor 19
GCA glycocholic acid
GCDCA glycochenodeoxycholic acid
GCP Good Clinical Practice
GDCA glycodeoxycholic acid
GGT gamma-glutamyl transferase
GLCA glycolithocholic acid
HAV hepatitis A virus
HBsAg hepatitis B surface antigen
hCG human chorionic gonadotropin
HCV hepatitis C virus
HCV Ab hepatitis C virus Antibody
HDL-C High-density lipoprotein cholesterol
hHSC human hepatic stellate cells
HIV human immunodeficiency virus
HRQoL health-related quality of life
hsCRP high sensitivity C-reactive protein
IB Investigator’s Brochure
IEC independent ethics committee
IgG immunoglobulin G
IgM immunoglobulin M
IL interleukin
INR international normalized ratio
IRB institutional review board
IRT interactive response technology
ITT intent-to-treat
IXRS interactive voice/web response system
LCA lithocholic acid
LDL-C low-density lipoprotein cholesterol
LLN lower limit of normal
LVDB last visit double blind

Page 138
MAR missing at random

MCP monocyte chemotactic protein
MDR3 multidrug resistance protein type 3
MDRD modification of diet in renal disease
MedDRA medical dictionary for regulatory activities
MELD-Na Model for End-Stage Liver Disease-Sodium
MMRM mixed model with repeated measurement
MRI magnetic resonance imaging
NA not applicable
NASH nonalcoholic steatohepatitis
NF-κB nuclear factor kappa B
NOAEL no observed adverse effect level
NRS numeric rating scale
OATP1B3 organic anion transporting polypeptide 1B3
OCA obeticholic acid
PAI Plasminogen activator inhibitor
PBC Primary biliary cholangitis
PDGF platelet-derived growth factor
PGIC patient global impression of change
PGIS patient global impression of severity
PK pharmacokinetics
PKS pharmacokinetics set
PP per-protocol
PPAR peroxisome proliferator-activated receptor
PRO patient reported outcome
PROMIS Patient Reported Outcome Measurement Information System
PSC Primary sclerosing cholangitis
PT prothrombin time
QoL quality of life
RNA ribonucleic acid
SADR serious adverse drug reaction
SAE serious adverse event
SAP statistical analysis plan
SD standard deviation
SDV Source data verification
SMA smooth muscle antibodies
SOP standard operating procedure
SS safety set
SUSAR suspected unexpected serious adverse reaction
SV screening visit
TB total bilirubin
TC total cholesterol
TCA taurocholic acid
TCDCA taurochenodeoxycholic acid
TDCA taurodeoxycholic acid

Page 139
TE transient elastography
TG triglycerides
TGF-β transforming growth factor beta
TIPS transjugular intrahepatic portosystemic shunts
TLCA taurolithocholic acid
TNF tumor necrosis factor-alpha
UDCA ursodeoxycholic acid
UK United Kingdom
ULN upper limit of normal
Urine ACR Urine albumin to creatinine ratio
UV-LLNA UV- local lymph node assay
VLDL very low density lipoprotein
WBC white blood count
WOCBP women of childbearing potential

Page 140
CLINICAL STUDY SYNOPSIS

Sponsor: Study Drug: Protocol Number:
IPSEN PHARMA SAS Elafibranor GFT505B-319-1
Title of the study:

Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis
with Inadequate Response or Intolerance to Ursodeoxycholic Acid
Phase: 3
Indication: Primary Biliary Cholangitis (PBC)
Study Design and dose levels:
This is a phase 3 double-blind (DB), randomized, placebo-controlled study with an open-label long
term extension (LTE) evaluating the efficacy and safety of Elafibranor 80 mg once daily versus
placebo in patients with PBC and inadequate response or intolerance to ursodeoxycholic acid
(UDCA).
In the DB period, patients will be randomized in a 2:1 ratio to receive Elafibranor 80 mg or placebo,
once daily. The DB period will last until the last completed week 52 (V6) or until a maximum of
104 weeks DB period, whichever happens first, to further collect safety and clinical outcomes data
in a DB manner. After the DB period, all patients will receive Elafibranor 80 mg daily for up to 5
years during the LTE period.
When applicable, patients should continue their pre-study dose of UDCA throughout the study
participation.
Footnotes:
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the
last completed V6 (W52), whichever occurs first
c. The LTE duration is up to 5 years after end of the DB period or until the patient’s total treatment
duration is 6 years, whichever occurs first
For exploratory purposes, all patients enrolled will be invited to participate in the following
voluntary procedures, which will require separate informed consent:
- collection of biobank samples for additional research on biomarkers associated with PBC
- collection of liver biopsy samples (at baseline and week 52)

Page 141
Route of Administration: Oral

Primary Objective:
To evaluate the effect of Elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint
over 52 weeks of the treatment compared to placebo
Key Secondary Objectives:

To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP)
over 52 weeks of the treatment compared to placebo
To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 52 weeks of the treatment
compared to placebo in patients with baseline PBC Worst Itch NRS score ≥4
To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 24 weeks of the treatment
compared to placebo in patients with baseline PBC Worst Itch NRS score ≥4
Secondary Objectives:
1) To evaluate the effect of Elafibranor (80 mg/day) over 52 weeks of treatment compared to
placebo on:
c) Lipid parameters
d) Bile acids
e) Pruritus Patient Reported Outcomes (PROs)
h) Health-related Quality of Life (HRQoL)
i) Health utility
j) Markers of bone turnover and bone density
2) To determine the pharmacokinetics (PK) parameters of elafibranor and its active metabolite
GFT1007, at steady state following daily oral administration at 80 mg in PBC patients
3) To evaluate the effect of Elafibranor (80 mg/day) during the LTE period on:
Exploratory objectives (for the patients having consented to participate):

1) To constitute a biobank for discovery and validation of biomarkers associated with PBC
2) Based on histology:
a) To assist the interpretation of efficacy and safety results of elafibranor
b) To explore the correlation of fibrosis scores with non-invasive markers of fibrosis (liver
stiffness, ELF test and ProC3)

Page 142
Patient Population: Patients with PBC and inadequate response or intolerance to UDCA
Number of Randomized Patients (Approximately): 150
Number of Participating Centers (Approximately): 120
Number of Participating Countries (Approximately): 15
Study Duration per Patient: Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the
screening period, 52 to 104 weeks for the DB period, 208 to 260 weeks for the LTE period, and 4
weeks for safety follow-up).

Page 143
Inclusion Criteria:
Patients must meet all of the following inclusion criteria to be eligible for randomization into the
study:
1) Must have provided written informed consent and agree to comply with the study
protocol
2) Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)
3) PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic
criteria:
b. Positive anti-mitochondrial antibodies (AMA) titers (> 1:40 on
immunofluorescence or M2 positive by enzyme-linked immunosorbent assay
[ELISA]) or positive PBC-specific antinuclear antibodies (ANA)
4) ALP ≥ 1.67x upper limit of normal (ULN) (based on two values – see section 3.5.1)
5) Total bilirubin (TB) ≤ 2x ULN
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term
clinical outcomes or moderate disease stage, approximately 10% of randomized
patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin
< lower limit of normal [LLN]) and approximately 20% will have a TB > 0.6 x ULN
(patients at risk of progression)
6) Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS)
during each of the 7 day intervals in the 14 days prior to randomization (V1), for a
total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to
randomization (V1)
7) UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable
to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per
country standard-of-care dosing)
8) If on colchicine must be on a stable dose for ≥ 3 months prior to screening
9) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone
or sertraline) must be on a stable dose for ≥ 3 months prior to screening
10) Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior
to screening
11) Females participating in this study must be of non-child bearing potential or must
be using highly effective contraception for the full duration of the study and for 1
month after the last drug intake:
• Non-child bearing potential: cessation of menses for at least 12 months due to
ovarian failure or surgical sterilization such as bilateral oophorectomy, or
hysterectomy
• Highly effective contraception includes:
a. Combined (estrogen and progrestogen containing) hormonal
contraception associated with inhibition of ovulation, oral, intravaginal
or transdermal
b. Progestogen-only hormonal contraception associated with inhibition of
ovulation, oral, injectable or implantable
c. Intrauterine device (IUD)
d. Intrauterine hormone release system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner

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g. Sexual abstinence, if required by local IRB/IEC regulations and/or

considered adequate by National laws (the reliability of sexual
abstinence needs to be evaluated in relation to the duration of the
clinical study and the preferred and usual lifestyle of the patient)
12) For patients who consent to have liver biopsy samples collected, patients in whom
it is safe and practical to proceed with a liver biopsy, and who agree to have:
• 1 liver biopsy during the Screening Period (if no historical biopsy within 6
months before screening is available)
• 1 liver biopsy after 52 weeks of treatment
Exclusion Criteria:
Patients presenting any of the following exclusion criteria will not be eligible for randomization into
the study:
a) Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or
positive hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus
(HCV) ribonucleic acid (RNA) (tested for in case of known cured HCV infection
or positive HCV Ab at screening)
b) Primary sclerosing cholangitis (PSC)
c) Alcoholic liver disease (ALD)
d) Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if
there is suspicion and evidence of overlap AIH features, that cannot be
explained alone by insufficient response to UDCA
e) Nonalcoholic steatohepatitis (NASH)
a) History of liver transplantation, current placement on a liver transplant list,
current Model for End-Stage Liver Disease-Sodium (MELD-Na) score ≥ 12
linked to hepatic impairment
b) Patients with cirrhosis/portal hypertension complications, including known
esophageal varices, ascites, history of variceal bleeds or related interventions
(e.g., insertion of variceal bands or transjugular intrahepatic portosystemic
shunts [TIPS]), and hepatic encephalopathy, history or presence of
spontaneous bacterial peritonitis, hepatocellular carcinoma
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s
disease) or which may diminish life expectancy to < 2 years, including known
cancers
4) Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2
at screening, or patient is known to have tested positive for HIV
5) Evidence of any other unstable or untreated clinically significant immunological,
endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as
evaluated by the investigator; other clinically significant medical conditions that
are not well controlled

Page 145
6) History of alcohol abuse, defined as consumption of more than 30 g pure alcohol

per day for men, and more than 20 g pure alcohol per day for women, or other
substance abuse within 1 year prior to screening visit (SV1)
7) For female patients: known pregnancy, or has a positive serum pregnancy test, or
lactating
a) 2 months prior to screening: fibrates and glitazones
b) 3 months prior to screening: azathioprine, cyclosporine, methotrexate,
mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids
(parenteral and oral chronic administration only); potentially hepatotoxic drugs
(including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
c) 12 months prior to screening: antibodies or immunotherapy directed against
interleukins (ILs) or other cytokines or chemokines
d) For patients with previous exposure to OCA, OCA should be discontinued 3
months prior to screening
9) Patients who are currently participating in, plan to participate in, or have
participated in an investigational drug study or medical device study containing
active substance within 30 days or five half-lives, whichever is longer, prior to
screening; for patients with previous exposure to seladelpar, seladelpar should be
discontinued 3 months prior to screening.
11) SV value of alanine aminotransferase (ALT) and/or aspartate aminotransferase
(AST) > 5x ULN
12) For patients with AT or TB values >ULN at SV1, Variability of AT or TB > 40% (see
section 3.5.1)
13) SV value of albumin < 3.0 g/dL
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin
< LLN)
15) SV value of international normalized ratio (INR) > 1.3 due to altered hepatic
function
16) SV value of creatine phosphokinase CPK > 2X ULN
17) Screening serum creatinine > 1.5 mg/dL
18) Significant renal disease, including nephritic syndrome, chronic kidney disease
(defined as patients with markers of kidney failure damage or estimated
glomerular filtration rate [eGFR] < 60 mL/min/1,73 m2) calculated by modification
of diet in renal disease (MDRD)
19) Platelet count < 150 X 103/µL
20) Alfa-fetoprotein (AFP) > 20 ng/mL with 4-phase liver computed tomography (CT)
or magnetic resonance imaging (MRI) suggesting presence of liver cancer
21) Known hypersensitivity to the investigational product or to any of the formulation
excipients of the elafibranor or placebo tablet
22) Mental instability or incompetence, such that the validity of informed consent or
ability to be compliant with the study is uncertain
Randomization:

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Patients who satisfy all eligibility criteria will be randomized in a 2:1 ratio to one of the following
groups:
• Placebo
A central randomization system (Interactive Voice/Web Response system (IXRS)) will be used.
The randomization will be stratified on two factors (ALP > 3 x ULN or bilirubin > ULN and Worst
Itch score averaged - over the 14 days preceding baseline - ≥ 4) at baseline (V1). During the LTE
period, all patients will receive Elafibranor 80 mg, once daily, for up to 5 years.
To ensure inclusion of a relevant ratio of patients with substantial risk of long term clinical outcomes
or moderate disease stage, approximately 15 patients (approximately10% of the total randomized
patients) will present a TB above ULN or albumin below LLN and approximately 30 patients
(approximately 20% of the total randomized patients) will present a TB above 0.6x ULN.
Criteria for Evaluation:

Primary Endpoint:
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease
≥ 15%.
Secondary Endpoints:
Key Secondary Endpoints:
1) Response to treatment based on ALP normalization at week 52.
2) Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with
baseline PBC Worst Itch NRS score ≥4.
3) Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with
baseline PBC Worst Itch NRS score ≥4

a) ALP < 1.5x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b) ALP < 3x ULN, AST <2x ULN and TB < 1 mg/dL (Paris I)
c) ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II)
f) TB ≤ 0.6 x ULN
g) ALP ≤ 1.67x ULN and TB ≤ 1 mg/dL [1]
h) No worsening of TB defined as level of TB ≤ ULN at week 52 or no increase from baseline of
more than 0.1XULN at week 52
i) Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin and INR
4) PBC risk scores at week 52: United Kingdom (UK) PBC score [2] and GLOBE score [3]

Page 147
5) Response based on bilirubin normalization (TB ≤ ULN) at week 52

6) Response based on albumin normalization at week 52
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST,
ALT, gamma-glutamyl transferase (GGT), 5’ NT, total and conjugated bilirubin, albumin, INR and
ALP fractionated (hepatic)
8) Change from baseline to week 52 in biomarkers of inflammation as measured by high-sensitivity
C-Reactive Protein (hsCRP), fibrinogen, haptoglobin and tumor necrosis factor-alpha (TNF-)
9) Change from baseline to week 52 in immune response as measured by immunoglobulin G (IgG)
and IgM
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis
as measured by enhanced liver fibrosis (ELF)(HA, PIINP, TIMP-1), plasminogen activator
inhibitor-1 (PAI-1), transforming growth factor beta (TGF-β), cytokeratin-18 (CK-18) (M65 and
M30), Pro-C3 and liver stiffness measured by Transient Elastography (TE) (continuous)
11) Change from baseline to week 52 in lipid parameters as measured by total cholesterol (TC), low-
density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), calculated
VLDL-C and TG
12) Change from baseline to week 52 in fasting plasma glucose (FPG)
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured
by bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF-
19)
14) Proportion of patients with no worsening of pruritus from baseline through week 52 and through
week 24 as measured by the PBC Worst Itch NRS
15) Proportion of responders in PBC Worst Itch NRS according to clinically meaningful change; at
least 30% reduction; and one point, two points or three points decrease in score from baseline
through week 52 and through week 24 in patients with a baseline NRS score≥ 4
17) Change from baseline to week 52 in Patient Reported Outcome Measurement Information System
(PROMIS) Fatigue Short Form 7a
18) Change from baseline to week 52 in the Epworth Sleepiness Scale (ESS)
21) Change from baseline to week 52 in serum markers of bone turnover and in bone density (hip
and lumbar) assessed by DEXA scanning
a) MELD-Na > 14 for patients with baseline MELD-Na <12
b) Liver transplant
c) Uncontrolled ascites requiring treatment
d) Hospitalization for new onset or recurrence of any of the following:
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven/Conn score of 2 or more
e) Death
23) Safety and tolerability as assessed by

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a) Serious adverse events (SAEs), adverse events (AEs), adverse events of special interest
(AESIs), physical examination, vital signs, medical history, electrocardiogram (ECG)
c) Liver markers
24) PK assessed by GFT505 and GF1007 concentrations measurement in plasma
Additionally, apart from histology (if applicable) and PK assessments, the same endpoints as for the
DB period will be collected over the LTE period to assess the maintenance of efficacy and safety of
the treatment.
Exploratory Endpoints (related to histological assessements):

1) Change from baseline in the histological scores:
b) Bile duct loss score
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct loss score)
f) Other exploratory scores (Fibrosis according to Ishak scoring, portal inflammation, ductular
reaction, cholestasis, concentric periductal fibrosis)
2) Correlation between histological fibrosis scores and non-invasive markers of fibrosis
(liver stiffness, ELF test, proC3)
Data Safety Monitoring Board (DSMB):

An independent DSMB will be established in order to review the progress of the study and to
perform a safety data review (including review of the adjudication reports issued from the clinical
events committee (CEC) on a regular basis during the study to protect patient welfare and preserve
study integrity.
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1
hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent
from the conduct of the study. The DSMB Charter will define the membership, role, responsibilities,
rules, and tasks of the DSMB.
Clinical Event committee (CEC)
The CEC will conduct adjudication of the clinical outcomes and DILI (Drug Induced Liver Injury)
events. The CEC assessment and adjudication will occur in a blinded (during DB period) and consistent
and unbiased manner throughout the course of the study to determine whether the event meets the
protocol specified criteria. The CEC will be comprised of 3 hepatologists; all of them will be
independent from the conduct of the study.
Statistical considerations:
Determination of the sample size
• an expected response rate in the placebo group slightly higher than that in the phase 3 pivotal
study supporting the regulatory approval of OCA (10%) [4],
• an expected response rate in the elafibranor group at least similar to OCA (47%).

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The response rates from phase 3 pivotal study supporting the regulatory approval of OCA has been
estimated after imputation of missing data as non-response.
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power
to demonstrate a statistically significant between group difference of 35% (47% in elafibranor group
vs 12% in placebo group) in the response rate at week 52 of the primary efficacy endpoint with a
two-sided alpha of 0.05 and using an exact Fisher test.
In addition, assuming 1/50 (2.0%) patient in the placebo group with ALP normalization at week 52
(key secondary endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power
to detect a statistically significant between group difference of 20.0% at a two-sided 0.05 alpha level.
Assuming a pooled standard deviation (SD) of 2.3 points, 60 patients (40 Elafibranor vs 20 placebo)
with baseline PBC Worst Itch NRS score ≥4 provide at least 80% power to detect a statistically
significant between group difference of 1.8 points in mean change from baseline in PBC Worst Itch
NRS score (second key secondary endpoint) at a two-sided 0.05 alpha level. It is assumed that the
same assumptions would apply to the two key secondary endpoints for pruritus (through week 52
and through week 24).
Analysis sets:
• Screened set: all patients who sign informed consent. This set will be used to summarize
disposition.
• Intent-to-treat (ITT) set: All randomized subjects.
• Per-protocol (PP) set: All subjects from the ITT set without any major protocol deviation
affecting the primary efficacy endpoint.
• Safety set (SS): All subjects who were administered at least one dose of study drug.
• Pharmacokinetics set (PKS): All patients who were administered at least one dose of study
drug and have at least one post-dose PK sample. Moreover, patients of the PK set must
have data for time of dosing, time of sampling and amount of drug administered. Whereas
all patients are sampled in order to maintain the blind, the pharmacokinetics set applies
only to patients under elafibranor.
• Exploratory (Histological) set: All subjects from the ITT set who consent to have liver
biopsy samples collected at baseline and/or week 52.
Efficacy analysis:
DB treatment period
The primary and secondary efficacy analyses will be performed primarily on the ITT set and
secondarily on the PP set. Each efficacy endpoint will be evaluated up to week 52. For patients
who completed additional visits during the DB period, descriptive statistics will be presented up to
the end of the DB period.
• Primary efficacy endpoint
The response rates (ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%) at week 52 will be
compared between the treatment groups using the exact Cochran-Mantel-Haentzel test stratified by
the randomization strata. Patients who stopped prematurely the study treatment will be considered
as non-responders.
A sensitivity analysis to the statistical model will be performed using an exact logistic regression model
with treatment group and randomization strata as factors.
Three supplementary/sensitivity analyses will be assessed using relevant multiple imputation methods
to manage missing data. One will assume Missing At Random (MAR) and use multiple imputation to

Page 150
impute values as if subjects would follow their initial treatment. A second one will impute values using
the information from the placebo group. The third one will be a tipping point analysis to explore a
number of scenarios about the missing outcomes.
A last supplementary analysis will use outcome value at week 52 regardless of treatment
discontinuation or use of rescue therapy.
• Key secondary endpoints
The response rates (proportion of patients with ALP normalization) at week 52 will be compared
between the treatment groups using the same method as for the primary efficacy endpoint, including
sensitivity and supplementary analyses.
The change from baseline in PBC Worst Itch NRS score through week 52 will be summarized by
treatment group and will be compared using a Mixed Model with Repeated Measurement (MMRM)
with stratification factors as fixed factors. A supplementary analysis based on treatment policy will
use outcome values at week 52 regardless of treatment discontinuation or use of rescue therapy. The
same analyses will be repeated for the change from baseline in PBC Worst Itch NRS score through
week 24.
• Other secondary endpoints
The continuous endpoints will be compared between the treatment groups using the MMRM.
The categorical endpoints will be analyzed using the exact Cochran-Mantel-Haentzel test stratified by
the randomization strata. As for the primary endpoint, the subject who do not complete the study
will be considered as non-responders/treatment failures.
• Control of type I error rate
The fixed-sequence testing approach will be used to control the overall Type I error rate at a two-
sided 0.05 level. If the primary endpoint is statistically significant at a two-sided 0.05 level, the first
key secondary endpoint (ALP normalization) will be tested at the same level. If the first key secondary
endpoint is statistically significant at a two-sided 0.05 level, the second key secondary endpoint
(change in pruritus through week 52) will be tested at the same level. If the second key secondary
endpoint is statistically significant at a two-sided 0.05 level, the third key secondary endpoint (change
in pruritus through week 24) will be tested at the same level.
LTE period
All the efficacy endpoints (apart from histology – if applicable - and PK) considered for the DB period
will be summarized using descriptive statistics by DB treatment group and overall on both ITT and
PP sets.
Safety analysis:
Descriptive statistics will be provided on the SS according to the treatment groups and an overall
summary will be produced. In addition, for AEs, exposure adjusted incidence rates (EAIR) will be
compared between treatment groups presenting estimates with their confidence intervals (CIs). No
formal significance testing is planned. Safety analyses will be performed for both DB treatment period
and LTE period.
Pharmacokinetic analysis:
The PK analysis will be performed on the PKS using a PK pop model approach.
PK parameters of elafibranor and GFT1007 will be calculated at steady state and summarized by
geometric mean, SD, coefficient of variation, minimum and maximum, and median.

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Exploratory analysis (related to histological assessments):

Descriptive statistics on the histological scores and the non invasive markers of fibrosis (liver
stiffness, ELF test and ProC3) will be provided by DB treatment groups and overall in the
Exploratory (Histological) set.
For assessing the correlation between the histological fibrosis endpoints (Nakanuma and Ishak
scores) and the non invasive markers of fibrosis, the correlation coefficients and their CIs will be
estimated depending on the nature and distribution of the endpoints considered.

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Table 1: Study General Assessment Schedule

Double Blind (DB) If Safety
Study Period Screening contact in Long-term Extension (LTE)
Common DB Variable DB applicable
variable DB
Visit number SV1 SV2 SV3 V1 V2 V3 V4 V5 V6 V7 V8 LVDBj EOT DBk & LTEl LT1 LT2 to LTn EOT-LTEk
DB period:
Safety -Week 65
At max. 13 13 Safety Follow-
Follow-up: -Week 91 LT2 13 weeks
weeks after weeks up: 16 to 30
16 to 30 LTE: after LT1
Weeks -12 to -2 0 4 13 26 39 52 78 104 last V5 for after days after last
days after - 13 weeks then every 26
the last last DB study drug
last drug after LT2 weeks
patient visit intake
intake then every
26 weeks
Week 65:
456 days
LT2: 91 days
Week 91: V6 or
after LT1
638 days V8 or
LTE: 91 d LVDB +
182 days up
after LT2 91 d
to 2185
then every
182 d
+/- +/- +/- +/- +/- +/- +/-
Tolerances (Days) NA NA +/- 14 +/- 14 +/- 14 NA
7 14 14 14 14 14 14
STUDY PROCEDURESa
Medical and Disease
X
History
Inclusion/Exclusion
X X
Criteria
Physical Examination
(Height at SV1 only)
12-lead
X X X X X X X
Electrocardiogram
PRO questionnaires b
PBC Worst Itch NRS Xf
PBC Worst Itch NRS-Past
X X X X X
Week
PGIS Xg X X X X X X X X X X X

Page 153

variable DB
DB period:
Safety -Week 65
Weeks -12 to -2 0 4 13 26 39 52 78 104 last V5for after days after last
intake then every
26 weeks
Week 65:
456 days
LT2: 91 days
Week 91: V6 or
after LT1
638 days V8 or
LTE: 91 d LVDB +
182 days up
after LT2 91 d
to 2185
then every
182 d
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
PROMIS Fatigue Short
Form 7a
Transient Elastography
X X X X X X X
(TE) (Fibroscan)
Liver Biopsy (optional) Xh X
X X X X
bladder)c
Hip and lumbar DEXA
X X X
scanningd
PK X i


Page 154

variable DB
DB period:
Safety -Week 65
Weeks -12 to -2 0 4 13 26 39 52 78 104 last V5for after days after last
intake then every
26 weeks
Week 65:
456 days
LT2: 91 days
Week 91: V6 or
after LT1
638 days V8 or
LTE: 91 d LVDB +
182 days up
after LT2 91 d
to 2185
then every
182 d
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Randomization X
Treatment Assignment e
X X
Dispense Study Drug X X X X X X X X Xm
Study Drug
Footnotes:
a. Procedures/assessments should be conducted in the following order during study visits: PROs (when completed at the study center), investigator assessments, safety and laboratory
assessments, administration of study drug
b. Refer to Table 3 (Schedule of PRO Questionnaires) for details
c. At baseline, US exam can be performed before randomization after the patient has been otherwise confirmed as eligible and up to randomization visit. Ultrasound exam to be performed every
year and for any visit post baseline, US exam can be performed with a tolerance of +/ 7 days around the planned visit date.
d. Hip and lumbar DEXA scanning to be performed in all patients where the exam is accessible to sites at baseline, at V6, and then 2 years later. At baseline, the exam can be performed before
randomization after the patient has been otherwise confirmed as eligible and up to randomization visit. For exam post baseline, DEXA exam can be performed with a tolerance of +/ 7 days
around the planned visit date.
e. The switch to elafibranor treatment will happen either at V8 or at LVDB (either V7 or V8, depending on when the last patient in the study completes his/her V5) .
f. During the screening period and DB period up to week 52 (V6), the PBC Worst Itch NRS score will be collected every evening via an eDiary. The mean score of the 14 days prior to randomization
(V1) will be used for stratification. Patients must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to V1, for a total of at least 8
values in the 14 days prior to V1

Page 155
g. Patient Global Impression of Severity (PGIS) will be collected at SV1 only during the screening period
h. For patients who have consented to have liver biopsy samples collected, Liver biopsy at inclusion to be done at any SV preferably in patients already confirmed as eligible and if at all possible
2 to 4 weeks prior to randomization. LB at week 52 can be performed with a tolerance of +/- 2 weeks around the planned visit V6.
j. Until the last patient in the study completes his/her V5, patients between V6 and V8, will complete LVDB according to Table 1 General Assessment Schedule. After the last patient in the study
completes his/her V5, patients between V6 and V8, will complete LVDB at the next scheduled visit (either V7 or V8). LVDB will replace V7 or V8. The same procedures as for V8 will be
performed for LVDB (except US exam). For patients who have not yet had V6 at the time the last patient completes his/her V5, LVDB will be scheduled at the latest 13 weeks after the date
on which V5 was completed for the last patient. For those patients, LVDB will coincide with V6, and patients will complete V6 and associated procedures to facilitate transition to the open-
label elafibranor treatment phase in the long-term extension study, in a timely manner. .
k. Safety contact by phone call every alternating 26 weeks starting 13 weeks after V6 in the DB period and starting after LT2 during LTE to check AEs and concomitant medications
l. If premature study drug discontinuation during DB period, end of treatment (EOT) DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue in
the study until V8, or until the last completed V6 whichever occurs first. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled
visit. If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake
m. Drug dispensation will be done up to LT10. There will be no drug dispensation at LT11

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Table 2: Study Biological Assessment Schedule

Visit number SV1 SV2 SV3 V1 V2 V3 V4 V5 V6 V7 V8 LVDB EOT DBi LT1 LT2 to LTn EOT-LTEi
At
Safety
max.
Follow- 13 Safety
13 LT2 13
up: weeks Follow-up:
weeks weeks after
16 to 30 after 16 to 30
Weeks -12 to -2 0 4 13 26 39 52 78 104 after LT1 then
days last days after
last V5 every 26
after last DB last study
for the weeks
drug visit drug intake
last
intake
patient
LT2: 91
V6 or
days after
V8 or
LT1 then
Days 1 29 92 183 274 365 547 729 NA NA LVDB NA
every 182
+ 91
days up to
d
2185
+/- +/- +/- +/- +/- +/- +/-
Tolerances (Days) +/- 14 NA NA +/- 14 NA
7 14 14 14 14 14 14
Serum Hematology
reticulocytes/RBC
Screening Serum Chemistry a
ALP, ALT, AST, GGT, CPK, total and conjugated

bilirubin, albumin, creatinine, sodium, AFP, X
eGFR (MDRD formula & CKD-EPI formula),
MELD-Na
Screening serum hCG pregnancy test
b X
Serum Chemistry

amylase, TC, LDL-C, HDL-C, VLDL-C, TG, CPK ,
FPG, eGFR, MELD-Na

Page 157

At
Safety
max.
Follow- 13 Safety
13 LT2 13
weeks weeks after
16 to 30 after 16 to 30
last V5 every 26
for the weeks
last
intake
patient
LT2: 91
V6 or
days after
V8 or
LT1 then
Days 1 29 92 183 274 365 547 729 NA NA LVDB NA
every 182
+ 91
days up to
d
2185
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Serology
X
Serum Bile Acids and Biomarkers of

Bile Acid Synthesis
Bile acids (cholic acid (CA), glycocholic
acid (GCA), taurocholic acid (TCA),
chenodeoxycholic acid (CDCA),
glycochenodeoxycholic acid (GCDCA), X X X X X X X
taurochenodeoxycholic acid (TCDCA),
deoxycholic acid (DCA), glycodeoxycholic
acid (GDCA), taurodeoxycholic acid
(TDCA), lithocholic acid (LCA),
glycolithocholic acid (GLCA),
taurolithocholic acid (TLCA)), C4, FGF-19
Inflammation
HsCRP, fibrinogen, haptoglobin, TNF- , X X X X X X X
IL-6, ELF (HA, PIINP, TIMP-1), PAI-1,
TGF-β, CK-18 (M65 and M30), Pro-C3

Page 158

At
Safety
max.
Follow- 13 Safety
13 LT2 13
weeks weeks after
16 to 30 after 16 to 30
last V5 every 26
for the weeks
last
intake
patient
LT2: 91
V6 or
days after
V8 or
LT1 then
Days 1 29 92 183 274 365 547 729 NA NA LVDB NA
every 182
+ 91
days up to
d
2185
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Cystatin C, urine albumin to creatinine X X X X X X X X X
ratio (urine ACR) , AFP c
Immunoglobulins
X X X X X X X
IgG, IgM
Serum Bone markers d
X X X X
CTX, P1NP

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At max.
Safety
13
Follow- 13
weeks Safety Follow-up:
up: weeks LT2 13 weeks
after 16 to 30 days
Weeks -12 to -2 0 4 13 26 39 52 78 104 16 to 30 after after LT1 then
last V5 after last study
days after last DB every 26 weeks
for the drug intake
last drug visit
last
intake
patient
V6 or LT2: 91 days
V8 or after LT1 then
Days 1 29 92 183 274 365 547 729 NA NA NA
LVDB + every 182 days
91 d up to 2185
+/- +/- +/- +/- +/- +/- +/-
7 14 14 14 14 14 14
Urinalysis (dipstick) e,
Specific gravity, pH, protein, glucose,

ketones, bilirubin, urobilinogen, blood,
nitrite, leukocytes

gonadotropin (hCG) Pregnancy Test f
urinary myoglobin, serum IgG and --------------------------------------------------------------X---------------------------------------------------------------------------

SMA g ----------------
Biobank (optional) h
X X X X X X X
Footnotes:
a. Repeated measured for AST, ALT, ALP and TB to be collected (See 3.5.1)
b. Serum pregnancy test must be performed at screening in all females of childbearing potential and may be repeated within one month prior to randomization in case the
screening period lasts more than 4 weeks.
c. AFP to be evaluated at V1, V6, and then every year, as well as at LVDB, if applicable (see section 6.3.5)
d. Serum bone markers to be assessed at baseline, week 13, week 26, and week 52
e. Microscopic evaluation will be performed if dipstick urinalysis indicated presence of any significant abnormality
f. In all females of childbearing potential, urine-based β-hCG pregnancy tests at any site visits from V1. In between site visits, a home pregnancy test is to be performed
every 4 weeks, starting after V1. If the urine-based test is positive, a confirmatory serum pregnancy test must be performed at site
g. Assessment of presence of myoglobin in urine (or blood myoglobin) to be done locally only in case of clinically significant CPK elevation; assessment of IgG and SMA to
be done locally in case of suspicion of AIH
h. Additional blood samples will be collected from patients, who have given their consent, to be used to discover or validate biomarkers in PBC and related diseases
i. If premature study drug discontinuation during DB period, EOT DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue
in the study until V8. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. If premature study
drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake
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Table 3: Schedule of Patient Reported Outcomes (PROs) Questionnaires

eDiary devices will be provided to patients at SV1 for daily completion throughout the study. eDiary devices will be collected at V6.
Platform Assessment Frequency and Duration of Assessment Time of Assessment
eDiary PBC Worst Itch NRS Once daily during screeninga and the Common DB periods (up to V6) Evening
eTablet PBC Worst Itch NRS-Past Week Throughout the Variable DB and LTE periods During study visitb
eTablet PGIC Throughout the DB period (starting at V2) and LTE periods During study visitb
eTablet PGIS Throughout the screening, DB, and LTE periods During study visitb
eTablet 5-D Itch Throughout the DB and LTE periods During study visitb
eTablet PROMIS Fatigue Short Form 7a Throughout the DB and LTE periods During study visitb
eTablet ESS Throughout the DB and LTE periods During study visitb
eTablet PBC-40 Throughout the DB and LTE periods During study visitb
eTablet EQ-5D-5L Throughout the DB and LTE periods During study visitb
Footnotes:
a. The mean PBC Worst Itch NRS score of the 14 days prior to randomization (V1) will be used for stratification. Patients must have at least 4 available values for PBC Worst Itch
NRS during each of the 7 day intervals in the 14 days prior to V1, for a total of at least 8 values in the 14 days prior to V1
b. Administered on-site

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TABLE OF CONTENTS
STUDY CONTACTS ................................................................................................................ 4
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................. 5
LIST OF ABBREVIATIONS.................................................................................................... 21
CLINICAL STUDY SYNOPSIS ................................................................................................ 25
TABLE OF CONTENTS ......................................................................................................... 46
1 INTRODUCTION AND RATIONALE............................................................................... 51
1.1. BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY CHOLANGITIS ..................51
1.2. SUMMARY OF NON CLINICAL STUDIES ................................................................................53
1.2.1. Nonclinical Pharmacology .......................................................................................53
1.2.1.1. In Vitro Pharmacology ................................................................................................... 53
1.2.1.1.1. Activity on Human and Murine PPAR isoforms ............................................................... 53
1.2.1.1.2. Anti-fibrotic Activity ................................................................................................. 53
1.2.1.2. In Vivo Pharmacology .................................................................................................... 53
1.2.1.2.1. Rat Model of CCl4-induced Hepatic Fibrosis .................................................................. 53
1.2.1.3. Safety Pharmacology ..................................................................................................... 53
1.2.1.4. Absorption/distribution/metabolism/excretion Studies (ADME) ............................................... 53
1.2.1.5. Toxicology .................................................................................................................. 54
1.2.1.5.1. Mutagenicity and Genotoxicity .................................................................................... 54
1.2.1.5.2. Acute Toxicity ......................................................................................................... 54
1.2.1.5.3. Repeated Dose Toxicity Studies ................................................................................... 55
1.2.1.5.4. Phototoxicity Studies ................................................................................................. 55
1.3. CLINICAL STUDIES ..........................................................................................................55
1.3.1. Phase 1 Program ...................................................................................................55
1.3.2. Phase 2 Program ...................................................................................................55
1.4. CONCLUSION .................................................................................................................56
1.5. RATIONALE FOR STUDY POPULATION .................................................................................56
1.6. JUSTIFICATION OF THE SELECTED DOSE ..............................................................................57
2 STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 58
2.1. OBJECTIVES ...................................................................................................................58
2.1.1. DB Period.............................................................................................................58
2.1.1.1. Primary Objective ......................................................................................................... 58
2.1.1.2. Key Secondary Objectives ............................................................................................... 58
2.1.1.3. Secondary Objectives ..................................................................................................... 58
2.1.1.4. Exploratory Objectives (related to histological assessements) .................................................. 58
2.1.2. LTE Period ...........................................................................................................59
2.2. ENDPOINTS ....................................................................................................................59
2.2.1. DB Period.............................................................................................................59
2.2.1.1. Primary Endpoint .......................................................................................................... 59
2.2.1.2. Secondary Endpoints...................................................................................................... 59
2.2.1.3. Exploratory Endpoints .................................................................................................... 60
2.2.2. LTE Period ...........................................................................................................61
3 STUDY DESIGN ............................................................................................................ 62
3.1. NUMBER OF PATIENTS .....................................................................................................64
3.2. TREATMENT GROUPS .......................................................................................................64
3.3. DOSE ADJUSTMENT CRITERIA ...........................................................................................64
3.4. DURATION OF STUDY PARTICIPATION .................................................................................64
3.5. STUDY PERIODS AND SCHEDULE OF ASSESSMENTS ...............................................................64
3.5.1. Screening Period ....................................................................................................65
3.5.2. DB period (Week 0 to max Week 104) ........................................................................65
3.5.3. LT period ..............................................................................................................66
3.5.4. Safety Follow up ....................................................................................................67
3.5.5. Optional Visits .......................................................................................................67

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3.5.5.1. Retesting and/or additional screening visits ......................................................................... 67

3.5.5.2. Unscheduled visits ......................................................................................................... 67
3.5.6. Off-site study procedures in case of crisis situation .......................................................67
4 PATIENT SELECTION .................................................................................................. 68
4.1 INCLUSION CRITERIA .......................................................................................................68
4.2 EXCLUSION CRITERIA ......................................................................................................69
5 STUDY PROCEDURES .................................................................................................. 71
5.1. SCREEN FAILURES...........................................................................................................71
5.2. PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ............................71
5.2.1. Permanent discontinuation of study drug/withdrawal from study .....................................71
5.2.2. Patients Lost to Follow-up .......................................................................................72
5.2.3. Replacement ..........................................................................................................72
5.2.4. Premature Discontinuation of the Study ......................................................................72
6 ASSESSMENTS ............................................................................................................. 73
6.1. EFFICACY AND SAFETY ASSESSMENT .................................................................................73
6.1.1. Biological assessment .............................................................................................73
6.1.1.1. Laboratory Assessments ................................................................................................. 73
6.1.1.2. Urinary Pregnancy Tests ................................................................................................. 74
6.1.1.3. Serology...................................................................................................................... 74
6.1.1.4. Other Parameters ........................................................................................................... 74
6.1.2. Constitution of biobank ...........................................................................................74
6.1.3. Bone density by DEXA scanning................................................................................74
6.1.4. Histological assessment ...........................................................................................74
6.1.4.1. Recommendations related to liver biopsy ............................................................................ 75
6.1.4.2. Liver biopsy reading ...................................................................................................... 75
6.1.5. Pharmacokinetic assessment ....................................................................................75
6.1.5.1. Pharmacokinetic blood sampling timepoints ........................................................................ 76
6.1.5.2. Pharmacokinetic blood handling procedures ........................................................................ 76
6.1.5.3. Bioanalytical analysis ..................................................................................................... 76
6.1.5.4. Description of pharmacokinetic evaluation parameters ........................................................... 76
6.1.6. Liver stiffness by transient elastography (FibroScan®)...................................................77
6.1.7. Patient Reported Outcomes Questionnaires .................................................................77
6.2. OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .........................................78
6.2.1. Physical Examination..............................................................................................78
6.2.2. Vital Signs and Weight ............................................................................................78
6.2.3. 12 Lead ECG.........................................................................................................79
6.3. IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES .......79
6.3.1. Creatine Phosphokinase ..........................................................................................79
6.3.2. Liver Function Monitoring .......................................................................................79
6.3.2.1. Treatment discontinuation rule for elevated Aminotransferase (AT) values regardless of baseline
values 80
6.3.2.2. Treatment discontinuation rules for elevated Aminotransferase (AT) values according to baseline
values 80
6.3.2.2.1. Monitoring of patients with normal baseline AT values ..................................................... 80
6.3.2.2.2. Monitoring of patients with abnormal baseline AT values .................................................. 81
6.3.2.2.3. Monitoring of patients with abnormal TB baseline values .................................................. 81
6.3.3. Auto-immune hepatitis monitoring .............................................................................81
6.3.4. Acute Pancreatitis Monitoring ..................................................................................82
6.3.4.1. Treatment discontinuation rule for suspected acute pancreatitis................................................ 82
6.3.5. Monitoring of hepatocellular and bladder cancer .........................................................82
6.3.5.1. Liver monitoring ........................................................................................................... 82
6.3.5.2. Bladder & urinary tract monitoring .................................................................................... 82
6.3.6. Safety Review ........................................................................................................82
6.3.7. Clinical event committee ..........................................................................................82
6.4. GUIDANCE FOR INVESTIGATORS ........................................................................................83

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6.4.1. Summary of safety data ...........................................................................................83

6.4.2. Benefit/risk assessment ............................................................................................84
7 TREATMENTS .............................................................................................................. 85
7.1. DESCRIPTION OF STUDY MEDICATIONS ...............................................................................85
7.2. PACKAGING AND LABELING .............................................................................................85
7.2.1. Packaging .............................................................................................................85
7.2.2. Labeling ...............................................................................................................85
7.3. DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ............................................85
7.4. METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .......................................................86
7.5. STORAGE CONDITIONS .....................................................................................................86
7.6. DISPENSING OF TREATMENT .............................................................................................86
7.7. TREATMENT REPLACEMENT ..............................................................................................86
7.8. PROCEDURE FOR BLINDING ..............................................................................................86
7.9. PROCEDURE FOR UNBLINDING...........................................................................................87
7.10. STUDY DRUG COMPLIANCE ..............................................................................................87
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION ..............................................87
7.12. OTHER MEDICATION .......................................................................................................88
7.12.1. Handling of Concomitant Medication .........................................................................88
7.12.2. Non-permitted Medication .......................................................................................88
7.12.3. Permitted Medication Under Conditions .....................................................................88
7.12.4. Permitted Medication ..............................................................................................88
8 ADVERSE EVENT AND TOXICITY MANAGEMENT ....................................................... 89
8.1. DEFINITIONS ..................................................................................................................89
8.1.1. Adverse Events (AEs) ..............................................................................................89
8.1.2. Adverse events of special interest (AESIs) ...................................................................90
8.1.3. Serious Adverse Event .............................................................................................90
8.1.4. Clarification on Serious Adverse Events .....................................................................91
8.1.5. Adverse Drug Reaction ............................................................................................91
8.1.6. Unexpected Adverse Event .......................................................................................91
8.2. ASSESSMENTS ................................................................................................................92
8.2.1. Intensity Assessment ...............................................................................................92
8.2.2. Relation to the Study Treatment ................................................................................92
8.2.3. Action Taken and Outcome ......................................................................................92
8.3. REPORTING ...................................................................................................................93
8.3.1. Reporting an AE ....................................................................................................93
8.3.2. Reporting a SAE or an AESI .....................................................................................93
8.3.3. Follow-up .............................................................................................................94
8.4. POST STUDY REPORTING REQUIREMENTS ............................................................................94
8.5. CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES OR SAES94
8.6. SPECIAL SITUATION REPORTS ............................................................................................95
8.6.1. Pregnancy ............................................................................................................95
8.6.2. Medication Error ...................................................................................................95
8.6.3. Misuse .................................................................................................................95
8.6.4. Overdose ..............................................................................................................95
8.6.5. Abuse ...................................................................................................................96
9 STATISTICAL METHODS AND DATA ANALYSIS ........................................................... 97
9.1. ESTIMANDS CONSIDERATIONS ...........................................................................................97
9.2. RANDOMIZATION AND TREATMENT ASSIGNMENT .................................................................99
9.3. ENDPOINTS ....................................................................................................................99
9.3.1. Primary Endpoint ...................................................................................................99
9.3.2. Secondary Endpoints ..............................................................................................99
9.3.3. Exploratory Endpoints (related to histological assessments) ......................................... 101
9.4. ANALYSIS SETS ............................................................................................................ 101
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9.5. ANALYSIS OF PRIMARY ENDPOINT ................................................................................... 102

9.6. OTHER STATISTICAL ANALYSIS ....................................................................................... 103
9.6.1. Key secondary endpoints ....................................................................................... 103
9.6.2. Other secondary endpoints ..................................................................................... 103
9.6.3. Subgroup analyses ................................................................................................ 104
9.7. STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 104
9.8. SAMPLE SIZE CALCULATION ........................................................................................... 105
9.8.1. Reduction in ALP and TB ....................................................................................... 105
9.8.2. Normalization in ALP ........................................................................................... 105
9.9. SAFETY ANALYSIS ........................................................................................................ 105
9.10. EXPLORATORY ANALYSIS (RELATED TO HISTOLOGICAL ASSESSEMENTS) .................................. 106
10 DATA HANDLING AND RECORD KEEPING................................................................. 107
10.1. DATA PROTECTION ........................................................................................................ 107
10.2. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................. 107
10.3. RETENTION OF RECORDS................................................................................................ 108
11 QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 109
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................... 109
11.2. ETHICAL PRINCIPLES ..................................................................................................... 109
11.3. QUALITY ASSURANCE.................................................................................................... 110
12 ETHICS AND REGULATORY ...................................................................................... 111
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ....................................... 111
12.2. COMPETENT AUTHORITY ................................................................................................ 111
12.3. PATIENT INFORMATION AND CONSENT.............................................................................. 111
12.4. PATIENT CONFIDENTIALITY ............................................................................................. 112
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 113
13 FINANCING AND INSURANCE .................................................................................... 114
13.1. FINANCIAL ISSUES ........................................................................................................ 114
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 114
14 STUDY RESULTS AND PUBLICATION POLICY ........................................................... 115
14.1. STUDY REPORT ............................................................................................................ 115
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND PUBLICATION.. 115
15 REFERENCES LIST .................................................................................................... 117
16 APPENDICES:............................................................................................................. 119
16.1. APPENDIX 1: ALCOHOL COMPARISON TABLE ...................................................................... 119
16.2. APPENDIX 2: PERMITTED/NON-PERMITTED MEDICATION ...................................................... 120
16.3. APPENDIX 3: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES: .................................. 122
16.3.1. PBC-40 .............................................................................................................. 122
16.3.2. Epworth Sleepiness Scale (ESS) .............................................................................. 126
16.3.3. 5-D Itch Scale ...................................................................................................... 127
16.3.4. PROMIS Fatigue Short Form 7a ............................................................................. 128
16.3.5. The Patient Global Impression of Change (PGIC) ...................................................... 129
16.3.6. The Patient Global Impression of Severity (PGIS) ...................................................... 130
16.3.7. PBC Worst Itch NRS ............................................................................................. 131
16.3.8. EuroQoL EQ-5D-5L ............................................................................................. 132

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LIST OF TABLES
Table 1: Study General Assessment Schedule ................................................................................................ 37
Table 2: Study Biological Assessment Schedule .............................................................................................. 41
Table 3: Schedule of Patient Reported Outcomes (PROs) Questionnaires .......................................................... 45
LIST OF FIGURES
Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN) ........................................................... 57
LIST OF SCHEMA
Schema 1: GFT505B-319-1 Study Design ...................................................................................................... 25
Schema 2: GFT505B-319-1 Study Design ...................................................................................................... 63

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1 INTRODUCTION AND RATIONALE
Elafibranor has been developed by Genfit for the treatment of PBC. In December 2021, Genfit and IPSEN
(“the partner”) entered into an exclusive licensing agreement for elafibranor, which gives the partner,
the exclusive worldwide license for the future development of elafibranor in PBC, with the exception of
China, Taiwan, Hong-Kong and Macau. The transfer of sponsorship from Genfit to IPSEN is anticipated
to take place within approximately 30 days of top line results for the double-blind portion of the study
(part A).
1.1. BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY

CHOLANGITIS
PBC is a rare, chronic, progressive liver disease of autoimmune etiology, characterized by injury of the
intrahepatic bile ducts that, in untreated patients or non-responders to existing therapies, may progress
to hepatic fibrosis, cirrhosis, hepatic decompensation, and death unless they receive a liver transplant
[5, 6]. PBC disproportionately affects women versus men (approximately 10:1) and is typically
diagnosed in patients between 40 years to 60 years of age. The incidence and prevalence rates for PBC
in Europe, North America, Asia, and Australia are reported as ranging from 0.33 to 5.8 per 100,000
inhabitants and 1.91 to 40.2 per 100,000 inhabitants, respectively [7]. Kim et al estimated that there
were 47,000 prevalent cases of PBC in the United States white population and that approximately 3500
new cases are diagnosed each year [8]. Over 60% of the newly diagnosed cases are asymptomatic.
The majority of asymptomatic patients become symptomatic within 10 years and the estimates for
developing symptoms at 5 and 20 years are 50% and 95%, respectively [6]. Patients with PBC progress
at varying rates, some experiencing liver decompensation over a period of several years while others
over decades [9, 10]. PBC is one of the leading indications for liver transplantation. Despite its rarity,
PBC remains an important cause of morbidity in the Western world. PBC has also been identified as an
important risk factor for hepatocellular carcinoma [11].
PBC is characterized by cholestasis caused by autoimmune destruction of biliary ductules with

progressive impairment of bile flow in the liver. This results in increased hepatocellular bile acid
concentrations which are toxic to the liver. Such hepatocellular injury is associated with a local
inflammatory response resulting early on in an abnormal elevation of serum ALP levels, a hallmark of
the disease. Antimitochondrial antibody and IgM are specific immunological hallmarks of PBC, and
antimitochondrial antibody is a diagnostic marker of the disease in approximately 90% of patients [12].
Liver biopsy, while confirmatory, is no longer the standard of care.
ALP is also routinely used to clinically monitor the disease and serves as a leading indicator of disease
progression. ALP increases with disease progression as bilirubin starts to decline in more advanced
disease (as the excretory function starts to decline), and both have been shown to be highly predictive
of long-term clinical outcomes (e.g., transplant-free survival) [13-15]. Two large clinical PBC databases,
the PBC Study Group (> 6100 patients) and the UK-PBC Research Cohort (> 5900 patients) have
confirmed a near log-linear correlation of both elevated ALP and bilirubin after 1 year of follow up with
long-term liver transplant-free survival [15].
As PBC advances, the transaminases ALT and AST may also be elevated due to hepatocellular damage
secondary to cholestasis. While GGT lacks specificity, elevation of this enzyme in the presence of
elevated ALP is confirmatory of a cholestatic condition such as PBC [16].

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The most common symptoms of PBC are fatigue and pruritus [17]. The mechanisms underlying these
symptoms are not well elucidated and neither correlates with disease stage or clinical outcomes.
Current Treatment Options

UDCA, an epimer of the primary human bile acid UDCA, was the only medicine currently approved to
treat PBC until May 2016. UDCA has been shown to improve ALP and bilirubin, and to delay histological
progression, thereby increasing liver transplant-free survival [18]. Accordingly, UDCA treatment has
been recommended as first line therapy for patients with PBC in the treatment guidelines of the
American Association for the Study of Liver Diseases [19] and the European Association for the Study
of the Liver (EASL) [20]. While UDCA has had a marked impact on clinical outcomes in PBC, a large
proportion of patients have an inadequate response. It is estimated [11] that up to 40% of UDCA-
treated patients have a suboptimal response to UDCA. Lammers et al. found that ALP remains elevated
in up to 70% of patients who are currently being treated or are intolerant to UDCA [15]. Such patients
remain at risk of disease progression and longer term adverse clinical outcomes.
Ocaliva (OCA), at doses from 5 to 10 mg, was approved as a second line therapy by the Food and Drug
Administration (FDA) in May 2016 under the accelerated approval regulations based on achieving a
primary endpoint. The primary endpoint was defined as a composite endpoint of an ALP level of less
than 1.67 times the ULN range, with a reduction of at least 15% from baseline, and a TB level at or
below the ULN range at 12 months. On a background of standard of care, the rate of the primary
endpoint was higher in the 5-10 mg group (46%) and in the 10 mg group (47%) compared to the
placebo group at month 12 (p<0.001 for both comparisons). Pruritus was the most common AE across
all groups, with a higher incidence reported in the 5-10 mg group (56%) and the 10 mg group (68%)
than in the placebo group (38%) [4].
A 24-month, DB, placebo-controlled, phase 3 study of bezafibrate, a pan-peroxisome proliferator-
activated receptor (PPAR) agonist, demonstrated efficacy in patients who had an inadequate response
to UDCA. In this study the primary outcome was the percentage of patients with a complete biochemical
response, which was defined as normal serum levels of ALP, AST, ALT, total bilirumin and albumin, as
well as a normal prothrombin index at 24 months. The result was the primary outcome occurred in 31%
of the patients assigned to bezafibrate and in 0% assigned to placebo (p<0.001). Results regarding
changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and ELF
score, were consistent with the results of the primary outcome [21].
Rationale for Evaluation of Elafibranor in PBC

Elafibranor is being developed by Ipsen for the treatment of PBC, based on its pharmacological
properties as a PPAR/δ agonist. Activation of PPAR receptors leads to a decrease in bile acid synthesis,
increase in bile acid uptake, and increased detoxification of bile acids through the increased uptake in
micelles. PPAR and PPARδ receptor activation also has anti-inflammatory effects by acting on different
pathways of inflammation (nuclear factor kappa B [NF-κB] and B-cell lymphoma 6 [BCL6] pathways).
Ligand-activated PPAR contributes to a range of actions, including cholesterol and bile acid
homeostasis. PPAR primarily downregulates bile acid synthesis. PPAR also interferes with pro-
inflammatory transcription factor pathways leading to the hypothesis that fibrates may exert their
beneficial effect on cholestatic liver function by also regulating anti-inflammatory pathways. Fenofibrate
may also ameliorate cholestatic liver disease through its transcriptional activation of multidrug resistance
protein type 3 (MDR3) [22].

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1.2. SUMMARY OF NON CLINICAL STUDIES
1.2.1. Nonclinical Pharmacology
1.2.1.1. In Vitro Pharmacology
1.2.1.1.1. Activity on Human and Murine PPAR isoforms
In Gal4- PPAR reporter gene assays, elafibranor (GFT505) and its main metabolite GFT1007 are PPAR
agonists with a similar selectivity profile on both the human and murine PPAR isoforms. Both (GFT505)
and GFT1007 activate the PPAR subtype with a 5-fold selectivity over PPARδ.
In human hepatocytes, elafibranor and GFT1007 induce the expression of mitochondrial genes
(pyruvate dehydrogenase kinase [PDK]4, carnitine palmitoyltransferase [CPT]1a) but not peroxisomal
PPAR target genes (acylCoA-oxidase [ACOX]1, enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase
[EHHADH]), likely via PPARδ activation.
In stimulated human monocytes, elafibranor decreases the secretion of inflammatory markers
(monocyte chemotactic protein (MCP)-1 and tumor necrosis factor [TNF-]) through combined PPAR
and PPARδ activation and parallel PPAR-independent mechanisms.
1.2.1.1.2. Anti-fibrotic Activity
Anti-fibrotic properties of (GFT505) were demonstrated in primary human hepatic stellate cells (hHSC).
(GFT505) inhibits hHSC proliferation induced by either fetal calf serum or platelet-derived growth factor
(PDGF)-BB. Moreover, (GFT505) specifically inhibited PDGF-BB-induced PDGF receptor β
phosphorylation in vitro. (GFT505) also inhibited hHSC activation (gene expression of fibrosis markers:
α-smooth muscle actin [αSMA], collagen [Col] 1α1 and Col4α1) induced by TGF β1.
1.2.1.2. In Vivo Pharmacology
1.2.1.2.1. Rat Model of CCl4-induced Hepatic Fibrosis
The liver-protective effects of (GFT505) have also been demonstrated in a rat model of carbon
tetrachloride (CCl4)-induced hepatic fibrosis. When administered concomitantly with CCl4, (GFT505)
totally prevented the development of liver fibrosis evaluated by macroscopic and microscopic
examination. In addition, (GFT505) significantly reduced CCl4-induced macro- and micro- steatosis and
liver inflammation. (GFT505) treatment prevented the CCl4-induced increase in liver expression of genes
involved in the inflammatory ( [IL]-1β, RANTES) and pro-fibrotic (collagens [Col1α1, Col1α2], TGFβ1,
TIMP-2, αSMA) response.
1.2.1.3. Safety Pharmacology
Any potential effects on the cardiovascular, respiratory, and central nervous system have been assessed
and no safety issue was identified.
1.2.1.4. Absorption/distribution/metabolism/excretion Studies (ADME)
In animal studies, elafibranor (GFT505) was well and rapidly absorbed although absolute bioavailability
was moderate (about 20% to 40%). (GFT505) is extensively metabolized and the activity is mainly
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carried by the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure
for both (GFT505) and GFT1007 linearly increase with the dose after single or repeated administrations.
(GFT505) and its metabolites are rapidly cleared from the plasma and they are totally excreted by both
fecal and renal route within 48 hours. In the rat, (GFT505) and/or its metabolites are rapidly excreted
into the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of (GFT505)
and/or GFT1007. The distribution study in the rat supports the liver targeting of (GFT505) and/or its
metabolites.
In vitro, (GFT505) does not inhibit cytochrome p450 (CYP) 1A2, CYP3A4, and CYP2D6, with moderate
inhibition of CYP2C9, and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not
produce any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of
CYP2C8 and CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam
as substrate. Thus, the risk of drug-drug interaction (DDI) due to an inhibition of the main cytochromes
involved in drug metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has
been assessed through a clinical study (GFT505-112-8) designed to evaluate potential PK interaction of
(GFT505) 120 mg administered for 14 days alone or with a single administration of warfarin. This study
demonstrated that (GFT505) administration did not affect the PK profile of warfarin (R-warfarin and
S-warfarin). A protein binding study showed that (GFT505) and GFT1007 were highly bound to human
serum albumin. The risk of DDI due to albumin binding should be limited since this binding is not
saturable.
In vitro studies have been performed to determine whether GFT505 and its principal metabolite
GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the potential
for DDI. Based on the results of the OATP1B3 (organic anion transporting polypeptide 1B3) transporter
inhibition assay, GFT505 has recently been assessed in a follow-up clinical DDI study with the
OATP1B3-sensitive substrate, atorvastatin.
For the other drug transporters studied, the interaction observed does not require follow-up studies
based on current regulatory guidance.
The metabolic stability and metabolism pathways of GFT505 have been studied on liver microsomes
and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no evidence of the
formation of unique human metabolites or metabolites formed at disproportionately higher levels in
human hepatocytes than in any other species.
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog,
minipig, and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although
absolute bioavailability was moderate (about 20% to 40%).
1.2.1.5. Toxicology
1.2.1.5.1. Mutagenicity and Genotoxicity
The toxicology program performed according to the International Conference on Harmonisation (ICH)
guidelines demonstrates that (GFT505) has no genotoxic or mutagenicity potential.
1.2.1.5.2. Acute Toxicity
According to acute toxicity study results, it can be concluded that (GFT505) is extremely safe when
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the
dose of 1000 mg/kg.

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1.2.1.5.3. Repeated Dose Toxicity Studies
The safety of (GFT505) has been assessed in multiple preclinical toxicology studies with repeated-dose
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year
repeated-dose carcinogenicity studies in mice and rats have been completed.
The only consistent safety concern raised by these studies is the expected PPAR-associated
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats).
However, it is well known that, compared to nonhuman primates and humans, rodents are highly
sensitive to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus,
available information on this class of drug which includes marketed fibrates together with the lack of
any liver side effects in monkeys treated with high doses of (GFT505) for 1 year support the non-
relevance to human [23]. Overall, these studies did not reveal any other safety issues up to the highest
doses tested. Notably, (GFT505) did not have any of the known PPAR-related concerns such as excess
weight gain, hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma.
Importantly, the non-clinical studies have demonstrated a reduced plasma ALP activity in monkeys
treated for 3 or 12 months with (GFT505).
1.2.1.5.4. Phototoxicity Studies
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 Neutral Red Uptake (NRU)
phototoxicity test and the UV-Local Lymph Node Assay (UV-LLNA) test in mice. GFT505, but not its
major metabolite GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was
performed in mice with oral dosing for 3 days at up to 800 mg/kg/day (GFT505). Although a very
conservative No Observed Adverse Effect Level (NOAEL) was set at 400 mg/kg/day based on isolated
findings at the highest dose, it is considered that data are more in favor of an absence of phototoxic
effect, given the tissue distribution of GFT505, and absence of phototoxicity signal in the clinical studies.
Additional information can be found in the Investigator’s Brochure (IB).
1.3. CLINICAL STUDIES
A Phase 1 program to assess the safety and the tolerability, as well as the PK profile, of elafibranor
currently comprises 13 completed and 4 ongoing clinical studies. As of 31 July 2022 (the date of the
most recent Development Safety Update Reports (DSUR) update (Development Safety Update Reports,
2019), 755 volunteers had been randomized in these studies, including 650 healthy and lean subjects,
60 overweight or obese but otherwise healthy subjects, 12 subjects with type 2 diabetes, 13 with renal
impairment (ESRD) and 20 with hepatic impairment (Child-Pugh class A, B or C). Elafibranor daily doses
ranged between 5 mg and 360 mg, with a maximum treatment duration of 14 to 16 days.

One phase 2 study with elafibranor was completed in PBC patients. Study GFT-505B-216-1 was a 12-
week, DB, randomized, parallel group, placebo-controlled, proof-of-concept study in PBC. A total of 45
adult patients were randomized to one of 3 treatments arms in a 1:1:1 ratio: elafibranor 80 mg,
elafibranor 120 mg, or placebo. In both elafibranor-treated groups, a significant decrease in mean ALP
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was achieved: -48% for the 80 mg dose and -41% for 120 mg dose, compared to a mean 3% increase
in ALP for subjects receiving placebo. This resulted in a highly significant treatment effect versus
placebo: -52% (95% CI: [-62.5;-41.5]) (p<0.001) for 80 mg and -43.9% (95% CI: [-55.7;-32.1]) (p<
0.001) for 120 mg elafibranor. There was no apparent difference in the magnitude of improvement
between the 2 elafibranor doses suggesting a plateau of the dose exposure-response. The effect was
observed from the first visit following baseline (Visit 2 [Week 2]) and was maintained and reinforced up
to the end of the active treatment period. A composite endpoint composed of ALP <1.67xULN and ALP
decrease >15% and TB <ULN, was achieved in 66.7% subjects at 80 mg and 78.6% of subjects at the
120 mg elafibranor dose (p= 0.002 and p< 0.001, respectively) as compared to 6.7% subjects on
placebo.

1.4. CONCLUSION
In summary, elafibranor may provide an effective therapeutic option for patients with PBC who are
inadequately responding to or unable to tolerate UDCA. As a result, elafibranor will be further evaluated
in this larger Phase 3 study with an open-label extension.
1.5. RATIONALE FOR STUDY POPULATION
Partial or suboptimal responders constitute up to 40% of UDCA-treated PBC patients [11]. This group
of patients along with patients intolerant to UCDA treatment will be randomized in this study.
This study targets patients with mild and moderately advanced disease and excludes patients with
advanced cirrhosis. ALP reduction is not a good predictive marker of long term benefit in the advanced
disease population [15]. Patients with moderately advanced disease are identified per Rotterdam Criteria
(TB > ULN or Albumin < LLN), liver stiffness measurement by Fibroscan [EASL Clinical Practice
Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis –2021 update, J
Hep 2021], or histology among those who undergo liver biopsy. Patients with cirrhosis will be identified
by elastography [24] or histology among those who undergo liver biopsy.
In addition, a recent publication has shown that in UDCA-treated and untreated patients with TB levels
≤1×ULN at baseline or 1 year, the TB threshold with the highest ability to predict LT or death at 1
year was 0.6×ULN. The risk for LT or death was stable below TB levels of 0.6×ULN and yet increased
beyond this threshold [25] and Figure 1.
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes or
moderate disease stage, approximately 10% of randomized patients will be moderately advanced per
Rotterdam Criteria. Patients will also be categorized as early or advanced disease stage based on liver
stiffness measurement at the baseline Fibroscan examination (LSM<=10 kPa or LSM >10 kPa), and
based on histology (absent or mild fibrosis vs. presence of bridging fibrosis or cirrhosis) among those
who undergo liver biopsy [EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver
disease severity and prognosis –2021 update, J Hep 2021]. Additionally, approximately 20% will have
a TB > 0.6 x ULN (patients at risk of progression).

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Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN)
1.6. JUSTIFICATION OF THE SELECTED DOSE
There was no apparent difference in the magnitude of improvement of cholestatic paramaters (ALP,
GGT and 5’ NT) between the two elafibranor doses (80 and 120 mg) in Study GFT-505B-216-1
suggesting a plateau of the dose-exposure-response. In addition, both doses were generally well-
tolerated. As a result, elafibranor 80 mg was selected for this study.

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2 STUDY OBJECTIVES AND ENDPOINTS
2.1. OBJECTIVES
2.1.1. DB Period
2.1.1.1. Primary Objective
To evaluate the effect of elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint
over 52 weeks of treatment compared to placebo.
2.1.1.2. Key Secondary Objectives
To evaluate the effect of elafibranor (80mg/day) over 52 weeks of treatment compared to placebo on:
- Normalization of ALP
- Pruritus based on change from baseline through week 52 in PBC Worst Itch NRS in patients
with baseline PBC Worst Itch NRS score ≥4
- Pruritus based on change from baseline through week 24 in PBC Worst Itch NRS in patients
with baseline PBC Worst Itch NRS score ≥4
2.1.1.3. Secondary Objectives
To evaluate the effect of elafibranor (80 mg/day) over 52 weeks of treatment compared to placebo on:
c) Lipid parameters
d) Bile acids
e) Pruritus Patient Reported Outcomes (PROs)
h) HRQoL
i) Health utility
j) Bone markers and bone density
To determine the PK parameters of elafibranor and its active metabolite GFT1007, at steady state
following daily oral administration at 80 mg) in PBC patients.Of note, and in order to further collect
safety and clinical outcomes data in a DB manner, placebo controlled treatment will be maintained until
the last completed week 52 visitor until a maximum of 104 weeks, whichever occurs first. When this
time point is reached, every patient will be switched to open-label Elafibranor 80 mg.
2.1.1.4. Exploratory Objectives (related to histological assessements)
For the patients having consented to participate:

1) To constitute a biobank for discovery and validation of biomarkers associated with PBC
2) Based on histology:
a) To assist the interpretation of efficacy and safety results of elafibranor
b) To explore the correlation of fibrosis scores with non-invasive markers of fibrosis (liver
stiffness, ELF test and ProC3)

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2.1.2. LTE Period
To evaluate the effect of elafibranor (80 mg/day) during the LTE period on:
2.2. ENDPOINTS
2.2.1. DB Period
2.2.1.1. Primary Endpoint
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥
15%.
2.2.1.2. Secondary Endpoints

1) Response to treatment based on ALP normalization at week 52.
b) ALP < 3 x ULN, AST <2x ULN and TB < 1 mg/dL (Paris I)
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II)
f) TB ≤ 0.6 x ULN
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline of
more than 0.1XULN at week 52
i) Complete biochemical response defined as normal ALP; TB; AST; ALT; albumin; and INR
4) PBC risk scores at week 52: UK PBC score [2] and GLOBE score [3]
ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
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8) Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP,

fibrinogen, haptoglobin and TNF-
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis as
measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver
stiffness measured by TE (continuous)
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated
VLDL-C and triglycerides (TG)
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured
by bile acids, C4 and FGF-19
through week 52 and through week 24 in patients with a baseline NRS score ≥ 4
15) Proportion of patients with no worsening of pruritus from baseline through week 52 and through
week 24 as measured by the PBC Worst Itch NRS
21) Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density
(hip and lumbar) assessed by DEXA scanning
a) MELD-Na >14 for patients with baseline MELD-Na <12
b) Liver transplant
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven score of 2 or more
e) Death
c) Liver markers
2.2.1.3. Exploratory Endpoints
Exploratory endpoints associated with Histological assessment (for patients who have consented to
having liver biopsy)
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b) Bile duct loss scores
reaction, cholestasis, concentric periductal fibrosis)
2) Correlation of Fibrosis scores with non-invasive markers of fibrosis (Liver stiffness, ELF test and
ProC3)
2.2.2. LTE Period
Additionally, apart from histology (if applicable) and PK assessments, the same endpoints as for the DB
period will be collected over the LTE period to assess the maintenance of efficacy and safety of the
treatment. The endpoints will be described using descriptive statistics by DB treatment group and overall
on both ITT and PP sets.

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3 STUDY DESIGN
This is a phase 3, randomized, DB, placebo-controlled, parallel group study followed by an open-label
LTE that evaluates the efficacy and safety of elafibranor in patients with PBC and inadequate response
or intolerance to UDCA.
In the DB period, approximately 150 patients will be randomized in a 2:1 ratio to receive elafibranor 80
mg or placebo, once daily, for maximum 104 weeks or until the last completed week 52 visit (V6),
whichever happens first. Placebo control will be maintained after week 52 notably to further collect
safety and clinical outcome data in a DB manner. At the end of the DB period, all patients will receive
elafibranor 80 mg, once daily, for up to 5 years or until the patient’s total treatment duration is 6 years,
whichever occurs first. When applicable, patients should continue their pre-study dose of UDCA
throughout the study participation.

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Footnotes:
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last completed V6 (W52), whichever occurs first
c. The LTE duration is 5 years after end of the DB period or until the patient’s total treatment duration is 6 years, whichever occurs first

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3.1. NUMBER OF PATIENTS
The study is projected to randomize approximately 150 patients, including approximately 15 patients
(10% of the total randomized patients) with a TB above ULN or albumin below LLN and approximately
30 patients (20% of the total randomized patients) with a TB above 0.6 x ULN.
3.2. TREATMENT GROUPS
The treatment groups will be allocated, in a 2:1 ratio, to receive either elafibranor 80 mg or placebo
during the DB period.
3.3. DOSE ADJUSTMENT CRITERIA
N/A
3.4. DURATION OF STUDY PARTICIPATION
Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the screening period, 52 to 104 weeks
for the DB period, 208 to 260 weeks for the LTE period, and 4 weeks for safety follow-up). The full
treatment period for each patient will last 312 weeks, with a variable number of weeks in the DB Period
and in the LTE Period depending the time point of the visit V8 or LVDB completed.
3.5. STUDY PERIODS AND SCHEDULE OF ASSESSMENTS
The study will be comprised of 3 periods: a screening period, a DB period and a LTE period.
A schedule of assessments by visit is presented in Table 1 and Table 2.

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3.5.1. Screening Period
As a first step, patients will be asked if they agree to participate in the study and sign the Informed
Consent Form (ICF). Each patient who has signed the ICF will perform procedures listed on Table 1 and
Table 2. Screening visits (SV1, SV2 or SV3) should be performed within 2 to 12 weeks of randomization.
At SV1, preliminary eligibility criteria will be reviewed.
For the purpose of establishing relevant baseline chemistries for suspected DILI, repeated measures of
AST, ALT and TB will be collected (see Laboratory Manual) ONLY if the first measure (M1) collected at
SV1 is > ULN. M1 and another value either a historical value (M0), collected at least 4 weeks and up to
12 weeks apart before SV1, or a second measure (M2) will be collected at SV2 (4 to 6 weeks after SV1).
This applies to only the analyte above ULN.
• If variability between M1 and either M0 or M2 is > 40% a third measure (M3) will collected at
SV3 (4 to 6 weeks after SV1 (if M0 compared) or SV2 (if M2 compared)):
o If variability between M1 and M3 is > 40% the patient is ineligible for the study
To assess the ALP eligibility criterion, two ALP values will be required. One value is the M1 collected at
SV1, and the other value is M0 collected at least 4 weeks and up to 12 weeks apart before SV1 or M2
collected at SV2 (4 to 6 weeks after SV1).
• If M1 is < 1.67 x ULN, the patient will be excluded and no further assessment will be performed
• If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is ≥ 1.67 x ULN, and variability
is ≤ 40% the patient is eligible
• If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is < 1.67 x ULN or variability
is > 40%, M3 collected at SV3 (4 to 6 weeks after SV1 (if M0 compared) or SV2 (if M2
compared)) will be required:
o If the mean of M1 and M3 is ≥ 1.67 x ULN and variability is ≤ 40%, the patient is
eligible
o If the mean of M1 and M3 is < 1.67 x ULN or variability is > 40%, the patient is ineligible
for the study
NOTE: M2 and M3 values for AST, ALT, TB and ALP can be obtained at local laboratory. Comparison
between M1 and local value(s) will be done on normalized values according to ULN.
For patients having consented to have liver biopsy samples collected and in absence of valid historical
liver biopsy, the liver biopsy can be performed at any visits during the screening period, preferably in
patients already confirmed as eligible and if at all possible 2 to 4 weeks prior to randomization.
Screening is a minimum duration of 2 weeks to help ensure the stability of the PBC Worst Itch NRS daily
scores for the calculation of the baseline score.
3.5.2. DB period (Week 0 to max Week 104)
At the Randomization visit 1 (week 0), all eligibility criteria will be reviewed for inclusion including lab
assessments obtained during the screening period.
Randomization in IXRS will be stratified based on central lab assessments obtained for ALP & TB at SV1,
as well as on the mean PBC Worst Itch NRS Score over the 14 days preceding the visit 1.

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At least 4 values of the PBC Worst Itch NRS during each of the 7-day intervals in the 14 days prior to
randomization (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to
randomization (V1) are required for randomizing the patients. In case this number is not achieved, the
screening period may be extended in order to obtain the expected number of NRS values.
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes
or moderate disease stage, approximately 10% of randomized patients will be moderately advanced
per Rotterdam Criteria (TB> ULN or Albumin < LLN) and approximately 20% will have a TB > 0.6 x
ULN (patients at risk of progression). Patients will also be categorized as early or advanced disease
stage based on liver stiffness measurement at the baseline Fibroscan examination (LSM<=10 kPa or
LSM >10 kPa), and based on histology (absent or mild fibrosis vs. presence of bridging fibrosis or
cirrhosis) among those who undergo liver biopsy [EASL Clinical Practice Guidelines on non-invasive
tests for evaluation of liver disease severity and prognosis –2021 update, J Hep 2021].
The DB period will last until the last completed week 52 (V6) visit or until a maximum of 104 weeks DB
period, whatever happens first.
During the DB period the patients will return to the site every 13 weeks (±2 weeks) from V1 up to V6
(week 52) except for the V2 (4 weeks after V1) and if applicable post V6, every 26 weeks up to V8;
Between V6 and V8, safety contacts will be performed by phone call between on site visits, every
alternating 26 weeks (+/-14 days), to collect information related to AEs, concomitant medications,
pregnancy, and study drug compliance. The first phone safety contact will start 13 weeks after V6 as
applicable.
Any patient completing V8 will be automatically switched to open-label LTE. The last V5 completed for
all randomized patients will trigger the switch to open-label LTE for all patients still in DB. The switch
will be operated either at V6 or at an additional onsite visit (LVDB). Until the last patient in the study
completes his/her V5, patients between V6 and V8, will complete LVDB according to Table 1 General
Assessment Schedule. After the last patient in the study completes his/her V5, patients between V6 and
V8, will complete LVDB at the next scheduled visit (either V7 or V8). LVDB will replace V7 or V8. The
same procedures as for V8 will be performed for LVDB (except US exam). For patients who have not
yet had V6 at the time the last patient completes his/her V5, LVDB will be scheduled at the latest 13
weeks after the date on which V5 was completed for the last patient. For those patients, LVDB will
coincide with V6, and patients will complete V6 and associated procedures to facilitate transition to the
open-label elafibranor treatment phase in the long-term extension study, in a timely manner.
In case of premature study drug discontinuation prior to visit 8 during DB period, EOT DB visit should
be performed between 16 and 30 days after last drug intake. The patients will continue in the study
until V8, or until the last completed V6 whichever occurs first, and will complete all visit procedures
except liver biopsy and PK (if not done prior to study drug discontinuation). In case the EOT DB visit
occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. For
any EOT patients, their EOS status will be registered in relevant study system(s) as applicable.
Patients will be contacted at least 1 week before each onsite visit to be reminded of procedures and
study drug return.
The study scheduled assessments will be performed as per Table 1 and Table 2.
3.5.3. LT period
After the last DB visit, patients will continue to the LTE period (open label). During the LTE period, all
patients will receive elafibranor 80 mg for up to 5 years after the DB period or until the patient’s total
treatment duration is 6 years, whichever occurs first.

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Apart from the first 2 visits in this LTE period which will occur at 13 weeks interval starting after the last
visit in the double-blind period (V6, V7, V8), patients will return to the site every 26 weeks (+/-14 days)
for procedures listed on Table 1 and Table 2, and safety contacts by phone call will be performed, every
alternating 26 weeks (+/-14 days) after LT2, to collect information related to AEs, concomitant
medications, pregnancy, and study drug compliance. The Investigator may subsequently decide to
perform an unscheduled visit (see Section 3.5.5.2).
If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed
between 16 and 30 days after last drug intake.
For any patients in the LTE, their EOS status will be registered in relevant study system(s) as applicable.
3.5.4. Safety Follow up
An EOT DB or EOT LTE visit will be performed between 16 to 30 days after the last drug intake for any
subjects who received the study drug. The study procedures will be assessed as per the Table 1 and
Table 2.
3.5.5. Optional Visits
3.5.5.1. Retesting and/or additional screening visits
• If CPK value is >2xULN at SV1, it can be repeated within 1 to 2 weeks, but prior to V1
If HCV Ab test is positive at SV1, a patient’s HCV infection status needs to confirmed by HCV RNA testing
prior to V1Any other retest deemed necessary by the Investigator should be discussed with the Study
Medical Monitor.
3.5.5.2. Unscheduled visits
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for
safety reasons or when repeat measurements are required out of the screening period (either to confirm
a measurement or in case of errors, measuring device failure, etc.).
3.5.6. Off-site study procedures in case of crisis situation
In cases of emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient
safety and minimize risks to study integrity, certain study procedures may be completed remotely (e.g.,
not on-site) for patients already randomized in the study. Any temporary changes to study conduct will
be defined based on a risk assessment specific to the crisis, and regulatory agencies and ethics
committees will be informed in accordance with local laws and regulations.
The temporary study conduct changes might include:
• Study visits conducted with the patient via phone
• Laboratory testing performed in the patient’s local lab
• Study drug shipped from the site or supplier to the patient, or delivered by the site study staff
to the patient
Certain changes may be applied on a case-by-case basis depending on the investigator’s judgment.
The investigator will confirm a patient's agreement before implementing any temporary study conduct
changes.

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4 PATIENT SELECTION
A patient will be eligible for the study only if all of the following criteria apply:
4.1 INCLUSION CRITERIA
1) Must have provided written informed consent and agree to comply with the study
protocol
2) Males or females age of 18 to 75 years inclusive at SV1
3) PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic
criteria:
b. Positive AMA titers (> 1:40 on immunofluorescence or M2 positive by ELISA or
positive PBC-specific ANA
4) ALP ≥ 1.67 x ULN (based on two values - see section 3.5.1)
5) TB ≤ 2 x ULN
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term
clinical outcomes or moderate disease stage, approximately 10% of randomized
patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin <
LLN) and approximately 20% will have a TB > 0.6 x ULN (patients at risk of
progression)
6) Must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day
intervals in the 14 days prior to randomization (V1), for a total of at least 8 values for
PBC Worst Itch NRS in the last 14 days prior to randomization (V1)
7) UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable
to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country
8) If on colchicine must be on a stable dose for ≥ 3 months prior to screening
9) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone
or sertraline) must be on a stable dose for ≥ 3 months prior to screening
screening
11) Females participating in this study must be of non-child bearing potential or must be
using highly effective contraception for the full duration of the study and for 1 month
after the last drug intake:
• Non-child bearing potential: Cessation of menses for at least 12 months due to
ovarian failure or surgical sterilization such as bilateral oophorectomy, or
hysterectomy
• Highly effective contraception methods include:
a. Combined (estrogen and progrestogen containing) hormaonal
contraception associated with inhibition of ovulation, oral, intravaginal or
transdermal
b. Progestogen-only hormonal contraception associated with inhibition of
ovulation, oral, injectable or implantable

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c. Intrauterine device (IUD)

d. Intrauterine hormoine release system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence, if required by local IRB/IEC regulations and/or
considered adequate by National laws (the reliability of sexual abstinence
needs to be evaluated in relation to the duration of the clinical study and
the preferred and usual lifestyle of the patient)
12) For patients who consent to have liver biopsy samples collected, patients in whom it
is safe and practical to proceed with a liver biopsy, and who agree to have:
a. 1 liver biopsy during the Screening Period (if no historical biopsy within 6 months before
screening is available)
4.2 EXCLUSION CRITERIA
Patients presenting any of the following exclusion criteria will not be included in the study:
a) Positive anti-HAV IgM antibodies or positive HBsAg or positive HCV RNA (tested for
in case of known cured HCV infection or positive HCV Ab at screening)
b) PSC
c) ALD
d) AIH or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence
of overlap AIH features, that cannot be explained alone by insufficient response to
UDCA
e) NASH
a) History of liver transplantation, current placement on a liver transplant list, current
MELD-Na score ≥ 12 linked to hepatic impairment
b) Patients with cirrhosis/portal hypertension complications, including known
esophageal varices, ascites, history of variceal bleeds or related interventions (e.g.,
insertion of variceal bands or TIPS, and hepatic encephalopathy, history or presence
of spontaneous bacterial peritonitis, hepatocellular carcinoma
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease)
or which may diminish life expectancy to < 2years, including known cancers
4) Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have
tested positive for HIV
5) Evidence of any other unstable or untreated clinically significant immunological,
endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated
by the investigator; other clinically significant medical conditions that are not well
controlled

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6) History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day
for men, and more than 20 g pure alcohol per day for women, or other substance abuse
within 1 year prior to screening visit (SV1)
7) For female patients: known pregnancy, or has a positive serum pregnancy test, or
lactating
a) 2 months prior to screening: fibrates and glitazones
b) 3 months prior to screening: OCA, azathioprine, cyclosporine, methotrexate,
mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids
(parenteral and oral chronic administration only); potentially hepatotoxic drugs
(including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
c) 12 months prior to screening: antibodies or immunotherapy directed against ILs or
other cytokines or chemokines
d) For patients with previous exposure to OCA, OCA should be discontinued 3 months
prior to screening
9) Patients who are currently participating in, plan to participate in, or have participated in
an investigational drug study or medical device study containing active substance within
30 days or five half-lives, whichever is longer, prior to screening; for patients with
previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to
screening
11) SV value ALT and/or AST > 5 x ULN
12) For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1)
13) SV value albumin<3.0 g/dl
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin <
LLN)
15) SV value INR > 1.3 due to altered hepatic function
16) SV value CPK > 2 x ULN
17) Screening serum creatinine > 1.5 mg/dl
18) Significant renal disease, including nephritic syndrome, chronic kidney disease (defined
as patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2)
calculated by MDRD
19) Platelet count < 150 x 103/µL
20) AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver
cancer
21) Known hypersensitivity to the investigational product or to any of the formulation
excipients of the elafibranor or placebo tablet
22) Mental instability or incompetence, such that the validity of informed consent or ability
to be compliant with the study is uncertain

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5 STUDY PROCEDURES
The procedures performed at each visit are summarized in the study schedules (Table 1 and Table 2
and Table 3) and in Section 3.5.
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of the
day for each patient. A patient may be seen at any time for reasons of safety.
During each visit, vital signs will be measured, and the patient will be queried in the form of an open
question regarding new or continuing events.
During any study visit during which PROs are performed, it is recommended to be completed by the
patient prior to the site performing any invasive procedures.
Procedures for premature discontinuation after randomization are described in Section 5.2.
5.1. SCREEN FAILURES
Screen failures are defined as patients who consent to participate in the clinical study but are not
subsequently randomized. A minimal set of screen failure information is required to ensure transparent
reporting of screen failure subjects. Minimal information includes demography, screen failure details,
eligibility criteria, and any SAE.
Individuals who screen failure because of a specified modifiable factor may be rescreened.
5.2. PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES
5.2.1. Permanent discontinuation of study drug/withdrawal from study
Patients will be informed that they have the right to discontinue the study at any time, for any reason,
without affecting future management and treatment.
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for
safety, behavioral, or administrative reasons.
The reason for permanent discontinuation of study drug should be documented in the electronic case
report form (eCRF) and the Medical Monitor informed. If the discontinuation of study drug is due to an
AE, the event should be documented in the eCRF.
Some possible reasons that may lead to permanent early study drug discontinuation include:
• At the discretion of the Investigator, any AE, AESI, SAE (described in Section 8.1.1 and 8.1.2),
or significant change in a laboratory value or worsening or disease progression that would
require in the patient’s best interest, initiation of any standard of care prohibited in the study..
Investigators are advised to call the Medical Monitor prior to making such a decision
• Non-permitted concomitant medication (described in Section 7.12 and 16.2)
• Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree
to use a reliable method of birth control during the study
• Non-compliance with the study treatment
• Uncooperative patient

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Patients permanently discontinued from study drug during the DB period will perform an EOT DB visit
within 16-30 days after the last drug intake and will continue to attend all scheduled visits until the visit
8 (without undergoing histology or PK assessment, if applicable), or until the last completed V6
whichever occurs first. Patients permanently discontinuing study drug during the LTE period will attend
the EOT LTE Visit within 16 to 30 days after the last administration of study drug (as described in Section
3.5.4).
5.2.2. Patients Lost to Follow-up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts
to contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up
by the site.
5.2.3. Replacement
No patient replacements are permitted in this study.
5.2.4. Premature Discontinuation of the Study
Premature termination of this clinical study may occur because of a Regulatory Authority decision,
change in opinion of the institutional review board/independent ethics committee (IRB/IEC), drug safety
problems, or at the discretion of the Sponsor. In addition, the Sponsor retains the right to discontinue
development of the study treatment at any time.
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended number of
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such
a decision, the Investigator must contact all participating patients within a reasonable period of time.
As directed by the Sponsor, all study materials must be collected and all case report forms (CRFs)
completed to the greatest extent possible.
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing.
In all cases IRB/IEC and Health Authorities should be informed.
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related
study materials must be returned to the Sponsor.

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6 ASSESSMENTS
6.1. EFFICACY AND SAFETY ASSESSMENT
6.1.1. Biological assessment
All blood samples for efficacy and/or for safety assessment will be returned and centralized by the
central laboratory.
A Laboratory Manual will be provided to each site.
The Manual will outline the collection process and shipping requirements for the specific central
laboratory. Blood sampling will be performed by trained personnel at each site. Blood samples will be
processed and shipped as outlined in the Laboratory Manual. Refer to the Laboratory Manual for exact
amounts of blood required for each test.
For all visits, reportable laboratory results (except serology) will be available at sites approximately 24-
48 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be
reviewed, signed and dated by the Investigator as soon as received. The Investigator should comment
upon out of range parameters and assess clinical significance.
In order to maintain the blind, ALP, GGT and 5’ NT obtained from blood samples from V2 to V8 / LVDB/or
last V6 whichever occurs first (up to end of DB period) will be kept in blinded condition during the DB
treatment period for each patient. Similarly, the same rule will apply to ALP, GGT and 5’-NT obtained
from blood samples until the first visit in the LTE period (LT1), including EOT LTE and unscheduled
visits. The Investigator will not be informed of these values until the database lock at the end of the DB
period.
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting
(to be performed at Retesting and/or additional SVs) is limited to CPK, and HCV RNA (in case of positive
HCV Ab at SV) as described Section 3.5.5 and in Table 2.
At visits for which blood samples will be drawn, patients must be fasting for at least 12 hours. These
visits should be scheduled in the morning.
Both blood and urine dipstick samples will be transported to the central laboratory for testing and
analysis except for urinary/blood myoglobin that should be tested at local laboratory when applicable.
Local laboratory assessments are allowed for repetition of assessment of ALT, AST, TB and ALP during
the screening period as well as for any required retest for liver function monitoring and assessment of
urinary/blood myoglobin, when applicable.
Local laboratory results will be entered in eCRF including corresponding normal ranges.
6.1.1.1. Laboratory Assessments
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured
at every visit as described in Table 2.
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine dipstick samples
will be transported to the central laboratory for testing and analysis.

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6.1.1.2. Urinary Pregnancy Tests
For WOCBP, serum pregnancy test will be performed at screening (and may be repeated within one
month prior to randomization in case the screening period lasts more than 4 weeks) while urinary
pregnancy tests will be administered at each visit from V1. Notably, the urine pregnancy test performed
at V1 is to occur on site prior to randomization. If such test is unclear, a follow-up serum pregnancy
test should also be performed prior to dosing. In addition, monthly urine home pregnancy test kits will
be provided during scheduled visits for use during non-visit months. In case of positive urinary test, a
confirmatory serum pregnancy test must be performed at site.
6.1.1.3. Serology
Screening for hepatitis and HIV will be performed during screening and will include:
• HIV Ab I/II
• Anti-HAV IgM
• HBsAg
• HCV Ab (If positive, a HCV RNA test will be performed to determine infection status)
6.1.1.4. Other Parameters
All other parameters will be measured according to the schedule described on Table 2.
6.1.2. Constitution of biobank
In order to be able to test other specific parameters which could be of interest regarding the elafibranor
development program or regarding diagnosis, prevention, or treatment of PBC or other related diseases,
an additional amount of blood will be sampled from patients who have given their consent for these
additional analyses by signature of the biobank ICF.
These samples will be destroyed 3 years after final study results at the latest.
6.1.3. Bone density by DEXA scanning
DEXA scanning (hip and lumbar) will be performed in patients at study sites at which DEXA scan
equipment is available and has been approved for use in this study. Study participants will have this
exam at baseline (before randomization after the patient has been otherwise confirmed as eligible and
up to randomization visit), at week 52 and then 2 years later as described in Table 1.
6.1.4. Histological assessment
For patients who consent to have liver biopsy samples collected, a liver biopsy (see Section 6.1.4.1 for
recommendations) will be performed:
• During the Screening period (unless an historical liver biopsy within 6 months before screening
is available)

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In addition, for any patient randomized in the study, a liver biopsy can be requested at any time in case
of suspicion of auto-immune hepatitis or for safety monitoring at the discretion of the investigator
(section 6.3.2 & 6.3.3).
A Laboratory Manual will be provided to each study site. The manual will outline the collection process,
and shipping requirements for the specific central laboratory.
6.1.4.1. Recommendations related to liver biopsy
The patient’s platelet count and PT should be checked according to local hospital standards before the
date of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they
are in everyday clinical practice. Usually a platelet count >80,000/mm 3, a PT >60% or longer by no
more than 4 seconds over the control, and a normal bleeding time are acceptable for performing
percutaneous liver biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days.
If these conditions are not all respected, a safer option would be to perform the liver biopsy by
transjugular route, when available.
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution
in liver disease.
The recommended biopsy procedure to be applied is:

• Needle core biopsy
• Biopsy obtained with a 16 or lower gauge needle
• A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length
• Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe
biopsy should be used for future biopsies.
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6
hours after the procedure.
The biopsies will be sent to the central laboratory and then stained and digitalized, before being
transfered for central reading. Biopsy slides will be blinded for patient and visit identification prior to
central reading.
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading,
other available slides or new slides to be prepared from an available block of tissue may be requested
to the site.
6.1.4.2. Liver biopsy reading
Liver biopsy samples will be sent to the central laboratory where they will be stained and digitalized.
Liver biopsy slides will be assessed and scored by at least two pathologists. Scores for fibrosis, bile duct,
cholangitis activity, interface hepatitis activity, will be evaluated and agreed. A liver biopsy management
plan will detail the process of management of the liver biopsy samples from collection to final
assessment. A liver biopsy assessment protocol will detail the reading methodology to be implemented.
6.1.5. Pharmacokinetic assessment
Elafibranor (GFT505) and GFT1007 plasma concentrations PopPK analysis is to be done at steady-state.
Thus the PK blood collection will be at steady state after repeated administration of elafibranor in order
to assess its PK and the one of its main active metabolites, GFT1007, in PBC patients. GFT505 and
GFT1007 will both be included in the PopPK analysis.

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6.1.5.1. Pharmacokinetic blood sampling timepoints
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at steady-
state after 4 weeks of treatment (V2).
The collection of PK blood samples is to be performed at the first visit post randomization (V2) in order
to limit as much as possible treatment compliance issues. Prior to sampling the patient, the investigator
will have to check the patient compliance over the preceding 16 days.
All patients (including patients under placebo in order to maintain the blind of the study) will be sampled
with 6 sampling timepoints: predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h.
The following restrictions should be applied to patients for the visit V2 where PK sampling are planned:
• Study treatment will be taken at site under fasting conditions after the blood sampling for
biological assessment (see section 6.1.1) and predose PK sampling and before further PK
samplings, in this strict order.
• The time of study drug intake (T0) should be at least 24h after the previous dosing.
• The date and time of study drug intake the day before the visit (V2) has to be recorded as well
as the day of the visit (V2).
• The predose PK sampling has to be collected as close as possible to the study drug intake (T0)
(within max 1h prior to T0).
Samples should be collected as close as possible to the therotical timepoints. Exact time of sampling
will be recorded in the eCRF.
6.1.5.2. Pharmacokinetic blood handling procedures
At each time point (predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h), 1 tube of 6 mL blood sample
should be drawn into lithium heparin Vacutainer® tube protected from light with foil. Plasma will be
separated, stored and shipped as described in the laboratory manual, first to the central laboratory (as
for all the other blood samples collected) where they will be stored until shipped to a specialized
laboratory for analysis.
The exact time of sample collection will be recorded in the source documents and reported in the eCRF.
6.1.5.3. Bioanalytical analysis
The bioanalysis part will be conducted at a specialized laboratory in compliance with its Standard
Operating Procedures (SOPs) in use.
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method
previously developed and validated as detailed in the Bioanalytical Study Plan.
6.1.5.4. Description of pharmacokinetic evaluation parameters
PK parameters (AUCss, clearance, volumes of distribution, etc.) will be determined from elafibranor and
GFT1007 plasma concentrations using a popPK model. A dedicated software for nonlinear mixed models
will be used for the analysis.
The population PK analyses will be described in a separate data analysis plan and reported in a
standalone report.

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An exploratory analysis will be performed to assess the relationship between PK and PD (efficacy or
safety endpoints). If a trend is shown, an attempt to build a PKPD model using a population approach
will be performed. Those analyses (population PK and, if applicable, population PKPD) will be described
in a separate data analysis plan and reported in a standalone report..
PK parameters of elafibranor and GFT1007 will be summarized by geometric mean, SD, coefficient of
variation, minimum and maximum, and median.
6.1.6. Liver stiffness by transient elastography (FibroScan®)
FibroScan® TE device (Echosens, Paris, France) is a non-invasive technique used to measure liver
stiffness, which correlates with fibrosis. This assessment will be performed on all patients as illustrated
by the Study General Assessment Schedule (Table 1). All sites must have designated staff trained in the
use of the device.
This assessment will be done the day of the visit. Failing this, it can be performed within 7 days of the
visit.
To ensure reliability of the assessments patients must be in a fasted state for at least 3 hours before
the examination. Additional instructions will be provided in a separate manual.
As presented in the paper from Corpechot et al [24], the threshold for classification of cirrhosis is ≥
16.9 KPa.
6.1.7. Patient Reported Outcomes Questionnaires
The following PROs will be assessed:

a) The PBC Worst Itch NRS (Appendix 16.3.7) is a simple, self-administered PRO questionnaire
that measures itch intensity. It uses 24-hour and 7-day recall periods and asks patients to rate
the intensity of their Worst Itch on an 11-point scale ranging from 0 (no itch) to 10 (Worst Itch
imaginable). Patients will record their scores once daily (24-hour recall) using the eDiary during
the screening and Common DB periods and during study visits (7-day recall; PBC Worst Itch
NRS-Past Week) during the Variable DB and LTE periods as outlined in Table 3. At
randomization, the patient’s daily scores (24-hour recall) over the previous 14 days will be
averaged to determine the baseline score for stratification and analysis; at least 4 available
values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to
randomization (for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior
to randomization) are required for the baseline score to be calculated.
b) The 5-D Itch scale (Appendix 16.3.3) is a questionnaire that has been validated in several
different diseases. It assesses symptoms in terms of 5 domains: degree, duration, direction,
disability and distribution [27]. Patients rate their symptoms over the preceding 2-week period
on a 1 to 5 scale, with 5 being the most affected. Patients will complete the 5-D Itch scale as
outlined in Table 3.
c) The PBC-40 (Appendix 16.3.1) is a validated, PBC-specific, HRQoL 40 question questionnaire

that assesses symptoms across six domains: fatigue, emotional and social, cognitive function,
general symptoms and itch [28]. Patients respond on a verbal response scale, depending on
the section options range from ‘never’ / ‘not at all’ / ‘strongly disagree’ to ‘always’ / ‘very much’
/ ‘strongly agree’. Five items (3/3 in the itch domain and 2/10 in the social domain) also include
a ‘does not apply’ option. A score for each domain is provided (but a total score is not
calculated), with each verbal response scale correlating to a score of 1-5 per item (0-5 on items
with a ‘does not apply’ option) with 5 being the most affected. The PBC-40 has a 4-week recall
period (Appendix 16.3.1). Patients will complete the PBC-40 as outlined in Table 3.
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d) The Euro quality of life (EuroQol) EQ-5D-5L (Appendix 16.3.8) is a 6-item, standardized
questionnaire that assesses mobility, self-care, usual activities, pain / discomfort, anxiety /
depression, and overall health state.
e) The ESS [29, 30] (Appendix 16.3.2) is a short, self-administered questionnaire that consists of
eight questions asking to rate how likely it is to fall asleep in everyday situations (each question
can be scored from 0 to 3 points; ‘0’ indicates no sleepiness, ‘3’ indicates significant sleepiness).
It provides a total score which has been shown to relate to the patient’s level of daytime
sleepiness (total score range 0–24 points). Patients will be asked to complete the ESS with
regard to the level of sleepiness they experienced over approximately the past 7 days as outlined
in Table 3.
f) The PROMIS Fatigue Short Form 7a (Appendix 16.3.4) consists of seven items that measure
both the experience of fatigue and the interference of fatigue on daily activities over the past
week (National Institute of Health, 2007). Patients will complete the PROMIS Fatigue Short Form
7a as outlined in Table 3.
g) The Patient Global Impression of Change (PGIC) (Appendix 16.3.5) is a single item 5 point scale
designed to assess the change in overall itch intensity since the baseline visit. PGIC-Itch scores
will be captured as outlined in Table 3.
h) The PGIS (Appendix 16.3.6) is a 1-item 5-point scale designed to assess patient’s impression of
itch severity. The PGIS-Itch scores will be captured as outlined in Table 3.
Of note, PGIC and PGIS are collected as anchors to facilitate the derivation of a clinically meaningful
threshold but will not be used to measure any treatment effect.
In order to avoid bias in the patients' responses to the questionnaires, it is recommended that site based
assessments be completed before any other evaluations or study procedures on the day of the study
visit and prior to discussions with the investigator or study site staff. Site procedures and assessments
should be conducted in the following order: PROs, investigator assessments, safety and laboratory
assessments, administration of study drug.
6.2. OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING
6.2.1. Physical Examination
A physical examination including neurological exam will be performed at the time points specified in the
study general assessment schedule of events (Table 1). Height will be measured at the SV only. The
physical examination will include the following: General appearance, weight, hair and skin, lymph nodes,
head, eyes/ears/nose, throat, neck, respiratory system, cardiovascular system, abdominal region,
musculoskeletal system, mental status and neurological system.
6.2.2. Vital Signs and Weight
Blood pressure (BP), heart rate, respiratory rate and temperature will be measured [26]. Weight will be
measured in pounds or kilograms. All measurements will be recorded in eCRF.

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6.2.3. 12 Lead ECG
ECGs will be analyzed by the Investigator or designee. Patients are to be supine position for at least 5
minutes prior to ECG assessments. A minimum of 3 cycles will be recorded per lead. Any potential
clinical significance of ECG changes will be determined by the Investigator with relation to the patient’s
medical history, physical examination, and concomitant medications and recorded in eCRF.
6.3. IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT

DISCONTINUATION RULES
6.3.1. Creatine Phosphokinase
If at any visit during the treatment period, a patient experiences diffuse myalgia, muscle tenderness,
and/or marked increase in muscle CPK values between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), an
additional visit and test must be performed within 48 to 72 hours, and an assessment of
myoglobinuria/myoglobinemia should be done locally. If, during that visit, the patient still experiences
diffuse myalgia, muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x
ULN (≥ 3 x ULN and ≤ 5 ULN), myopathy must be considered and the patient must be discontinued
from study treatment immediately and followed up as described in Section 5.2.1.
If at any visit during the treatment period, a patient experiences marked increase in muscle CPK values
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as
described in Section 5.2.1.
6.3.2. Liver Function Monitoring
Patients will be closely monitored and evaluated for other causes of liver injury and for the potential of
DILI. Relevant assessment for suspected DILI includes:
• Establishing baseline values (by at least two samples obtained at least 4 weeks and no more
than 12 weeks apart)
• Obtaining a more detailed history of symptoms and prior or concurrent disease
• Obtaining a history of concomitant drug use (including nonprescription medications and herbal
and dietary supplement preparations), alcohol use, recreational drug use, and special diets
• Ruling out acute viral hepatitis types A, B, C, D and E; autoimmune or alcoholic hepatitis; NASH;
hypoxic/ischemic hepatotoxicity; and biliary tract disease
• Obtaining a history of exposure to environmental chemical agents
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin)
• Considering gastroenterology or hepatology consultations
In addition, guidelines for management of any sign of liver function deterioration are given in the several
subsequent sections below.
For any of the cases below, if a patient lives in a remote area from the site, laboratory testing can be
performed in a local lab. The results should be promptly communicated to the investigator site.
Liver function monitoring will be done with respect to Liver Function Tests baseline values. Of note, in
the absence of large prospective comparative data, there is little evidence to support one threshold over
another [31] therefore the IQ-DILI best practice recommendations have been adopted for this protocol.
The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ
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Consortium), a science-focused, not-for-profit organization launched the IQ-DILI Initiative in 2016,

reached consensus, and proposed the following best practices related to DILI with respect to patients
with elevated ALT at baseline:
- If ALT ≥ 3 x baseline and there is no change in TB or liver-related symptoms, repeat measures
and initiate close observation [32]
- If ALT ≥ 3 x baseline, TB is normal or elevated and liver-related symptoms (i.e., severe fatigue,
nausea, vomiting, right upper quadrant pain), interrupt study drug and initiate close observation
[32]
In addition to management guidelines, the criteria used for reporting a potential DILI for adjudication
are given below and correspond to the criteria leading to permanent study drug discontinuation.
For any suspicion of DILI or for any other liver related event, it is left to the discretion of the investigator
to request a liver biopsy in accordance with the local clinical standards, in order to further assess the
case.
6.3.2.1. Treatment discontinuation rule for elevated Aminotransferase (AT) values

regardless of baseline values
In all cases, whether baseline Aminotransferase (AT) values are normal or elevated, an increase of AT
>10 x ULN will lead to permanent discontinuation of the patient from study drug, and scheduling of
EOT DB/EOT LTE visit.
6.3.2.2. Treatment discontinuation rules for elevated Aminotransferase (AT) values
according to baseline values
6.3.2.2.1. Monitoring of patients with normal baseline AT values
For patients with normal baseline AT values at V1 who at any visit from V2 onwards during the treatment
periods exhibit:
• Increase in AT to ≤ 3 x ULN: no additional action required, schedule next visit as per assessment
schedule.
• Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours.
o AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring
(twice a week). Frequency of repeated testing can decrease to once a week or less if
abnormalities stabilize or the study drug has been discontinued and the patient is
asymptomatic
o AT increases to >5 x ULN: permanently discontinue patient from study drug and
schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT >5 x ULN: retest after 48 to 72 hours.
o AT remains >5 x ULN: permanently discontinue patient from study drug and schedule
EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4)
o AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (twice a week).
Frequency of repeated testing can decrease to once a week or less if abnormalities
stabilize or the study drug has been discontinued and the patient is asymptomatic.
• Increase in AT >3 x ULN and increase in TB > 2 ULN: permanently discontinue patient from
study drug and schedule EOT DB /EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT >3 x ULN and increase in INR>1.5 (in the absence of anti-coagulant therapy):
permanently discontinue patient from study drug and schedule EOT Visit (see Section 5.2.1 and
Section 3.5.4).

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• Increase in AT >3 x ULN and fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT
DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT >3 x ULN and eosinophilia (> 5%) with total count > ULN: permanently
discontinue patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and
Section 3.5.4).
6.3.2.2.2. Monitoring of patients with abnormal baseline AT values
For patients with abnormal AT baseline values at V1 who at any visit post V1 onwards during the
treatment periods exhibit:
• Increase in AT to ≤ 3 x baseline value: no additional action required, schedule next visit as per
assessment schedule.
• Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours:
o If baseline value < 2 x ULN:
 AT increase ≤ 5 x baseline: continue the drug with close serial monitoring
(twice a week)
 AT increase > 5 x baseline: permanently discontinue patient from study drug
and schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section 3.5.4)
o If baseline value > or equal 2 x ULN but < 5 x ULN:
 AT increase ≤ 3 x baseline: no additional action required, schedule next visit
as per assessment schedule
 AT increase remains > 3 x baseline: permanently discontinue patient from
study drug and schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section
3.5.4)
• Increase in AT >3 x baseline value and increase in TB > 2 x baseline: permanently discontinue
patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section
3.5.4).
• Increase in AT > 3 x baseline value and increase in INR by above > 0.2 compared to baseline
INR (in the absence of anti-coagulant therapy): permanently discontinue patient from study
drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT > 3 x baseline value and fatigue, nausea, vomiting, right upper quadrant pain
or tenderness, fever, rash: permanently discontinue patient from study drug and schedule
EOT/EOS Visit (see Section 5.2.1 and Section 3.5.4).
• Increase in AT > 3 x baseline and eosinophilia (> 5%) with total count > ULN: permanently
discontinue patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and
Section 3.5.4).
6.3.2.2.3. Monitoring of patients with abnormal TB baseline values
For patients with abnormal TB values at V1 who at any visit post V1 onwards during the treatment
periods exhibit:
• Increase in TB to > 1.5 x baseline value: retest after 48 to 72 hours
o TB remains >1.5 x baseline value: continue study drug and implementation of close
observation (testing and physical examination 2-3 times per week). Discontinuation of
study should be considered.
6.3.3. Auto-immune hepatitis monitoring
For patients who at any visit post V1 onwards during the treatment periods, exhibits ALT>5 X ULN, IgG
serum or smooth muscle autoantibody should be tested (these tests are to be done locally);

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if IgG is >2XULN or smooth muscle autoantibody positive, a liver biopsy should be performed at an
unscheduled visit; if moderate or severe interface hepatitis is detected on histology, AIH will be
confirmed and patient should be discontinued from study drug (if not already discontinued according to
discontinuation rules described in Section 6.3.2).
6.3.4. Acute Pancreatitis Monitoring
6.3.4.1. Treatment discontinuation rule for suspected acute pancreatitis
If at any visit during the treatment period, a patient experiences serum amylase and lipase ≥ 3 x ULN,
associated with abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe,
epigastric pain often radiating to the back), an ultrasound exam or CT scan will be performed for the
diagnosis of pancreatitis. If confirmed, the patient must be discontinued from the study drug
immediately and followed up as described in Section 5.2.1.
6.3.5. Monitoring of hepatocellular and bladder cancer
6.3.5.1. Liver monitoring
Ultrasonography of liver and analysis of AFP will be performed at baseline, & then every year (V6, V8,
LT3, LT5 , LT7, and LT9 if applicable), AFP will be performed at LVDB, if applicable, as described in
Table 1 and Table 2.
6.3.5.2. Bladder & urinary tract monitoring
Ultrasonography of bladder and urinary tract will be performed at baseline, & then every year (V6, V8,
LT3, LT5 , LT7, and LT9 if applicable) as described in Table 1.
6.3.6. Safety Review
Safety oversight will be implemented under the direction of a DSMB composed of at least five
experienced physicians (an endocrinologist, cardiologist, oncologist, hepatologist and nephrologist) and
one independent statistician, all independent from the conduct of the study. Members of the DSMB
should be free of conflicts of interest. The members of DSMB will review the progress of the study and
perform a safety data review (including review of the adjudication reports issued from the CEC) on a
regular basis (at least every six months) to ensure patient safety and preserve study integrity.
A DSMB charter will define the membership, roles, responsibilities, rules and tasks of the DSMB.
6.3.7. Clinical event committee
The CEC will conduct adjudication of the clinical outcomes and DILI events. The CEC assessment and
adjudication will occur in a blinded (during DB period) and consistent and unbiased manner throughout
the course of the study to determine whether the endpoint meets the protocol specified criteria.
The CEC will be comprised of 3 hepatologists, all of them will be independent from the conduct of the
study.

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6.4. GUIDANCE FOR INVESTIGATORS
6.4.1. Summary of safety data
The safety and tolerability of elafibranor were confirmed in Phase 1 to Phase 3 studies.
A Phase 1 program has been conducted to assess the safety and tolerability, as well as the PK profile,
of elafibranor. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up
to 16 days. Importantly a PK study in hepatic impaired subjects was recently conducted and concluded
that no dose adjustment is required in cirrhotic patients, unless there is a safety concern.
A Phase 2 program has been conducted to assess the safety and efficacy profile of elafibranor in patients
suffering from cardiometabolic disorders and NASH.
A Phase 2 study (GFT505B-216-1) in PBC was also completed and included forty five (45) patients with
PBC and inadequate response to UCDA. This study evaluated the efficacy and safety of elafibranor at
daily doses of 80 mg and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor
daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months.
2157 patients with NASH and fibrosis have been randomized in a Phase 3 study (Study GFT505-315-1).
In this study, the subjects were receiving 120 mg/day elafibranor or placebo for up to 72 weeks during
the first treatment period, followed by a long-term treatment period to assess efficacy on progression
to cirrhosis, all-cause mortality and liver-related clinical outcomes as measured by the onset of any of
the listed adjudicated events of portal hypertension/cirrhosis related events. Given the failure to meet
the predefined primary surrogate efficacy endpoint (i.e. NASH resolution without worsening of fibrosis)
and following further in-depth review of the efficacy dataset, despite absence of safety issue, it was
decided to prematurely terminate the study in October 2020 following sponsor decision.
Based on the cumulative experience gathered to date, gastro-intestinal disorders (nausea , vomiting
renal and urinary disorders, and pruritus are considered common non-serious adverse reactions
reasonably associated with elafibranor; most of them are of mild to moderate severity. Of note, these
AEs are to be monitored as AESIs (see Section 8.1.2) as well as other AESIs which could be considered
as class effect AEs.
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical
studies, given the known effects of PPAR agonists on the increase of CPK enzyme, this parameter is
monitored in clinical studies. For this reason, it is recommended that investigators review these lab
results in the course of clinical studies.
Other known effects of PPAR agonists include the increase of creatinine, which was observed in our
clinical studies, in a range of 1-10%. This increase was reversible at EOT. This should also be monitored
in clinical studies.
Liver enzymes will also be monitored in clinical studies, with specific attention paid to DILI. In the
elafibranor clinical development program to date, there has been no imbalance in DILI events in
individuals who received elafibranor compared to individuals who received placebo.
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date,
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation
Group (CTFG) document Recommendations related to contraception and pregnancy testing in clinical
studies [33].

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As such, all clinical studies with elafibranor including WOCBP request a negative pregnancy test before
Randomization, effective contraceptive measures throughout the study and mandatory study
discontinuation upon becoming pregnant. Contraception should be maintained up to 1 month after the
last drug intake. Pregnancy tests should be repeated as stated in the Table 2.
6.4.2. Benefit/risk assessment
Clinical studies completed to date have not raised any major safety concerns associated with elafibranor
treatment, thus providing a favorable efficacy/safety profile for the drug candidate.
A Phase 2 study in PBC subjects who had an inadequate response to UDCA demonstrated improvement
in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels was observed,
resulting in significant treatment effects versus placebo on the primary endpoint, whilst also meeting
the composite endpoint used for drug registration (i.e. serum ALP <1 .67 x ULN, an ALP decrease >
15%, and TB < ULN).
Plasma concentrations and PK parameters measured for GFT505 and GFT1007 in subjects with PBC
were similar with that measured in healthy volunteers in previous studies with comparable dose
regimen. The results obtained in this study suggest that the PK of GFT505 and its active metabolite
(GFT1007) are not modified in subjects with PBC.
Despite this favorable benefit-risk profile, an independent DSMB will be established in order to review
the safety of the treatment during the study in an unblinded manner, to protect patient welfare and
preserve study integrity (Section 6.3.6).
In conclusion, the safety data collected so far and the current knowledge on GFT505 confirm the
favorable balance between risks and anticipated efficacy/benefits.

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7 TREATMENTS
7.1. DESCRIPTION OF STUDY MEDICATIONS
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl]

phenoxy]-2-methylpropanoic acid) will be supplied as 80 mg white to off-white round coated tablets
with no printed inscription. The tablet contains elafibranor and inactive ingredients (microcrystalline
cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium stearate, Opadry II HP
85F18422).
Placebo tablets to match elafibranor 80 mg will be provided as a white to off-white round coated tablet
with no printed inscription. Of note, in the placebo tablet formulation, lactose monohydrate is used for
replacing the active substance.
7.2. PACKAGING AND LABELING
7.2.1. Packaging
Elafibranor/placebo:
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil
blisters. This has been shown to be a suitable primary packaging for tablets.
Blisters, containing 7 tablets each, will be packed in child proof wallets.
Each childproof wallet will contain 5 blisters (covering approximately one month of treatment). Three
wallets (covering the period between each visit) will be packaged inside a period box.
7.2.2. Labeling
All labels for study drugs will meet all applicable requirements of the US FDA and the EU annex 13 of
Good Manufacturing Practices: Manufacture of Investigational Medicinal Products (February 2010) and
/or other local regulations, as applicable.
Distribution of study drug will be performed according to the Good Distribution Practices.
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required
by national and regional guidelines/regulations. The label will contain the statements “For clinical study
use only” or other similar/appropriate statements as well as the following instructions “Please return
empty packaging and unused products to your doctor at your next visit.”
7.3. DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO
Patients will be informed to take 1 tablet per day of elafibranor 80 mg or placebo orally before breakfast
with a glass of water each morning.

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7.4. METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP
If the patient fulfills all criteria to enter the DB treatment period, the Investigator will register the patient
in the IXRS system to randomize him/her.
The Investigator will log into the system using his identification number and access code. The IXRS will
then allocate the patient to a treatment group (placebo or elafibranor 80 mg) through a treatment
number.
A specific IXRS manual will be provided to the pharmacy and investigator site.
The randomization list will be generated by the Clinical Research Organization (CRO) for data
management & statistics, and will be kept under blinded condition to the study patients, investigator
site, sponsor and sponsor representative until the database lock and the Sponsor authorization to
unblind the study.
7.5. STORAGE CONDITIONS
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage
conditions are specified on the label.
7.6. DISPENSING OF TREATMENT
The Investigator will confirm each study drug dispensation in the IXRS.
At every visit from V1 up to visit V6 (apart from visit V2), every randomized patient will be delivered
with one period box.
From visit V6, two period boxes will be delivered at each site visit.
7.7. TREATMENT REPLACEMENT
Treatment replacement, if needed, will be explained in a specific IXRS procedure manual.
7.8. PROCEDURE FOR BLINDING
The Investigator, patient, and study personnel will be blinded to the treatment. Both elafibranor and
placebo tablets and packaging are indistinguishable.
Identification numbers will be assigned to a patient at the SV. The number will also be reported in the
eCRF. Upon completion of the SV, eligible patients will be randomly assigned to elafibranor 80 mg or
placebo at the randomization visit.

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7.9. PROCEDURE FOR UNBLINDING
The randomization code may be broken by the Investigator when urgent action is required for the
clinical management of the patient. For each patient, the list of treatment numbers allocated to the
patient will be stored in the IXRS. The Investigator will be able to unblind any treatment period box that
was dispensed to the patient by connecting to the IXRS (24-hour and 7-day access) and entering their
identification number and access code. A back-up phone Interactive Response Technology (IRT) module
will also be available should the site be unable to access the internet. The IXRS will verify the
authorization to unblind the entered treatment period box number and the screen will then display the
treatment group. When completed, a blinded confirmatory email will be sent to the Investigator and the
Sponsor. The reason for unblinding should be clearly and fully documented by the Investigator.
Unblinding of treatment arm will occur after the database lock of the DB period and the Sponsor
authorization.
7.10. STUDY DRUG COMPLIANCE
From Visit 1 and at every subsequent visit while the patient is being treated with study drug, the patient
will be directed to bring back all used and unused period box/wallets. Compliance will be checked by
the Investigator during those visits and recorded in the eCRF.
The compliance will be collected within the 16 days prior the Visit V2 for further PK assessment.
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be
documented.
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION
The Investigator, pharmacist or designee will acknowledge receipt for each study treatment on the day
of receipt. A study drug accountability record should be maintained by the person responsible for
dispensing the study drug to the patient.
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion
of the study.
Upon Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used
or unused) and will proceed to their destruction only after the Sponsor provides written authorization.
If the site has an appropriate SOP for study drug destruction, the site may destroy used and unused
study drugs in accordance with the site SOP and always after the drug accountability has been
performed by the monitor.
If study drug is destroyed at the site, the Investigator must maintain accurate records for treatment
cartons destroyed recording:
• Treatment carton (kit) number
• Quantity destroyed
• Method of destruction
• Person who disposed of the study drug

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7.12. OTHER MEDICATION
7.12.1. Handling of Concomitant Medication
In a general manner, patients should be discouraged from starting any new medication without
consulting the Investigator unless the new medication is required for emergency purpose. Similarly, any
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see Non-
permitted medication and condition, Appendix 16.2). In the event such a change becomes necessary
during the study, it should be recorded by the Investigator in the eCRF (including concomitant
medications taken within 30 days prior to Screening) and information should be communicated to the
Medical Monitor in order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as
on an “as needed” basis.
7.12.2. Non-permitted Medication
Some medications are not allowed within the timeframe given in Appendix 16.2.
If it is identified after Randomization that these non-permitted drugs have been administered to a
patient within the excluded timeframes, the decision to permanently discontinue the patient will be
discussed with the medical monitor (see Section 5.2).
7.12.3. Permitted Medication Under Conditions
The following medications are permitted under the condition of steady dosage prior to screening:
• UDCA if taken for at least 12 months (and stable dose for ≥ 3 months) prior to screening (SV1)
• Statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to screening
• Colchicine provided the dosage is kept stable for at least 3 months prior to screening.
• Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or
sertraline) must be on a stable dose for ≥ 3 months prior to screening
7.12.4. Permitted Medication
Any medications other than those listed above are permitted. However, the dosage of a current
medication for a chronic disease should remain unchanged as far as possible in order to reduce the risk
of bias.
In the event that additional concomitant therapy becomes necessary during the study, it should be
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting
the Investigator unless the new medication is required for emergency purpose.

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8 ADVERSE EVENT AND TOXICITY MANAGEMENT
8.1. DEFINITIONS
8.1.1. Adverse Events (AEs)
Any untoward medical occurrence in a patient or clinical investigation subject administered a

pharmaceutical (investigational) product and which does not necessarily have a causal relationship with
this treatment will be considered as an AE. The term AE is synonymous with the term “adverse
experience” as used by the FDA.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding
or, symptom, or disease temporally associated with the use of a medicinal (investigational) product,
whether or not considered related to the medicinal product.
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms
and signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-
existing condition or underlying disease; recurrence of a pre-existing condition; lack of effect,
complication, and termination of pregnancy.
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal,
drug abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero and
breastfeeding.
The criteria for determining whether an abnormal objective test finding should be reported as an AE are
as follows:
• Test result is associated with accompanying symptoms
• Test result requires additional diagnostic testing or medical/surgical intervention
• Test result leads to a change in study dosing or discontinuation from the study, significant
additional concomitant drug treatment, or other therapy
• Test result is considered to be an AE by the Investigator or Sponsor.
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE.
Any abnormal test result that is determined to be an error does not require reporting as an AE.
An AE does not include the following:

• Medical or surgical procedures performed; the condition that leads to the procedure may be an
AE if applicable
• Pre-existing disease, condition or laboratory abnormalities present or detected before the SV
that do not worsen
• Any medical condition or clinically significant laboratory abnormality with an onset before the
consent form is signed. Such a medical condition is considered to be pre-existing and should be
documented on the medical history of the eCRF.
The questions concerning whether the condition existed before the start of the active phase of the study
and whether it has increased in severity and/or frequency will be used to determine whether an event
is a treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when
the active phase of the study begins and is not a chronic condition that is part of the patient’s medical
history, or (2) it is present at the start of the active phase of the study or as part of the patient’s medical
history, but the severity or frequency increases during the active phase. The active phase of the study
begins at the time of the first dose of the study drug. The active phase of the study ends at the last
study visit.
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8.1.2. Adverse events of special interest (AESIs)
AESIs are treatment emergent AEs corresponding to the conceptual definition of:
• Muscle injury symptoms of severe intensity corresponding to:
o Muscle weakness
discontinuation
o Hepatic injury
o Hepatic failure
• Gastrointestinal symptoms of severe intensity corresponding to:
o Abdominal pain
o Constipation
o Diarrhea
o Nausea
o Vomiting
o Acute cholecystis
• Serum creatinine elevations of severe intensity or leading to permanent study drug
discontinuation
• Renal injury events of moderate or severe intensity corresponding to:
o Renal injury
o Renal failure
o Renal impairment
o Renal colic
o Tremor
o Ataxia
o Fasciculations
o Non-fatal stroke
o Unstable Angina
o Coronary Revascularization (bypass or percutaneous coronary intervention )
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are
described in the Section 8.6.1.
8.1.3. Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

• Results in death
• Is life-threatening
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• Requires in-patient hospitalization or prolongation of existing hospitalization

• Results in persistent or significant disability/incapacity
or
• Is a congenital anomaly/birth defect.
8.1.4. Clarification on Serious Adverse Events
• Death is an outcome of an AE, not an AE in itself.

• A SAE may occur even if the patient was not being treated with the study drug at the
occurrence of the event.
• Life-threatening means that patient is at immediate risk of death.
• Complications that occur during hospitalizations are AEs. If a complication prolongs the
hospitalization, it is a SAE.
• Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned
hospital stays or hospital stays for nonmedical social reasons will not be considered as
hospitalization. Of note, a procedure for protocol/disease-related investigations (e.g., biopsy)
should not be reported as SAE. Hospitalization or prolonged hospitalization for a complication
of such procedures should be reported as SAE.
• Only a persistent or significant or incapacitating disability is implied. This item refers to a
substantial disruption of a person’s ability to conduct normal life functions. Thus, disability is
not intended to include experiences of relatively minor medical significance such as headache,
nausea, vomiting, diarrhea, influenza, and accidental trauma.
• Congenital anomaly/birth defect includes foetal malformations associated with spontaneous
abortions or elective abortions.
• Medical and scientific judgment should be exercised in deciding whether expedited reporting
is appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize the patient
or may require intervention to prevent one of the other outcomes listed in the definition above.
These should also usually be considered serious.
• Any illnesses reported before starting active treatment or AE meeting the criteria of seriousness
(as defined above) and considered to be possibly related (according to the Investigator) to any
study-specific procedure (e.g. wash-out period, laboratory testing procedure, etc…) must be
reported as SAE.
8.1.5. Adverse Drug Reaction
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and
unintended at any dose and that is considered causally related to an investigational medicinal product.
A serious ADR (SADR) is an ADR which meets the seriousness criteria.
8.1.6. Unexpected Adverse Event
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature
of severity or specificity that is not consistent with the applicable IB or that is symptomatically and
pathophysiologically related to a known toxicity but differs because of a greater severity or specificity.
“Unexpected” refers to an ADR that has not been previously reported rather than an event that has not
been anticipated based on the properties of the drug.

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8.2. ASSESSMENTS
The Investigator will establish whether or not any AE have occurred at each visit from the date of
consent. The patient will be questioned in a general manner to determine specific symptoms without
offering the patient any suggestion.
8.2.1. Intensity Assessment
The intensity of the AE will be graded as follows:

• Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type
causing no loss of time from normal activities. Symptoms do not require therapy or a medical
evaluation; signs and symptoms are transient.
• Moderate: Events introduce a low level of inconvenience or concern to the subject and may
interfere with daily activities, but are usually improved by simple therapeutic measures;
moderate experiences may cause some interference with functioning.
• Severe: Events interrupt the subject’s normal daily activities and generally require systemic
drug therapy or other treatment; they are usually incapacitating.
8.2.2. Relation to the Study Treatment
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related
to study treatment. The Investigator will evaluate any changes in laboratory values, make a
determination as to whether or not the change is clinically important, and whether or not the changes
were related to study drug. However, even if the Investigator feels there is no relationship to the study
drug, the AE or clinically significant laboratory abnormality must be recorded in the CRF.
The Investigator will record the relation to the study treatment according to the following causality
terms:
• Related: the AE or laboratory test abnormality follows a reasonable temporal sequence from
the time of drug administration and it cannot be explained by the patient's clinical state or the
study procedures/conditions or other drugs. The AE abates upon discontinuation of the study
drug and reappears when the study drug is introduced.
• Possibly related: the AE follows a reasonable temporal sequence from the time of drug
administration, but could have been produced by the patient's clinical state or the study
procedures/conditions.
• Unlikely related: the temporal association between the AE and the study drug is such that
the study drug is not likely to have any reasonable association with the AE. The relationship is
not likely because of other plausible explanations.
• Not related: the AE must definitely be caused by the patient's clinical state or the study
procedure/conditions. A reasonable explanation must be given, e.g., no study drug taken,
preplanned elective medical intervention, or incompatible temporal relationship.
• Not assessable: the report suggesting an adverse reaction cannot be judged because
information is insufficient or contradictory and data cannot be supplemented or verified.
8.2.3. Action Taken and Outcome
The Investigator will record the action taken with drug and outcome of the event for each AE according
to the following:
Action taken with study drug

• Drug withdrawn – in case a patient is permanently withdrawn from the study drug
• Drug interrupted – in case the study drug is temporarily withdrawn
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• Dose not changed – in case no action is taken regarding the study drug
• Unknown
• Not applicable – an AE started before initiation of treatment with study drug, the treatment
had been completed prior to reaction/event, or the patient has died
Outcome
• Recovered/resolved
• Recovering/resolving
• Not recovered/not resolved
• Recovered/resolved with sequelae
• Fatal
• Unknown
Note: In case of irreversible congenital anomalies, the choice not recovered/not resolved should be
used. “Fatal” should be used when death is possibly related to the reaction/event.
8.3. REPORTING
8.3.1. Reporting an AE
All AEs regardless of seriousness or relationship to study drug, including those occurring during the
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s
medical record from the ICF signature until the last study visit of the patient. Whenever possible,
symptoms should be grouped as a single syndrome or diagnosis. The Investigator should specify the
date of onset, maximal intensity, action taken with respect to study drug, corrective therapy given,
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE was caused by
the study drug.
AE reporting begins from signature of the patient ICF at the first SV and ends at the last study visit.
8.3.2. Reporting a SAE or an AESI
SAE reporting begins from signature of the patient ICF and ends at the last study visit.
AESI reporting starts from first study drug intake and ends at study end for each patient.
Investigators must notify by email, or fax the Sponsor of all SAEs or AESIs IMMEDIATELY (within
24 hours of the Investigator becoming aware of the event) regardless of the causality. The
Investigator will be requested to supply as much detailed information regarding the event that is
available at the time of the initial contact (such as examinations carried out and laboratory results).
The Investigator is also required to submit follow-up reports to Sponsor or its representative within 24
hours of becoming aware of additional information such as diagnosis, outcome, causality
assessment, results of specific investigations and any new significant information that has not been
previously reported. Copies of additional laboratory tests, consultation reports, post mortem reports,
hospital case reports, autopsy reports, and other documents should be sent when requested and
applicable.
In case of death, a comprehensive narrative report of the case should be prepared by the Investigator
and sent to the Sponsor with the SAE/AESI form, retaining a copy on site with the CRF. If an autopsy
is performed, copy of autopsy report should be actively sought by the Investigator and sent to the
Sponsor as soon as available, retaining a copy on site with the CRF.
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Initial and follow-up report will be completed by the Investigator using appropriate template provided
to him by the Sponsor.
The expected / unexpected status of the serious and related AE will be judged by the Sponsor or its
designated Representative with regards to the reference documents (IB).
The Sponsor or its designated Representative will report all the relevant safety information to the
concerned IRB/IEC concerned according to the country specific requirements.
The Investigator must also fulfill his/her obligation regarding AE reporting according to the law in force
in his/her country.
8.3.3. Follow-up
The Investigator should take all appropriate measures to ensure the safety of the patients, notably
he/she should follow-up the outcome of any AE until the return to normal or until consolidation of the
patient condition.
The patient must be followed-up until clinical recovery is complete and laboratory results have returned
to normal, or until progression has been stabilized. This may imply that follow-up will continue after the
patient has left the study and that additional investigations may be requested by the Sponsor, notably
for the potential related AEs, and that additional investigations may be requested by the Sponsor . This
information should be documented in the patient’s medical records.
8.4. POST STUDY REPORTING REQUIREMENTS
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality,
should be reported.
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and
which is considered by him/her to be caused by the study drug within a reasonable possibility, should
be reported.
8.5. CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS

AES OR SAES
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory
abnormalities that are considered clinically relevant by the Investigator must be recorded as an AE or
SAE as applicable.
Reporting timelines for AEs and SAEs/AESIs are described respectively in Section 8.3.1 and Section
8.3.2

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8.6. SPECIAL SITUATION REPORTS
8.6.1. Pregnancy
In case of pregnancy a communication will be sent by the Investigator to the Sponsor by emailing a
completed pregnancy form within 24 hours of his/her knowledge of the pregnancy.
Pregnancies of females partners of male patients exposed to study drug should also be reported to the
Sponsor using the corresponding pregnancy form, provided that females partners sign the
corresponding and separate ICF.
Female patients must be instructed to discontinue the study drug immediately and inform the
Investigator as soon as possible once they are aware of being pregnant or suspect that they are
pregnant during the study or within 30 days of the last dose of the study drug.
Female patients will be requested, as part of the general ICF, to provide informed consent to allow
reasonable attempts to be made to obtain information on any possible study drug exposure to an
embryo or fetus and to follow up on the outcome of the pregnancy.
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome
of pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the
procedure for reporting SAEs/AESIs as detailed in Section 8.3.2.
8.6.2. Medication Error
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of

a medicinal product while in the control of the healthcare professional, patient, or consumer. All
medication errors will be documented in the eCRF and, in case of any potential risk to patient safety,
would be reported as appropriate.
8.6.3. Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used not in
accordance with the protocol. All misuse will be documented in the eCRF and, in case of any potential
risk to patient safety, would be reported as appropriate.
8.6.4. Overdose
This refers to the administration of a quantity of a medicinal product given per administration or
cumulatively, which is above the maximum recommended dose. Clinical judgment should always be
applied.

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8.6.5. Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which
is accompanied by harmful physical or psychological effects.

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9 STATISTICAL METHODS AND DATA ANALYSIS
This section is an overview of the key elements of the statistical analysis for this study. Further details
on statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This
SAP may be revised during the study only to accommodate protocol amendments and to make changes
to adapt to unexpected issues in study execution and data collection that could affect planned analyses.
In all circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The
first approved version of the SAP should be available within 3 months of first patient randomized and
before the first DSMB data review meeting.
Descriptive summary statistics for continuous variables will include the number of patients, mean, SD,
median, and range. Descriptive summary statistics for categorical variables will include frequency counts
and percentages. Unless stated otherwise, the denominator for percentage calculations will be the
number of patients with non-missing data.
9.1. ESTIMANDS CONSIDERATIONS
The primary objective of the study is to evaluate the effect of elafibranor (80 mg/day) on cholestasis
The cholestasis is predominantly characterized by elevation of serum ALP. In the Phase 2 study, a
significant effect of elafibranor on ALP serum levels was observed from the first visit following baseline
and was reinforced up to the end of the active treatment period. Thus, a rapid decrease of the ALP
serum levels in elafibranor group and no change in placebo group can be expected.
To limit the occurrence of intercurrent events (ICEs) such as study treatment discontinuations due to
lack of efficacy and/or use of rescue medication such as OCA, the patients and the investigators will
remain blinded of the ALP, GGT and 5’ NT results until the dabase lock and the Sponsor authorization
to unblind the study. Thus, no between group imbalance in the occurrence of these events that might
bias the treatment effect estimate in favor of elafibranor is expected.
As detailed below, in line with ICH E9 (R1) addendum; five attributes (treatment condition ,population,
endpoint, ICEs and population level summary) have been specified to translate the primary objective
into treatment effect that is to be estimated (estimands):
• Primary estimand
The composite strategy imputing non response for patients who experienced ICEs prior to week 52 will
be applied.
intolerant to UDCA,
- B. Population: Randomized patients with PBC and Inadequate Response or Intolerance to UCDA
- C. Endpoint: Response to treatment (binary variable) indicating a successful response at week
52 for a subject with ALP <1.67 x ULN, TB ≤ ULN and ALP decrease ≥ 15%, and who does not
stop prematurely the study treatment nor use any rescue therapy,
The primary estimand can be defined as the between treatment group difference in proportions of
patients, from all randomized patients, achieving response at week 52, defined as ALP < 1.67 x ULN,
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TB ≤ ULN and ALP decrease ≥ 15%, and not stopping prematurely the study treatment nor using rescue
therapy.
In addition, two strategies will be explored as supplementary analysis:

- The hypothetical strategy will be investigated comparing the potential outcomes that
would have been observed at week 52 between the treatment arms as if:
o The patients who experienced an ICE would follow their initial randomized
treatment
o The patients who experienced an ICE from both arms would continue on
placebo
In addition, a tipping point analysis will explore various scenarios among the hypothetical strategy where
missing outcomes experienced after an ICE vary independently from Elafibranor and placebo groups
- The treatment policy strategy will be investigated where patients are classified as
responders based on their outcome value at week 52 regardless of treatment
• Key secondary estimands
Key-secondary endpoint: Response to treatment based on ALP normalization at week 52.

be applied.
intolerant to UDCA,
- C. Endpoint: Response to treatment (binary variable) indicating a successful normalization of
ALP at week 52 without stopping prematurely the study treatment not using any rescue therapy,
The key secondary estimand can be defined as the between treatment groups difference in proportions
of patients, from all randomized patients, who successfully normalized their ALP at week 52 and who
do not prematurely stop the study treatment nor use any rescue therapy.
The same hypothetical and treatment policy strategies as for the primary estimand will be applied as
supplementary and sensitivity analyses.
Key-secondary endpoint: Change in pruritus from baseline through week 52 based on PBC Worst Itch
NRS in patients with baseline PBC Worst Itch NRS score ≥4.
The hypothetical strategy assuming that patients who experienced an ICE would have continued within
their treatment arm will be applied.
intolerant to UDCA,
- C. Endpoint: Change from baseline through week 52 in PBC Worst Itch NRS in patients with
baseline PBC Worst Itch NRS score ≥4,
- D. Intercurrent events: Any outcome value collected after a treatment discontinuation or use of
rescue therapy will be considered as missing,
- E. Population-level summary: Between treatment group difference in mean changes from
baseline.

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The key secondary estimand can be defined as the between treatment groups difference in PBC Worst
Itch NRS mean change from baseline from randomized patients with baseline PBC Worst Itch NRS score
≥4 through week 52 or week 24 assuming they continued the assigned treatment after they experienced
an ICE.
As for the key binary endpoints, a tipping point analysis point analysis will be performed to explore
several scenarios where missing outcomes experienced after an ICE vary independently from Elafibranor
and placebo groups.
In addition, the treatment policy strategy will be investigated where all outcome values until week 52
will be used regardless of treatment discontinuation or use of rescue therapy.
Key-secondary endpoint: Change in pruritus from baseline through week 24 based on PBC Worst Itch
NRS in patients with baseline PBC Worst Itch NRS score ≥4.
The estimand approach for the change in pruritus from baseline through week 24 based on PBC Worst
Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4 will be the same as defined for week
52.
9.2. RANDOMIZATION AND TREATMENT ASSIGNMENT
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis
and stratified by the following factors:
1) ALP > 3 x ULN or TB > ULN: Yes/No
2) PBC Worst Itch NRS score (averaged over the 14 days preceding randomization) ≥ 4: Yes/No
During the LTE period, all patients will receive elafibranor 80 mg.
9.3. ENDPOINTS
9.3.1. Primary Endpoint
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥
15%.
9.3.2. Secondary Endpoints

1-Response to treatment based on ALP normalization at week 52.
2-Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with baseline
PBC Worst Itch NRS score ≥4.
3-Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with

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b) ALP < 3 x ULN, AST <2 x ULN and TB < 1 mg/dL (Paris I)
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5 x ULN and TB ≤ ULN (Paris II)
f) TB ≤ 0.6 x ULN
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline
of more than 0.1XULN at week 52
i) Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin and INR
4) PBC risk scores at week 52: UK PBC score and GLOBE score
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by
AST, ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated
(hepatic)
fibrinogen, haptoglobin and TNF-
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis
as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and
liver stiffness measured by TE (continuous)
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C,
calculated VLDL-C and TG
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as
measured by bile acids, C4 and FGF-19
through week 52 and through week 24 in patients with a baseline NRS score ≥ 4
15) Proportion of patients with no worsening of pruritus from baseline through week 52 and
through week 24 measured by the PBC Worst Itch NRS
20) Change from baseline to week 52 in health utility as measured by EQ-5D-5L
21) Change from baseline to week 52 in serum markers of bone turnover and in bone mineral
density (hip and lumbar) assessed by DEXA scanning
a) MELD-Na > 14 for patients with baseline MED-Na <12
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b) Liver transplant
i) variceal bleed
ii) hepatic encephalopathy defined as West-Haven/Conn of 2 or more
e) Death
c) Liver markers
24) PK assessed by GFT505 and GFT2007 concentrations measurement in plasma
Additionally, the same endpoints as for the DB period (except histology – if applicable - and PK
assessment) will be collected over the LTE period to assess the maintenance of efficacy and safety of
the treatment.
9.3.3. Exploratory Endpoints (related to histological assessments)

reaction, cholestasis and concentric periductal fibrosis)
2) Correlation between histological fibrosis scores (Nakanuma and Ishak scores) and non invasive
markers of fibrosis (liver stiffness, ELF test and ProC3)
9.4. ANALYSIS SETS
The following analysis sets will be used in this study:
• Screened set: all patients who signed ICF. This set will be used to summarize disposition.
• ITT set: all randomized subjects. This set will be used to summarize efficacy.
• PP set: all subjects from the ITT set without any major protocol deviation affecting the primary
efficacy endpoint.
• SS: all subjects who were administered at least one dose of study drug. This set will be used to
summarize safety.
• PKS: All patients who were administered at least one dose of study drug and have at least
one post-dose PK sample. Moreover, patients of the PK set must have data for time of dosing,
time of sampling and amount of study drug administered. Whereas all patients are sampled

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in order to maintain the blind, the pharmacokinetics set applies only to patients under
elafibranor.
• Exploratory (Histological) set: All subjects from the ITT set who consent to have liver biopsy
samples collected at baseline and/or week 52
Patients in the ITT and PP sets will be analyzed based on randomized treatment. Patients in the SS will
be analyzed based on actual treatment received.
9.5. ANALYSIS OF PRIMARY ENDPOINT
The null hypothesis for response to treatment based on the primary endpoint is that there is no
difference in response rates between elafibranor and placebo groups. The alternative hypothesis is that
there is a difference in response rates between both groups. The null hypothesis will be tested at a two-
sided alpha of 0.05 (see Section 9.6). The efficacy analysis will be performed at the end of the common
DB period (week 52) only, but descriptive statistics will be provided over the entire DB period (up to
week 104).
The number and percentage of patients with favorable response to treatment will be summarized by
treatment group at the end of the 52 weeks of the common DB treatment period as well as at the end
of the overall DB period (either V6/V8/LVDB). The response rates (ALP < 1.67 x ULN and TB ≤ ULN and
ALP decrease ≥ 15%) at week 52 will be compared between the treatment groups using the exact
Cochran-Mantel-Haentzel test stratified by the randomization strata. The estimate of the odds ratio, its
95% CI and the corresponding p-value will be provided. The main analysis will be based on the ITT. To
assess the robustness of the results, the same analysis will be replicated on the PP set.
A sensitivity analysis to the statistical model will be performed on both ITT and PP sets, using an exact
logistic regression model with treatment group and randomization strata as factors.
Subjects who stopped prematurely the study treatment will be considered as non-responders.
Three supplementary/sensitivity analyses imputing outcome experienced after an ICE at Week 52 will
be applied using relevant multiple imputation methods. The imputations will be based on patients
completing the week 52 treatment period and relevant baseline covariates:
1) Outcomes will be imputed assuming that patients would follow their initial treatment (rather
than switching to placebo after discontinuation). Therefore, the treatment arm will be included
in the imputation model as a covariate or separate models will be fitted by treatment arm.
2) Outcomes will be imputed for both placebo and treatment dropouts as if they would continue
on placebo (using placebo-based multiple imputation (PBI)).
3) A tipping point analysis will be performed where outcomes will be imputed assuming that the
missing outcomes on the two arms vary independently.
A last supplementary analysis will use outcome value at week 52 regardless of treatment discontinuation
or use of rescue therapy.

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9.6. OTHER STATISTICAL ANALYSIS
9.6.1. Key secondary endpoints
The number and percentage of patients with favorable response to treatment (according to ALP
normalization) will be described at the end of the common DB treatment period and at the end of the
overall DB period (either V6/V8/LVDB), and the same statistical methods as for the primary endpoint
will be applied to evaluate the treatment effect at week 52.
The change from baseline in PBC Worst Itch NRS score through week 52 or through Week 24, in patients
with baseline PBC Worst Itch NRS score ≥4, will be summarized by treatment group using monthly
scores computed every 28 days and will be compared using a MMRM with stratification factors as fixed
factors. The statistical model will be used to calculate the mean treatment difference (elafibranor -
placebo), 95% CI and the corresponding p-value. The main analysis assumes that patients who
experienced an ICE would have continued within their treatment arm. A tipping point sensitivity analysis
will evaluate the impact on imputing outcomes in both treatment arms independently. A supplementary
analysis based on treatment policy will use outcome values at week 52 regardless of treatment
discontinuation or use of rescue therapy. Additionally, the PBC Worst Itch NRS-Past week score obtained
during the variable DB period will be described.
The same analyses as described above for the change from baseline in PBC Worst NRS score through
week 52 will be repeated for the change from baseline in PBC Worst NRS score through week 24.
All key secondary endpoints will be analysed on ITT and PP sets.
During the DB period
The continuous endpoints will be described all along the DB period. At week 52, they will be compared
between treatment groups using the MMRM with stratification factors as fixed factors. The statistical
model will be used to estimate the mean treatment difference and its 95% CI. As for the key secondary
endpoint, patients who will experience an ICE will be analyzed as if they would have continued within
their treatment arm.
The categorical endpoints will be described at week 52 and at the end of the DB period, and will be
analyzed using the exact Cochran-Mantel-Haentzel test stratified by the randomization strata. The
statistical model will be used to estimate the odds ratios and its 95% CI. As for the primary endpoint,
subjects with missing data will be considered as non-responders.
All the analyses of other secondary endpoints will be performed based on the ITT and additionally, on
the PP.

PK assessment are described in Section 6.1.4. The statistical considerations applicable to the popPK
modeling will be fully described in a dedicated Analysis Plan (popPK SAP).
During the LTE period

All the endpoints defined as primary or secondary endpoints (apart from histology – if applicable - and
PK endpoints) will be assessed during the LTE period at the appropriate timepoint to assess the
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maintenance of efficacy of the treatment. The endpoints will be summarized by treatment group using
descriptive statistics based on both ITT and PP.
9.6.3. Subgroup analyses
Exploratory analyses of the primary and key secondary endpoints will be done for the following
subgroups:
• Age (< or ≥ 65 years)

• Gender
• Race
• ALP level at baseline (≤ or > 3 x ULN)
• TB at baseline (≤ or > 1 x ULN)
• TB at baseline > ULN or albumin at baseline < LLN (Yes/No)
• TB > 0.6 x ULN (Yes/No)
• Geographic region
• PBC Worst Itch NRS score ≥ 4 (Yes/No)
• ALP > 3 x ULN or TB > ULN (Yes/No)
• Cirrhotic defined by Liver stiffness at baseline ≥ 16.9KPa at Fibroscan exam (Yes/No) and/or
cirrhosis on histology
• Advanced disease stage defined as liver stiffness at baseline >10 kPa at Fibroscan exam and/or
bridging fibrosis or cirrhosis on histology
Forest plots will be generated for each endpoint for patients in the ITT population. Further details will
be provided in the SAP.
9.7. STRATEGIES TO CONTROL TYPE I ERROR
The overall type I error for the primary and key secondary endpoints is two-sided α=0.05.
The fixed-sequence testing approach will be used to control the overall type I error rate at a two-sided
0.05 level. If the primary endpoint is statistically significant at a two-sided 0.05 level, the first key
secondary endpoint (ALP normalization) will be tested at the same level. If the first key secondary
endpoint is statistically significant at a two-sided 0.05 level, the second key secondary endpoint (change
in pruritus through week 24) will be tested at the same level. If the second key secondary endpoint is
statistically significant at a two-sided 0.05 level, the third key secondary endpoint (change in pruritus
through week 24) will be tested at the same level.
Statistical testing for other secondary endpoints will be of exploratory nature.

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9.8. SAMPLE SIZE CALCULATION
All sample size calculations were done in East® 6.5.
9.8.1. Reduction in ALP and TB
• An expected response rate in the placebo group slightly higher than that in the phase 3 pivotal
study supporting the regulatory approval of OCA (10%) [4]
• An expected response rates in the Elafibranor group at least similar to OCA (47%)
estimated after imputation of missing or non reliable data as non response.
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power
to demonstrate a statistically significant between group difference of 35% (47% in elafibranor group vs
12% in placebo group) in the response rate at week 52 of the primary efficacy endpoint with a two-
sided alpha of 0.05 and using an exact Fisher test.
9.8.2. Normalization in ALP
Assuming 1/50 (2.0%) patient in the placebo arm with ALP normalization at week 52 (key secondary
endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power to detect a
statistically significant between group difference of 20.0% at a two-sided 0.05 alpha level.
9.8.3. Change in pruritus
Assuming a pooled SD of 2.3 points, 60 patients (40 elafibranor vs 20 placebo) with baseline PBC Worst
Itch NRS score ≥4 provide at approximately 80% power to detect a statistically significant between
group difference of 1.8 points in mean change from baseline in PBC Worst Itch NRS at a two-sided 0.05
alpha level. It is assumed that the same assumptions would apply to the two key secondary endpoints
for pruritus (through week 52 and through week 24).
9.9. SAFETY ANALYSIS
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will be summarized by
treatment group and overall using descriptive statistics after both DB period and LTE period. The main
summaries of safety will be based on the SS.
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
Descriptive statistics will be presented giving the number and percentage of patients reporting at least
one AE, the number of events and the EAIR. In addition, comparison of treatment arms will be
performed giving EAIR estimates and their CIs. An overall summary of AEs will be provided. AEs will
also be presented by MedDRA System Organ Class and Preferred Term. The AEs will be summarized by
worst severity and relationship to study drug. SAEs, AESIs, and AEs leading to discontinuation will also
be summarized. Narratives will be written for all SAEs, AESIs, and AEs leading to discontinuation.
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Clinical laboratory values (hematology, chemistry, and urinalysis) recorded at each timepoint and
change from baseline will be summarized by treatment group and overall using descriptive statistics.
Clinical laboratory values for each parameter will be assigned a classification according to whether the
value is lower than, within, or higher than the reference range for that parameter. The values will then
be summarized using shift tables to evaluate categorical changes from baseline to end of the 52 weeks
treatment period and end of DB period with respect to reference ranges. The number and percentage
of patients reporting markedly abnormal clinical laboratory values will also be summarized by treatment
group and overall.
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group
and overall using descriptive statistics.
9.10. EXPLORATORY ANALYSIS (RELATED TO HISTOLOGICAL ASSESSEMENTS)
Descriptive statistics on the histological scores and the non invasive markers of fibrosis (liver stiffness,
ELF test and ProC3) will be provided by DB treatment groups and overall in the Exploratory (Histological)
set.
Change over time on the histological scores will be described using shift tables. In addition, the value
at each visit as well as the change from baseline will be described on the non invasive markers of
fibrosis.
For assessing the correlation between the histological fibrosis endpoints (Nakanuma and Ishak scores)
and the non invasive markers of fibrosis, the correlation coefficients and their CIs will be estimated
depending on the nature and distribution of the endpoints considered.

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10 DATA HANDLING AND RECORD KEEPING
10.1. DATA PROTECTION
The contract between the sponsor and their vendors, and study sites specifies the responsibilities of the
parties related to data protection, including handling of data security breaches and respective
communication and cooperation of the parties.
Information technology systems used to collect, process, and store study-related data are secured by
technical and organizational security measures designed to protect such data against accidental or
unlawful loss, alteration, or unauthorized disclosure or access.
In the event of a potential data security breach concerning personal data processed on behalf of the
sponsor, the data protection officer must be informed without undue delay and no later than 24 hours
from the discovery of the event. The data protection officer will evaluate the event and notify the Data
Protection Authorities within 72 hours, if required. Corrective actions and preventive actions will be
implemented to mitigate the possible adverse effects. Affected study participants will be informed
accordingly. Ipsen Data Protection Officer can be contacted by email: dataprivacy@ipsen.com.
10.2. CASE REPORT FORM AND SOURCE DOCUMENTS
An eCRF is required and should be completed for each screened patient. The completed eCRFs are the
sole property of the Sponsor and should not be made available in any form to third parties, except for
authorized Sponsor’s representatives or appropriate regulatory authorities, without written permission
from the Sponsor.
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and
conform to source documents, in accordance with specific instructions accompanying the eCRFs
designed specifically for this study. The CRF being used for this study is an electronic CRF that has been
fully certified as being compliant with the ICH Good Clinical Practice (GCP) guidance requirements.
All study required patient data generated during the study will be recorded in the eCRF, with the
exception of SAE forms which will be collected in paper. PRO data and central lab data will be transferred
from electronic (source data) in the SDTM datasets. Patients will not be identified by name in the eCRF
or on any study documents to be collected by the Sponsor (or designee), but will be identified by a
unique patient number.
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as
attestation of the Investigator’s responsibility for ensuring that all data entered in the eCRF are
complete, accurate, and authentic.
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized
person and explained (if necessary). All corrected data will be tracked through an audit trail.
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical
file (medical history, concomitant diseases, patient identification number, date of informed consent, visit
dates, administration of study drug, AEs [start and stop dates] and all concomitant medications [start
and stop dates]). All data recorded in the eCRF will be documented by source data.

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10.3. RETENTION OF RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of the study to
be fully documented and the study data to be subsequently verified.
The Investigator will be provided with a study file, which should be used to file the IB,
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae,
and correspondence with the IRB/IEC, Sponsor, and other study-related documents.
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees
to keep records, including the identity of all participating patients, all original signed ICFs, copies of all
eCRFs, source documents, and detailed records of treatment disposition.
The Investigator must retain the study documentation until at least 2 years after the last approval of a
marketing application in an ICH region and until there are no pending or contemplated marketing
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical
development of the study drug. However, these documents should be retained for a longer period if
required by the applicable regulatory requirements or by an agreement with the Sponsor. All hospital
records will be archived according to local regulation.
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from
the study. The study records must be transferred to an acceptable designee, such as another
Investigator, another institution, or to the Sponsor.

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11 QUALITY CONTROL AND QUALITY ASSURANCE
11.1. QUALITY CONTROL & MONITORING PROCEDURES
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the
protocol, GCP (ICH topic E6 R2), applicable regulatory requirements, and the current Declaration of
Helsinki and that valid data are entered into the eCRFs.
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time,
the Sponsor in the maintenance of attributable, legible, and contemporaneously recorded, original or a
true copy, accurate (ALCOA), well-organized, and easily retrievable data.
Before screening any patients in this study, the Study Monitor will review the protocol, the IB, the eCRFs
and instructions for their completion and return, the procedure for obtaining informed consent, and all
other study procedures (e.g. the laboratory manual, electronic patient-reported outcomes [ePRO]
manual, IXRS manual, etc) including the reporting AEs, AESIs and SAEs with the Investigator. In
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable
regulations concerning the clinical evaluation of the study drug.
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory.
A Study Monitor from the CRO will be responsible for monitoring this clinical study. To this end, the
Study Monitor will visit the study site at suitable intervals and be in frequent contact through verbal and
written communication. The eCRFs and related source documents, as well as drug accountability will be
reviewed in detail by the monitor, in accordance with relevant SOPs and GCP (ICH topic E6 R2)
regulations. This includes results of tests performed as a requirement for participation in this study and
any other medical records required to confirm information contained in the eCRFs, such as past medical
history.
In cases of emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure data
monitoring, according to national regulations and under the responsibility of the Investigator, remote
access to source documents can be provided to the Study Monitor to perfom remote Source Data
Verification (SDV).Further details can be found in the monitoring plan.
It is essential that the Study Monitor has access to all documents (related to the study and the individual
subjects) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected
to cooperate with the Study Monitor, to be available during a portion of the monitoring visit to answer
questions, and to provide any missing information.
All monitoring activities will be reported and archived in the Trial Master File.
11.2. ETHICAL PRINCIPLES
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki,
1964) and all applicable amendments laid down by the World Medical Assemblies and the GCP
guidelines.
This study also complies with applicable local regulatory requirements and laws of each country in which
the study is performed, as well as any applicable guidelines.

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11.3. QUALITY ASSURANCE
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements,
the Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable
regulatory authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to
his/her study records for review, being understood that these personnel will adhere to all requirements
for patient confidentiality, and as such will not disclose any personal identity or personal medical
information.
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the
Sponsor and authorize the Sponsor to participate to this inspection if permitted by the Authorities.
The confidentiality of the data verified and the anonymity of the patients should be respected during
these inspections.
The clinical study protocol, each step of the data capture procedure, and the handling of the data,
including the final clinical study report, will be subject to independent Quality Assurance activities. Audits
may be conducted at any time during or after the study to ensure the validity and integrity of the study
data.

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12 ETHICS AND REGULATORY
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
The GCP guidelines and the US Code of Federal Regulations (CFR) Title 21 Section 56 (21 CFR 56)
require that approval must be obtained from an IRB/IEC prior to participation of human patients in
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient
recruitment, and any other written information regarding this study to be provided to the patient must
be approved by the IRB/IEC. The Sponsor will supply relevant material for the Investigator to submit to
the IRB/IEC for the protocol’s review and approval. Verification of the IRB/IEC’s unconditional approval
of the protocol and the written ICF statement will be transmitted to the Investigator. Documentation of
the relevant IRB/IEC approval and of the IRB/IEC compliance with GCP guideline will be maintained by
the site and will be available for review by the Sponsor or its designee or by the authorized members
of regulatory agencies.
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of
the clinical research before the start of the study.
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC.
If any alterations, other than changes of administrative nature only, are made to the study protocol, a
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of
subsequent protocol amendments and of suspected unexpected serious adverse reactions (SUSARs).
Approval for protocol amendments will be transmitted in writing to the Investigator.
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported
to the IRB/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the
required time frame.
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing
direct access to source data/documents.
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed
one year) and a Study Progress Report following the completion, termination, or discontinuation of the
Investigator’s participation in the study.
12.2. COMPETENT AUTHORITY
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from
Competent Authorities should be granted before the beginning of the study. If applicable, Amendments
will also be submitted to CA for approval.
12.3. PATIENT INFORMATION AND CONSENT
Written ICF for the study will be obtained from each patient before protocol-specific procedures are
carried out. The ICF used by the Investigator for obtaining the patient's informed consent must be

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reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC.
The Investigator or a person designated by the Investigator (according to applicable regulatory

requirements), will explain the nature of the study and the action of the study drug. The patients will
be informed that participation is voluntary and that they can withdraw from the study at any time. In
accordance with 21 CFR 50 local regulations, ICH guidelines, privacy and data protection requirements,
where applicable, the informed consent process shall be documented by the use of a written ICF
approved by the designated IRB/IEC and will be signed and personally dated by the patient and by the
person who conducted the informed consent discussion prior to protocol-specific procedures being
performed.
A separate consent form will be obtained for optional biomarker samples to be collected and to be
stored in the blood bank.
Participants to the optional research biobanking programme have the right to withdraw their consent at
any time and for any reason during the study or during the period of sample storage (i.e. the entire 15
years during which samples are kept).
If a participant wishes to withdraw their consent for optional biobanking and the samples are still at the
investigator site or at the central laboratory at the time, the investigator must inform the study monitor
in writing of the participant’s decision and destroy the samples.
If the samples are at the sponsor’s repository (biobanking vendor), the investigator must inform the
sponsor directly using the e-mail address: IpsenBiobanking@ipsen.com, mentioning only the participant
ID in this e-mail. The sponsor will ensure destruction of the samples and all corresponding aliquots and
issue confirmation of the destruction, which will be forwarded to the investigator. Analyses conducted
before the withdrawal will not be affected.
In addition separate consent forms will be obtained for optional liver biopsy sample collection, as well
as for pregnant partner data collection.
The Investigator must maintain the original, dated and signed ICFs. A copy of the signed ICFs must be
given to the patient.
12.4. PATIENT CONFIDENTIALITY
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion
of privacy. Throughout this study and any subsequent data analyses, all data will be identified only by
protocol number and patient number.
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and
shall not be published or disclosed to a third party without the prior written consent of the Sponsor.
Investigators who has/have contributed significantly to the study will be asked to endorse the final
report. The endorsement is required by some regulatory agencies.
The Investigator shall not make a patent application based on the results of this study and shall not
assist any third party in making such an application without the written authorization of the Sponsor
unless otherwise specified in the Clinical Trial Agreement (CTA).

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12.5. DEFINITION OF THE END OF THE RESEARCH
The end of the study is defined as completion of the last visit or procedure of the last patient
participating in the study globally (last EOT DB/EOT LTE visit).

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13 FINANCING AND INSURANCE
13.1. FINANCIAL ISSUES
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation
of the study.
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial
information as requested to allow the Sponsor to submit complete and accurate financial certification or
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for
providing information on financial interests during the course of the study and for one year after
13.2. INSURANCE AND PATIENT INJURY
The patients taking part in the study will be covered by the insurance taken by the Sponsor for this
study, if they were to suffer any prejudice as a result of taking part in the study.
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable
and necessary medical treatment for the injury, to the extent the expenses are not covered by the
patient’s medical insurance, a government program, or other responsible third party. If laws or
regulations of the locality in which the study is taking place require additional payment of expenses, the
Sponsor shall comply with such law or regulation.
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its
civil liability and that of everyone involved in the research, and notably that of the Investigators and
their colleagues with regard to any accidents or damage concerning the administration of the drug or
paraclinical examinations directly linked to the performance of the study.

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14 STUDY RESULTS AND PUBLICATION POLICY
14.1. STUDY REPORT
The final report will be written in English upon completion of study and statistical analysis according to
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable.
The Sponsor will prepare an integrated Clinical Study Report (CSR). Prior to issuing the final CSR, the
CRO will prepare a draft report for approval by the Sponsor and by the study Steering Committee. The
draft report will be submitted for Quality Control, the findings of which will be incorporated into the final
version.
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND
PUBLICATION
All materials, information (oral or written), and unpublished documentation provided to the Investigators
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the
IB, are the exclusive property of the Sponsor and may not be published, given, or disclosed, either in
part or in whole, by the Investigator or by any person under his/her authority to any third party without
the prior express consent of the Sponsor.
However, the submission of this protocol and other necessary documentation to IRB/IEC and the
Competent Authority is expressly permitted, their members having the same obligation of confidentiality.
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or
deduced) in the course of the study, other than that information to be disclosed by law, as confidential
and shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s
prior written consent.
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other
information collected during this study. Therefore, the Sponsor reserves the right to use the data from
the present study, either in the form of CRFs (or copies of these), or in the form of a report, with or
without comments and with or without analysis, in order to submit them to the Health Authorities of
any country.
Investigators who has/have contributed significantly to the study will be asked to endorse the CSR. The
endorsement is required by some regulatory agencies.
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting
on his/her behalf according to local requirements) shall refrain from filing patent application(s) on such
results, which will be filed by the Sponsor or its designees in its own name and at its expense.
Protocol information and (final/interim) study results will be made publicly available on the US website
(www.clinicaltrials.gov) and on the EU Clinical Trials Register (www.clinicaltrialsregister.eu) or EU
Clinical Trials Portal (https://euclinicaltrials.eu/home). The sponsor also provides clinical trial information
to other national clinical trial registries or databases according to local requirements/legislation. A lay
summary of the study will be made available on the EU Clinical Trials Portal
(https://euclinicaltrials.eu/home) and/or Sponsor website.

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It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results.
The study results may be published or presented at scientific meetings after agreement between the
Sponsor and the Investigators.
If this is foreseen, the investigator should discuss specific publication concepts, including data to be
covered, target congress/journal and proposed authors, with the Sponsor for agreement before
initiation. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its
employees appear or not appear in such publication. The investigator agrees to submit all manuscripts
or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary
information and to provide comments.

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15 REFERENCES LIST
1 Lammers, W.J., K.V. Kowdley, and H.R. van Buuren, Predicting outcome in primary biliary
cirrhosis. Ann Hepatol, 2014. 13(4): p. 316-26.
2 Carbone, M., et al., The UK-PBC risk scores: Derivation and validation of a scoring system for
long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology, 2016.
63(3): p. 930-50.
3 Lammers, W.J., et al., Development and Validation of a Scoring System to Predict Outcomes of
Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy.
Gastroenterology, 2015. 149(7): p. 1804-1812 e4.
4 Nevens, F., et al., A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
New England Journal of Medicine, 2016. 375(7): p. 631-643.
5 Kuiper, E.M., et al., Relatively high risk for hepatocellular carcinoma in patients with primary
biliary cirrhosis not responding to ursodeoxycholic acid. Eur J Gastroenterol Hepatol, 2010.
22(12): p. 1495-502.
6 Kumagi, T. and E.J. Heathcote, Primary biliary cirrhosis. Orphanet J Rare Dis, 2008. 3: p. 1.
7 Boonstra, K., U. Beuers, and C.Y. Ponsioen, Epidemiology of primary sclerosing cholangitis and
primary biliary cirrhosis: a systematic review. J Hepatol, 2012. 56(5): p. 1181-8.
8 Kim, W.R., et al., Epidemiology and natural history of primary biliary cirrhosis in a US
community. Gastroenterology, 2000. 119(6): p. 1631-6.
9 Al-Harthy, N. and T. Kumagi, Natural history and management of primary biliary cirrhosis. Hepat
Med, 2012. 4: p. 61-71.
10 Selmi, C., et al., Environmental pathways to autoimmune diseases: the cases of primary biliary
cirrhosis and multiple sclerosis. Arch Med Sci, 2011. 7(3): p. 368-80.
11 Ali, A., T. Byrne, and K. Lindor, Orphan drugs in development for primary biliary cirrhosis:
challenges and progress. 2015. 5: p. 83-97.
12 Hirschfield, G.M. and M.E. Gershwin, The immunobiology and pathophysiology of primary biliary
cirrhosis. Annu Rev Pathol, 2013. 8: p. 303-30.
13 Beuers, U. and K.D. Lindor, A major step towards effective treatment evaluation in primary
biliary cirrhosis. J Hepatol, 2011. 55(6): p. 1178-80.
14 Carbone, M., et al., Sex and age are determinants of the clinical phenotype of primary biliary
cirrhosis and response to ursodeoxycholic acid. Gastroenterology, 2013. 144(3): p. 560-569 e7;
quiz e13-4.
15 Lammers, W.J., et al., Levels of alkaline phosphatase and bilirubin are surrogate end points of
outcomes of patients with primary biliary cirrhosis: an international follow-up study.
Gastroenterology, 2014. 147(6): p. 1338-49 e5; quiz e15.
16 Giannini, E.G., R. Testa, and V. Savarino, Liver enzyme alteration: a guide for clinicians. CMAJ,
2005. 172(3): p. 367-79.
17 Crosignani, A., et al., Clinical features and management of primary biliary cirrhosis. World J
Gastroenterol, 2008. 14(21): p. 3313-27.
18 Corpechot, C., et al., Biochemical response to ursodeoxycholic acid and long-term prognosis in
primary biliary cirrhosis. Hepatology, 2008. 48(3): p. 871-7.
19 Lindor, K.D., et al., Primary biliary cirrhosis. Hepatology, 2009. 50(1): p. 291-308.
20 EASL, EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol,
2009. 51(2): p. 237-67.
21 Corpechot, C., et al., A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.
New England Journal of Medicine, 2018. 378(23): p. 2171-2181.
22 Ghonem, N.S., D.N. Assis, and J.L. Boyer, Fibrates and cholestasis. Hepatology, 2015. 62(2): p.
635-43.
23 Cattley, R., et al., Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard
to Humans? Regulatory Toxicology and Pharmacology, 1998. 27(1): p. 47-60.
24 Corpechot et al Noninvasive Elastography-Based Assessment of Liver Fibrosis Progression and
Prognosis in Primary Biliary Cirrhosis. Hepatology 2012; 56 (1). p 198-212.

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25 Murillo Perez, C.F., et al., Goals of Treatment for Improved Survival in Primary Biliary
Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization
of Alkaline Phosphatase. Am J Gastroenterol, 2020.
26 Pickering, T.G., et al., Recommendations for blood pressure measurement in humans and
experimental animals: part 1: blood pressure measurement in humans: a statement for
professionals from the Subcommittee of Professional and Public Education of the American
Heart Association Council on High Blood Pressure Research. Circulation, 2005. 111(5): p. 697-
716.
27 Elman, S., et al., The 5-D itch scale: a new measure of pruritus. Br J Dermatol, 2010. 162(3):
p. 587-93.
28 Jacoby, A., et al., Development, validation, and evaluation of the PBC-40, a disease specific
health related quality of life measure for primary biliary cirrhosis. Gut, 2005. 54(11): p. 1622-
9.
29 Broderick, J.E., et al., Pittsburgh and Epworth sleep scale items: accuracy of ratings across
different reporting periods. Behav Sleep Med, 2013. 11(3): p. 173-88.
30 Johns, M.W., A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
Sleep, 1991. 14(6): p. 540-5.
31 Chalasani, N. and A. Regev, Drug-Induced Liver Injury in Patients With Preexisting Chronic Liver
Disease in Drug Development: How to Identify and Manage? Gastroenterology, 2016. 151(6):
p. 1046-1051.
32 Regev, A., et al., Consensus: guidelines: best practices for detection, assessment and
management of suspected acute drug-induced liver injury during clinical trials in patients with
nonalcoholic steatohepatitis. Aliment Pharmacol Ther, 2019. 49(6): p. 702-713.
33 CTFG, Recommendations related to contraception and pregnancy testing in clinical trials.
Available at:https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.
1_updated.pdf.

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16 APPENDICES:
16.1. APPENDIX 1: ALCOHOL COMPARISON TABLE
Alcohol Alcohol by Volume Amount of alcohol

type volume (ABV) Fluid ounce mL Units Grams
Beer 3.5% 12 350 0.7 9.8
Beer 5% 12 350 1 14
Cider 7% 12 350 1.4 19.6
Distilled
spirits or 40% 1.5 45 1 14
liquor
Wine 12% 5 150 1 14
Footnote:
1. e.g., gin, rum, vodka, whiskey.
2. Units calculated using the Cleave Books calculator for units of drink, using the US definition of 1 unit of alcohol as
17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm)

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16.2. APPENDIX 2: PERMITTED/NON-PERMITTED MEDICATION
A. NON-PERMITTED MEDICATION AND CONDITION
Medications When
Same pharmacological class (PPAR agonists)
Thiazoledinediones (glitazones [pioglitazone and
rosiglitazone]) From 2 months prior to screening and
throughout the study
Fibrates
Other Medications
Obeticholic acid (OCA) From 3 months prior to screening and
throughout the study
Seladelpar
Budesonide and other systemic Corticosteroids (parenteral
& oral chronic administration only)
Azathioprine
Cyclosporine
Methotrexate
Mycophenolate
From 3 months prior to screening and
Pentoxyfilline throughout the study
Alpha-methyl-dopa
Sodium valproic acid
Isoniazide
Nitrofurantoin
Amiodarone
Tamoxifen
Antibodies or immunotherapy directed against ILs or other From 12 months prior to screening and
cytokines or chemokines throughout the study

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B. PERMITTED MEDICATION AND CONDITION
Medications When
Therapies for treatment of PBC
Taken for at least 12 months prior to screening with
Dose stability required from at least 3 months prior to
UCDA screening and throughout the study.
Therapies for treatment of pruritus
Cholestyramine
Rifampin Dose stability required for at least 3 months prior to
Naltrexone screening and up to the end of the Double Blind period.
Sertraline
Other Medications
Colchicine
Lipid lowering therapy
Statins Dose stability required from at least 2 months prior to
Ezetimibe screening

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16.3. APPENDIX 3: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES:
16.3.1. PBC-40

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Page 239

Page 240

Page 241
16.3.2. Epworth Sleepiness Scale (ESS)

Page 242
16.3.3. 5-D Itch Scale

Page 243
16.3.4. PROMIS Fatigue Short Form 7a

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16.3.5. The Patient Global Impression of Change (PGIC)

Page 245
16.3.6. The Patient Global Impression of Severity (PGIS)

Page 246
16.3.7. PBC Worst Itch NRS
PBC Worst Itch NRS
PBC Worst Itch NRS-Past Week

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16.3.8. EuroQoL EQ-5D-5L

Page 248

IPSEN GROUP Page 249 GFT505B-319-1
CONFIDENTIAL
PROTOCOL V1.0 VS V5.0 PAGE 1/44
Summary of Amended Protocol Changes
A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term

Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with
Primary Biliary Cholangitis with Inadequate Response or Intolerance to
Ursodeoxycholic Acid
Original Protocol (v1.0) Date: 22 July 2020

Current Protocol (v5.0) Date: 20 December 2022
Study Drug: Elafibranor
Protocol number: GFT505B-319-1

EudraCT number: N°2019-004941-34
Sponsor:
IPSEN PHARMA SAS

65 Quai Georges Gorse
CONFIDENTIAL
Summary change table from original version of the protocol

Any new or amended text in the protocol is indicated in bold (IS column).
Deletions are marked in strikeout text (WAS column).
Minor formatting and editing are not included.
Section WAS (Version 1.0, 22 JULY 2020) IS (Version 5.0, 20 DECEMBER 2022)
All pages Protocol version 1.0 22 July 2020 Protocol version 5.0 20 December 2022
(header)
All pages GENFIT IPSEN PHARMA SAS
(header)
CONFIDENTIAL
Title page International International

Coordinating PPD Toronto Centre for Liver Coordinating PPD Elson S. Floyd College of
Investigator MB Disease, University Health Investigator MD Medicine
Committee BChir, PhD Network and University of Committee Director, Washington State University
Professor of Toronto, Toronto, Canada Liver Institute 3216 NE 45th Place, Suite 212
Medecine, Phone: +1 416-340-4548 Northwest Seattle, WA, USA 98105
Division of Email: Clinical Phone: +1 206-459-8479
Gastroenterology PPD Professor Email:
PPD
PPD Elson S. Floyd College of
MD Medicine PP Department of Medicine
Director, Liver Washington State University D University Medical Center
Institute 3216 NE 45th Place, Suite 212 MD Mainz
Northwest Seattle, WA, USA 98105 Langenbeckstraße,1
Director,
Clinical Professor Phone: +1 206-459-8479 55131 Mainz, Germany
Metabolic
Email: Liver Phone: +49 6131 176074
PPD Research Email:
Program PPD
PP Department of Medicine
D University Medical Center
Mainz
MD
Langenbeckstraße,1
Director, 55131 Mainz, Germany
Metabolic Liver
Phone: +49 6131 176074
Research
Program Email:
PPD
Sponsor
GENFIT Sponsor
Parc Eurasanté IPSEN PHARMA SAS
885, Avenue Eugène Avinée 65 Quai Georges Gorse
59120 Loos, France 92100 Boulogne-Billancourt, France
Represented by: Represented by:

CONFIDENTIAL
PPD MD PPD MD, MSc
Deputy CMO Senior Medical Development Director
Phone: +33 320 16 40 38 Phone: +1 857-600-8195
Email: PPD Email: PPD
Clinical study Pages deleted and replaced by the corresponding ‘Sponsor signatory’
protocol page of the Ipsen Protocol Template
signature page
Clinical study Page deleted and replaced by the corresponding ‘Principal investigator
protocol – signature’ page of the Ipsen Protocol Template
Investigator
signature page
CONFIDENTIAL
Study contacts International Coordinating Investigator Committee International Coordinating Investigator Committee
PPD Toronto Centre for Liver Disease, PPD MD Elson S. Floyd College of
Professor of Medicine, Division University Health Network and Director, Liver Institute Medicine
of Gastroenterology University of Toronto, Toronto, Northwest Washington State University
Canada Clinical Professor 3216 NE 45th Place, Suite 212
Phone:+1 416-340-4548 Seattle, WA, USA 98105
Email: Phone: +1 206-459-8479
PPD PPD Email:
PPD MD Elson S. Floyd College of PPD
Director, Liver Institute Medicine PPD MD Department of Medicine
Northwest Washington State University Director Metabolic Liver University Medical Center Mainz
Clinical Professor 3216 NE 45th Place, Suite 212 Research Program Langenbeckstraße,1
Seattle, WA, USA 98105 55131 Mainz, Germany
Phone: +1 206-459-8479 Phone: +49 6131 176074
Email: Email:
PPD PPD
PPD MD Department of Medicine
Director Metabolic Liver University Medical Center Mainz
Research Program Langenbeckstraße,1 Sponsor
55131 Mainz, Germany
Phone: +49 6131 176074 Represented by: IPSEN Pharma SAS
Email: PPD MD, MSc 65 Quai Georges Gorse
PPD Senior Medical Development 92100 Boulogne-Billancourt,
Director France
Phone: +1 857-600-8195
Sponsor Email: PPD
Represented by: Parc Eurasanté

PPD MD 885, Avenue Eugène Avinée
Deputy CMO 59120 Loos, France
Phone: +33 320 16 40 38
Email: PPD
CONFIDENTIAL
CRO for project Covance Covance Clinical and

management, Periapproval Services
regulatory activities, Limited,
site data monitoring Osprey House,
and medical Maidenhead Office
monitoring and Park,
Clinical Study Westacott Way,
Report Maidenhead,
SL6 3QH, UK
management & 39 rue d’Aboukir
statistics 75002 Paris, France
Pharmacovigilance SGS Life Science SGS
Services Medical Generaal De
Affairs Wittelaan 19A bus 5
2800 Mechelen –
Belgium
Study drug supplier ALMAC ALMAC Clinical
Services
9 Charlestown Road,
Seagoe Industrial
Estate Craigavon
BT63 5PW, UK
9 Plaça de Catalunya,
Floor 5
Barcelona, Spain
Central laboratory Cerba Research NV 3, Industriepark
Zwijnaarde
B-9052 Ghent,
Belgium
BARC USA Inc
5 Delaware Drive
Lake Success
NY 11042-1114,
United States
CONFIDENTIAL
PK assessments ADME-bioanalysis 75, Chemin de
Sommières
30310 Vergèze –
France
ePRO ERT ERT
1818 Market Street,
Suite 1000,
Philadelphia,
Pennsylvania 19103,
USA
Protocol - Added section to comply with Ipsen Protocol template

amendment
summary of
changes
Clinical study Changes included in the protocol were implemented in the clinical
synopsis study synopsis, Table 1 and Table 2.
1. Introduction 1.1. Background and rationale for elafibranor in primary biliary Elafibranor has been developed by Genfit for the treatment of PBC.
and Rationale cholangitis In December 2021, Genfit and IPSEN (“the partner”) entered into an
exclusive licensing agreement for elafibranor, which gives the
Characterization of the disease partner, the exclusive worldwide license for the future development
… of elafibranor in PBC, with the exception of China, Taiwan, Hong-
Kong and Macau. The transfer of sponsorship from Genfit to IPSEN
is anticipated to take place within approximately 30 days of top line
results for the double-blind portion of the study (part A).
1.1. Background and rationale for elafibranor in primary

biliary cholangitis

…
CONFIDENTIAL
1.3 Clinical 1.3.1 Phase 1 Program 1.3.1 Phase 1 Program
Studies
A Phase 1 program to assess the safety and the tolerability, as well as the PK A Phase 1 program to assess the safety and the tolerability, as well as the
profile, of elafibranor currently comprises 13 completed and 4 ongoing PK profile, of elafibranor currently comprises 13 completed and 4 ongoing
clinical studies. As of 31 July 2019 (the date of the most recent Development clinical studies. As of 31 July 2022 (the date of the most recent
Safety Update Reports (DSUR) update (Development Safety Update Reports, Development Safety Update Reports (DSUR) update (Development
2019), 659 volunteers had been randomized in these studies, including 561 Safety Update Reports, 2019), 755 volunteers had been randomized in
healthy and lean subjects, 60 overweight or obese but otherwise healthy these studies, including 650 healthy and lean subjects, 60 overweight or
subjects, 12 subjects with type 2 diabetes, 6 with end stage renal disease and obese but otherwise healthy subjects, 12 subjects with type 2 diabetes, 13
20 with hepatic impairment (Child-Pugh class A, B or C). Elafibranor daily with renal impairment (ESRD) and 20 with hepatic impairment (Child-
doses ranged between 5 mg and 360 mg, with a maximum treatment duration Pugh class A, B or C). Elafibranor daily doses ranged between 5 mg and
of 14 to 16 days. 360 mg, with a maximum treatment duration of 14 to 16 days.
Additional information can be found in the IB. Additional information can be found in the IB.
CONFIDENTIAL
1.5 Rationale Partial or suboptimal responders constitute up to 40% of UDCA-treated PBC Partial or suboptimal responders constitute up to 40% of UDCA-treated
For Study patients [11]. This group of patients along with patients intolerant to UCDA PBC patients [11]. This group of patients along with patients intolerant to
Population treatment will be randomized in this study. UCDA treatment will be randomized in this study.
This study targets patients with mild and moderately advanced disease and This study targets patients with mild and moderately advanced disease and
excludes patients with advanced cirrhosis. ALP reduction is not a good excludes patients with advanced cirrhosis. ALP reduction is not a good
predictive marker of long term benefit in the advanced disease population predictive marker of long term benefit in the advanced disease population
[15]. Patients with moderately advanced disease are identified per Rotterdam [15]. Patients with moderately advanced disease are identified per
Criteria (TB > ULN or Albumin < LLN). Rotterdam Criteria (TB > ULN or Albumin < LLN), liver stiffness
In addition, a recent publication has shown that in UDCA-treated and measurement by Fibroscan [EASL Clinical Practice Guidelines on
untreated patients with TB levels ≤1×ULN at baseline or 1 year, the TB non-invasive tests for evaluation of liver disease severity and
threshold with the highest ability to predict LT or death at 1 year was prognosis –2021 update, J Hep 2021], or histology among those who
0.6×ULN. The risk for LT or death was stable below TB levels of 0.6×ULN undergo liver biopsy. Patients with cirrhosis will be identified by
and yet increased beyond this threshold [24] and Fig1. elastography [24] or histology among those who undergo liver biopsy.
To ensure adequate representation of moderately advanced disease patients In addition, a recent publication has shown that in UDCA-treated and
and of patients at risk of progression to clinical outcomes, at least 10% of untreated patients with TB levels ≤1×ULN at baseline or 1 year, the TB
randomized patients will be moderately advanced per Rotterdam Criteria and threshold with the highest ability to predict LT or death at 1 year was
at least 20% will have a TB > 0.6 x ULN (patients at risk of progression). 0.6×ULN. The risk for LT or death was stable below TB levels of
0.6×ULN and yet increased beyond this threshold [25] and Fig1.
To ensure inclusion of a relevant ratio of patients with substantial risk
of long-term clinical outcomes or moderate disease stage,
approximately 10% of randomized patients will be moderately advanced
per Rotterdam Criteria. Patients will also be categorized as early or
advanced disease stage based on liver stiffness measurement at the
baseline Fibroscan examination (LSM<=10 kPa or LSM >10 kPa),
and based on histology (absent or mild fibrosis vs. presence of
bridging fibrosis or cirrhosis) among those who undergo liver biopsy
[EASL Clinical Practice Guidelines on non-invasive tests for
evaluation of liver disease severity and prognosis –2021 update, J Hep
2021]. Additionally, approximately 20% will have a TB > 0.6 x ULN
(patients at risk of progression).
CONFIDENTIAL
2. Study To evaluate the effect of elafibranor (80mg/day) over 52 weeks of treatment To evaluate the effect of elafibranor (80mg/day) over 52 weeks of
Objectives and compared to placebo on: treatment compared to placebo on:
Endpoints - Normalization of ALP - Normalization of ALP
2.1 Objectives - Pruritus based on change from baseline through week 52 in PBC - Pruritus based on change from baseline through week 52 in PBC
2.1.1 DB Period Worst Itch NRS score Worst Itch NRS in patients with baseline PBC Worst Itch NRS
2.1.1.2 Key score ≥4
Secondary - Pruritus based on change from baseline through week 24 in
Objectives PBC Worst Itch NRS in patients with baseline PBC Worst
Itch NRS score ≥4
2.1.1.3 To evaluate the effect of elafibranor (80 mg/day) over 52 weeks of treatment To evaluate the effect of elafibranor (80 mg/day) over 52 weeks of
Secondary compared to placebo on: treatment compared to placebo on:
Objectives a) Hepatobiliary injury and liver function markers a) Hepatobiliary injury and liver function markers
b) Inflammation and hepatic fibrosis b) Inflammation and hepatic fibrosis
c) Lipid parameters c) Lipid parameters
d) Bile acids d) Bile acids
e) liver histology e) Pruritus Patient Reported Outcomes (PROs)
f) Patient-reported Fatigue f) Patient-reported Fatigue
g) Patient-reported Sleep g) Patient-reported Sleep
h) HRQoL h) HRQoL
i) Health utility i) Health utility
j) Safety and tolerability j) Bone markers and bone density
2.1.14 For the patients having consented to participate:
Exploratory 1) To constitute a biobank for discovery and validation of
Objectives biomarkers associated with PBC
(related to 2) Based on histology:
histological a) To assist the interpretation of efficacy and safety
assessements) results of elafibranor
b) To explore the correlation of fibrosis scores with
non-invasive markers of fibrosis (liver stiffness, ELF test and
ProC3)
CONFIDENTIAL
2.2.1.2 Key Secondary Endpoint Key Secondary Endpoints

Secondary Response to treatment based on ALP normalization at week 52. 1) Response to treatment based on ALP normalization at week 52.
Endpoints Change in pruritis from baseline through week 52 based on PBC Worst Itch 2) Change in pruritus from baseline through week 52 based on PBC
NRS score. Worst Itch NRS in patients with baseline PBC Worst Itch NRS
score ≥4.
3) Change in pruritus from baseline through week 24 based on PBC
Worst Itch NRS in patients with baseline PBC Worst Itch NRS
score ≥4
Other Secondary Endpoints Other Secondary Endpoints
1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks 1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
2) ALP response defined as 10%, 20% and 40% ALP reduction from 2) ALP response defined as 10%, 20% and 40% ALP reduction
baseline at week 52 from baseline at week 52
3) Response to treatment at week 52 according to: 3) Response to treatment at week 52 according to:
a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b) ALP < 3 x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I) b) ALP < 3 x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris II) c) ALP ≤ 1.5 x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II)
d) TB response rate of 15% change d) TB response rate of 15% change
e) Normalization of abnormal TB and/or albumin (Rotterdam) e) Normalization of abnormal TB and/or albumin (Rotterdam)
f) TB ≤ 0.6 x ULN f) TB ≤ 0.6 x ULN
g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1] g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1]
h) No worsening of TB defined as level of TB at week 52 < ULN or no h) No worsening of TB defined as level of TB at week 52 < ULN
increase from baseline of more than 0.1XULN at week 52 or no increase from baseline of more than 0.1XULN at week 52
4) PBC risk scores at week 52: UK PBC score [2] and GLOBE score i) Complete biochemical response defined as normal ALP; TB;
[3] AST; ALT; albumin; and INR
5) Response based on the normalization of bilirubin at week 52 4) PBC risk scores at week 52: UK PBC score [2] and GLOBE score
6) Response based on the normalization of albumin at week 52 [3]
7) Change from baseline to week 52 in hepatobiliary injury and liver 5) Response based on the normalization of bilirubin at week 52
function as measured by AST, ALT, GGT, 5’ NT, total and conjugated 6) Response based on the normalization of albumin at week 52
bilirubin, albumin, INR and ALP fractionated (hepatic) 7) Change from baseline to week 52 in hepatobiliary injury and liver
8) Change from baseline to week 52 in biomarkers of inflammation as function as measured by AST, ALT, GGT, 5’ NT, total and conjugated
measured by hsCRP, fibrinogen, haptoglobin and TNF-α bilirubin, albumin, INR and ALP fractionated (hepatic)
9) Change from baseline to week 52 in immune response as measured 8) Change from baseline to week 52 in biomarkers of inflammation
by IgG and IgM as measured by hsCRP, fibrinogen, haptoglobin and TNF- α
10) Change from baseline to week 52 in biomarkers, non-invasive and 9) Change from baseline to week 52 in immune response as
invasive measures of hepatic fibrosis as measured by ELF (HA, PIINP, measured by IgG and IgM
TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver stiffness
measured by TE (continuous)
CONFIDENTIAL
11) Change from baseline to week 52 in lipid parameters as measured 10) Change from baseline to week 52 in biomarkers, and non-
by TC, LDL-C, HDL-C, calculated VLDL-C and triglycerides (TG) invasive measures of hepatic fibrosis as measured by ELF (HA, PIINP,
12) Change from baseline to week 52 in FPG TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver
13) Change from baseline to week 52 in bile acids and biomarkers of stiffness measured by TE (continuous)
bile acid synthesis as measured by bile acids, C4 and FGF-19 11) Change from baseline to week 52 in lipid parameters as measured
14) Response in PBC Worst Itch NRS defined as at least 30% reduction by TC, LDL-C, HDL-C, calculated VLDL-C and triglycerides (TG)
from baseline of NRS at week 52 in patients with a baseline NRS ≥ 4 12) Change from baseline to week 52 in FPG
15) Proportion of patients with no worsening of pruritus from baseline 13) Change from baseline to week 52 in bile acids and biomarkers of
to week 52 as measured by the PBC Worst Itch NRS bile acid synthesis as measured by bile acids, C4 and FGF-19
16) Change from baseline to week 52 in 5D-Itch 14) Proportion of responders in PBC Worst Itch NRS according
17) Change from baseline to week 52 in PROMIS Fatigue Short Form to clinically meaningful change; at least 30% reduction; and one point,
7a two points or three points decrease in score from baseline through
18) Change from baseline to week 52 in ESS week 52 and through week 24 in patients with a baseline NRS score ≥ 4
19) Change from baseline to week 52 in PBC-40 15) Proportion of patients with no worsening of pruritus from
20) Change from baseline to week 52 in health utility as measured by baseline through week 52 and through week 24 as measured by the PBC
the EQ-5D-5L Worst Itch NRS
21) Onset of clinical outcomes described as a composite endpoint 16) Change from baseline to week 52 in 5D-Itch
composed of: 17) Change from baseline to week 52 in PROMIS Fatigue Short
a) MELD-Na >14 for patients with baseline MELD-Na ≤12 Form 7a
b) Progression to histological cirrhosis for non cirrhotic patients at 18) Change from baseline to week 52 in ESS
baseline 19) Change from baseline to week 52 in PBC-40
c) Liver transplant 20) Change from baseline to week 52 in health utility as measured by
d) Uncontrolled ascites requiring treatment the EQ-5D-5L
e) Hospitalization for new onset or recurrence of any of the following: 21) Change from baseline to week 52 in serum markers of bone
i) variceal bleed turnover and in bone mineral density (hip and lumbar) assessed by
ii) hepatic encephalopathy defined as West-Haven score of 2 or more DEXA scanning
iii) spontaneous bacterial peritonitis 22) Onset of clinical outcomes described as a composite endpoint
f) Death composed of:
22) Change from baseline in the histological scores a) MELD-Na >14 for patients with baseline MELD-Na ≤12
a) fibrosis stage according to Nakanuma scoring b) Liver transplant
b) Bile duct scores c) Uncontrolled ascites requiring treatment
c) Cholangitis activity d) Hospitalization for new onset or recurrence of any of the
d) Interface Hepatitis activity following:
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct i) variceal bleed
score) ii) hepatic encephalopathy defined as West-Haven score of 2 or
f) Other exploratory scores such as Fibrosis (per modified Ishak more
scoring), Portal inflammation, ductular reaction, Cholestasis and concentric iii) spontaneous bacterial peritonitis
periductal fibrosis e) Death
CONFIDENTIAL
23) Safety and tolerability as assessed by: 23) Safety and tolerability as assessed by:
a) SAE, AE, AESI, physical examination, vital signs, medical history, a) SAE, AE, AESI, physical examination, vital signs, medical
ECG history, ECG
b) Chemistry and hematology b) Chemistry and hematology
c) Liver markers c) Liver markers
d) Renal biomarkers (including urinalysis) d) Renal biomarkers (including urinalysis)
e) Other biochemical safety markers e) Other biochemical safety markers
f) Histology 24) PK assessments by GFT505 and GF1007 concentrations
measurement in plasma
2.2.1.3 Exploratory endpoints associated with Histological assessment (for
Exploratory patients who have consented to having liver biopsy)
Endpoints 1) Change from baseline in the histological scores
b) Bile duct loss scores
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and
Bile duct loss score)
f) Other exploratory scores (Fibrosis according to Ishak
scoring, portal inflammation, ductular reaction, cholestasis,
concentric periductal fibrosis)
2) Correlation of Fibrosis scores with non-invasive markers of
fibrosis (Liver stiffness, ELF test and ProC3)
3. Study Design Screening visits (SV1, SV2 or SV3) should be performed within 2 to 12 As a first step, patients will be asked if they agree to participate in the
3.5.1 Screening weeks of randomization. At the SV1, preliminary eligibility criteria will be study and sign the Informed Consent Form (ICF). Each patient who has
Period reviewed. Eligible patients will be asked if they agree to participate in the signed the ICF will perform procedures listed on Table 1 and Table 2.
study and sign the Informed Consent Form (ICF). Each patient who has Screening visits (SV1, SV2 or SV3) should be performed within 2 to
signed the ICF will perform procedures listed on Table 1 and Table 2. 12 weeks of randomization. At SV1, preliminary eligibility criteria
… will be reviewed.
In absence of valid historical liver biopsy, the Liver biopsy can be performed …
at any visits as long as it is completed at the latest 4 weeks prior to the planned For patients having consented to have liver biopsy samples collected
randomization visit. and in absence of valid historical liver biopsy, the Liver biopsy can be
performed at any visits during the screening period, preferably in
patients already confirmed as eligible and if at all possible 2 to 4 weeks
prior to randomization.
CONFIDENTIAL
3.5.2 DB Period … …
(Week 0 to max To ensure adequate representation of moderately advanced disease or patients To ensure inclusion of a relevant ratio of patients with substantial risk
Week 104) at risk of progression to clinical outcomes, at least 10% of randomized of long-term clinical outcomes or moderate disease stage,
patients will be moderately advanced per Rotterdam Criteria (TB> ULN or approximately 10% of randomized patients will be moderately advanced
Albumin < LLN) and at least 20% will have a TB > 0.6 x ULN (patients at per Rotterdam Criteria (TB> ULN or Albumin < LLN) and
risk of progression). approximately 20% will have a TB > 0.6 x ULN (patients at risk of
… progression). Patients will also be categorized as early or advanced
disease stage based on liver stiffness measurement at the baseline
Fibroscan examination (LSM<=10 kPa or LSM >10 kPa), and based
on histology (absent or mild fibrosis vs. presence of bridging fibrosis
or cirrhosis) among those who undergo liver biopsy [EASL Clinical
Practice Guidelines on non-invasive tests for evaluation of liver disease
severity and prognosis –2021 update, J Hep 2021].
…
Any patient completing V8 will be automatically switched to open LTE. The Any patient completing V8 will be automatically switched to open-label
last visit V6 completed for all randomized patients will trigger the switch to LTE. The last V5 completed for all randomized patients will trigger the
open LTE for all patients still in DB. The switch will be operated either at V6 switch to open-label LTE for all patients still in DB. The switch will be
for this last patient or at an additional onsite visit (LVDB) to be scheduled operated either at V6 or at an additional onsite visit (LVDB). Until the
within 13 weeks of this timepoint to allow switching all patients in a timely last patient in the study completes his/her V5, patients between V6 and
manner. In case the LVDB visit occurs within the time window of the next V8, will complete LVDB according to Table 1 General Assessment
scheduled visit, LVDB visit replaces the scheduled visit. The same Schedule. After the last patient in the study completes his/her V5,
procedures as for V8 will be performed for LVDB. patients between V6 and V8, will complete LVDB at the next scheduled
… visit (either V7 or V8), LVDB will replace V7 or V8. The same
procedures as for V8 will be performed for LVDB (except US exam). For
patients who have not yet had V6 at the time the last patient completes
his/her V5, LVDB will be scheduled at the latest 13 weeks after the
date on which V5 was completed for the last patient. For those
patients, LVDB will coincide with V6, and patients will complete V6
and associated procedures to facilitate transition to the open-label
elafibranor treatment phase in the long-term extension study, in a
timely manner.
…
CONFIDENTIAL
4. Patient Patients must meet all of the following inclusion criteria to be eligible for Patients must meet all of the following inclusion criteria to be eligible for
Selection randomization into the study: randomization into the study:
4.1 Inclusion 1) Must have provided written informed consent and agree to comply 1) Must have provided written informed consent and agree to
Criteria with the study protocol comply with the study protocol
2) Males or females age of 18 to 75 years inclusive at SV1 2) Males or females age of 18 to 75 years inclusive at SV1
3) Definite or probable PBC diagnosis as demonstrated by the presence 3) PBC diagnosis as demonstrated by the presence of ≥ 2 of the
of ≥ 2 of the following 3 diagnostic criteria: following 3 diagnostic criteria:
a. History of elevated ALP levels for ≥ 6 months prior to a. History of elevated ALP levels for ≥ 6 months prior to
randomization (V1) randomization (V1)
b. Positive AMA titers (> 1/40 on immunofluorescence or M2 b. Positive AMA titers (> 1/40 on immunofluorescence or M2
positive by ELISA or positive PBC-specific ANA positive by ELISA or positive PBC-specific ANA
c. Liver biopsy consistent with PBC c. Liver biopsy consistent with PBC
4) Patients in whom it is safe and practical to proceed with a liver biopsy, 4) ALP ≥ 1.67 x ULN (based on two values - see section 3.5.1)
and who agree to have: 5) TB ≤ 2 x ULN
a. 1 liver biopsy during the Screening Period (if no historical To ensure inclusion of a relevant ratio of patients with substantial risk
biopsy within 12 months before screening is available) of long-term clinical outcomes, or moderate disease stage,
b. 1 liver biopsy after 52-weeks of treatment approximately 10% of randomized patients will be moderately advanced
5) ALP ≥ 1.67 x ULN per Rotterdam Criteria (TB > ULN or Albumin < LLN) and
6) TB ≤ 2 x ULN approximately 20% will have a TB > 0.6 x ULN (patients at risk of
To ensure adequate representation of moderately advanced disease or at risk progression)
of progression to clinical outcomes, at least 10% of randomized patients will 6) Must have at least 4 available values for PBC Worst Itch NRS
be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < during each of the 7 day intervals in the 14 days prior to randomization
LLN) and at least 20% will have a TB > 0.6 x ULN (patients at risk of (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last
progression) 14 days prior to randomization (V1)
7) Must have at least 4 available values for PBC Worst Itch NRS during 7) UDCA for at least 12 months (stable dose ≥ 3 months) prior to
each of the 7 day intervals in the 14 days prior to randomization (V1), screening, or unable to tolerate UDCA treatment (no UDCA for ≥ 3
for a total of at least 8 values for PBC Worst Itch NRS in the last 14 months) prior to screening (per country standard-of-care dosing)
days prior to randomization (V1) 8) If on colchicine must be on a stable dose for ≥ 3 months prior to
8) UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening
randomization, or unable to tolerate UDCA treatment (no UDCA for ≥ 9) Medications for management of pruritus (e.g., cholestyramine,
3 months) prior to randomization (per country standard-of-care dosing) rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3
9) If on colchicine must be on a stable dose for ≥ 3 months prior to months prior to screening
randomization 10) Patients taking statins or ezetimibe must be on a stable dose for
10) Medications for management of pruritus (e.g., cholestyramine, ≥ 2 months prior to screening
rifampin, naltrexone or sertraline) must be on a stable dose for ≥ 3 11) Females participating in this study must be of non-child bearing
months prior to randomization potential or must be using highly effective contraception for the full
11) Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 duration of the study and for 1 month after the last drug intake:
months prior to randomization
CONFIDENTIAL
12) Females participating in this study must be of non-child bearing • Non-child bearing potential: Cessation of menses for at least 12
potential or must be using highly efficient contraception for the full months due to ovarian failure or surgical sterilization such as bilateral
duration of the study and for 1 month after the last drug intake: oophorectomy, or hysterectomy
• Non-child bearing potential: Cessation of menses for at least 12 • Highly effective contraception methods include:
months due to ovarian failure or surgical sterilization such as a. Combined (estrogen and progrestogen containing)
bilateral oophorectomy, hysterectomy, or medically documented hormaonal contraception associated with inhibition of
ovarian failure for > 6 months prior to randomization ovulation, oral, intravaginal or transdermal
• If required by local IRB regulations and/or National laws, sexual b. Progestogen-only hormonal contraception associated with
abstinence may be considered adequate (the reliability of sexual inhibition of ovulation, oral, injectable or implantable
abstinence needs to be evaluated in relation to the duration of the c. Intrauterine device (IUD)
clinical study and the preferred and usual lifestyle of the patient) d. Intrauterine hormone release system (IUS)
• Using a highly effective non-hormonal medical contraception e. Bilateral tubal occlusion
(bilateral tubal occlusion, vasectomized partner or intra-uterine f. Vasectomized partner
device) for ≥ 3 months prior to screening g. Sexual abstinence, if required by local IRB/IEC regulations
• Highly effective contraception with barrier or highly effective and/or considered adequate by National laws (the reliability of
hormonal method of contraception (oral, intravaginal or sexual abstinence needs to be evaluated in relation to the duration
transdermal combined estrogen and progestogen hormonal of the clinical study and the preferred and usual lifestyle of the
contraception associated with inhibition of ovulation, oral, patient)
injectable or implantable progestogen-only hormonal contraception 12) For patients who consent to have liver biopsy samples
associated with inhibition of ovulation or intrauterine hormone- collected, patients in whom it is safe and practical to proceed with
releasing system). The hormonal contraception must be started at ≥ a liver biopsy, and who agree to have:
one month prior to screening a. 1 liver biopsy during the Screening Period (if no historical
biopsy within 6 months before screening is available)
CONFIDENTIAL
4.2 Exclusion Patients presenting any of the following exclusion criteria will not be Patients presenting any of the following exclusion criteria will not be
Criteria included in the study: included in the study:
… …
5) Evidence of any other unstable or untreated clinically significant 5) Evidence of any other unstable or untreated clinically significant
immunological, endocrine, hematologic, gastrointestinal, neurological, or immunological, endocrine, hematologic, gastrointestinal, neurological, or
psychiatric disease as evaluated by the investigator psychiatric disease as evaluated by the investigator; other clinically
6) Other clinically significant medical conditions that are not well controlled significant medical conditions that are not well controlled
or for which medication needs are anticipated to change during the study 6) History of alcohol abuse, defined as consumption of more than 30 g
7) History of alcohol abuse, defined as consumption of more than 30 g pure pure alcohol per day for men, and more than 20 g pure alcohol per day for
alcohol per day for men, and more than 20 g pure alcohol per day for women, women, or other substance abuse within 1 year prior to screening visit
or other substance abuse within 1 year prior to screening visit (SV1) (SV1)
8) For female patients: known pregnancy, or has a positive urine pregnancy 7) For female patients: known pregnancy, or has a positive serum
test (confirmed by a positive serum pregnancy test), or lactating pregnancy test, or lactating
9) Administration of the following medications are prohibited as specified 8) Administration of the following medications are prohibited as specified
below: below:
a) 2 months prior to randomization and throughout the study (up to the a) 2 months prior to screening: fibrates and glitazones
last study visit): fibrates and glitazones b) 3 months prior to screening: OCA, azathioprine, cyclosporine,
b) 3 months prior to randomization and throughout the study (up to the methotrexate, mycophenolate, pentoxifylline, budesonide and other
last study visit): OCA, azathioprine, cyclosporine, methotrexate, systemic corticosteroids (parenteral and oral chronic administration
mycophenolate, pentoxifylline, budesonide and other systemic only); potentially hepatotoxic drugs (including α-methyl-dopa, sodium
corticosteroids; potentially hepatotoxic drugs (including α-methyl- valproic acid isoniazid, or nitrofurantoin)
dopa, sodium valproic acid isoniazid, or nitrofurantoin) c) 12 months prior to screening: antibodies or immunotherapy
c) 12 months prior to randomization and throughout the study (up to directed against ILs or other cytokines or chemokines
the last study visit): antibodies or immunotherapy directed against d) For patients with previous exposure to OCA, OCA should be
ILs or other cytokines or chemokines discontinued 3 months prior to screening
10) Patients who are currently participating in, plan to participate in, or have 9) Patients who are currently participating in, plan to participate in, or have
participated in an investigational drug study or medical device study participated in an investigational drug study or medical device study
containing active substance within 30 days or five half-lives, whichever is containing active substance within 30 days or five half-lives, whichever is
longer, prior to screening; patients with previous exposure to seladelpar are longer, prior to screening; patients with previous exposure to seladelpar,
excluded seladelpar should be discontinued 3 months prior to screening
11) Patients with previous exposure to elafibranor 10) Patients with previous exposure to elafibranor
12) SV value ALT and/or AST > 5 x ULN 11) SV value ALT and/or AST > 5 x ULN
13) SV value albumin<3.0 g/dl 12) For patients with AT or TB>ULN at SV1, variability of AT or TB
14) Severely advanced patients according to Rotterdam criteria (TB > ULN > 40% (see section 3.5.1)
and albumin < LLN) 13) SV value albumin<3.0 g/dl
15) SV value INR > 1.3 due to altered hepatic function 14) Severely advanced patients according to Rotterdam criteria (TB >
16) SV value CPK > 2 x ULN ULN and albumin < LLN)
CONFIDENTIAL
17) Screening serum creatinine > 1.5 mg/dl 15) SV value INR > 1.3 due to altered hepatic function
18) Significant renal disease, including nephritic syndrome, chronic kidney 16) SV value CPK > 2 x ULN
disease (defined as patients with markers of kidney failure damage or eGFR 17) Screening serum creatinine > 1.5 mg/dl
< 60 mL/min/1,73 m2) calculated by MDRD 18) Significant renal disease, including nephritic syndrome, chronic
19) Platelet count < 150 x 103/µL kidney disease (defined as patients with markers of kidney failure damage
20) AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting or eGFR < 60 mL/min/1,73 m2) calculated by MDRD
presence of liver cancer 19) Platelet count < 150 x 103/µL
20) AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting
presence of liver cancer
21) Known hypersensitivity to the investigational product or to any of
the formulation excipients of the elafibranor or placebo tablet
22) Mental instability or incompetence, such that the validity of
informed consent or ability to be compliant with the study is uncertain
5. Study …. ….
Procedures Some possible reasons that may lead to permanent early study drug Some possible reasons that may lead to permanent early study drug
5.2 Patient discontinuation include: discontinuation include:
Withdrawal and • Any AE, AESI, SAE (described in Section 8.1.1 and 8.1.2), or • At the discretion of the Investigator, any AE, AESI, SAE
Patient significant change in a laboratory value in the opinion of the (described in Section 8.1.1 and 8.1.2), or significant change in a laboratory
Treatment Investigator. Investigators are advised to call the Medical Monitor value or worsening or disease progression that would require in the
Discontinuation prior to making such a decision patient’s best interest, initiation of any standard of care prohibited in
Rules • Non-permitted concomitant medication (described in Section 7.12 the study. Investigators are advised to call the Medical Monitor prior to
5.2.1 Permanent and Section 16.3 - appendix 3A) making such a decision
discontinuation • Female patients who are pregnant (see Section 8.6.1) or are • Non-permitted concomitant medication (described in Section
of study breastfeeding or who do not agree to use a reliable method of birth 7.12 and 16.2)
drug/withdrawal control during the study • Female patients who are pregnant (see Section 8.6.1) or are
from study • Non-compliance with the study treatment breastfeeding or who do not agree to use a reliable method of birth control
• Uncooperative patient during the study
• The patient requests to stop study drug permanently. • Non-compliance with the study treatment
… • Uncooperative patient
…
CONFIDENTIAL
6. Assessments … …
6.1 Efficacy and In order to maintain the blind, ALP, GGT and 5’ NT obtained from blood In order to maintain the blind, ALP, GGT and 5’ NT obtained from blood
Safety samples from V2 to V8 / LVDB/or last V6 whichever occurs first (up to end samples from V2 to V8 / LVDB/or last V6 whichever occurs first (up to
Assessment of DB period) will be kept in blinded condition during the treatment period end of DB period) will be kept in blinded condition during the DB
6.1.1 Biological for each patient. The Investigator will not be informed of these values until treatment period for each patient. Similarly, the same rule will apply to
assessment the database lock at the end of the DB period. ALP, GGT and 5’-NT obtained from blood samples until the first visit
… in the LTE period (LT1), including EOT LTE and unscheduled visits.
The Investigator will not be informed of these values until the database
lock at the end of the DB period.
…
Both blood and urine dipstick samples will be transported to the central Both blood and urine dipstick samples will be transported to the central
laboratory for testing and analysis except for urinary myoglobin that may be laboratory for testing and analysis except for urinary/blood myoglobin
tested at local laboratory when applicable. that should be tested at local laboratory when applicable.
Local laboratory assessments are allowed for repetition of assessment of Local laboratory assessments are allowed for repetition of assessment of
ALT, AST, TB and ALP during the screening period as well as for any ALT, AST, TB and ALP during the screening period as well as for any
required retest for liver function monitoring and assessment of urinary required retest for liver function monitoring and assessment of
myoglobin, when applicable. urinary/blood myoglobin, when applicable.
…. ….
6.1.1.2 Urinary For WOCBP, urinary pregnancy tests will be administered at each visit. For WOCBP, serum pregnancy test will be performed at screening
Pregnancy Tests Monthly urine home pregnancy test kits will be provided during scheduled (and may be repeated within one month prior to randomization in
visits for use during non-visit months. case the screening period lasts more than 4 weeks) while urinary
pregnancy tests will be administered at each visit from V1. Notably,
the urine pregnancy test performed at V1 is to occur on site prior to
randomization. If such test is unclear, a follow-up serum pregnancy
test should also be performed prior to dosing. In addition, monthly
urine home pregnancy test kits will be provided during scheduled visits
for use during non-visit months. In case of positive urinary test, a
confirmatory serum pregnancy test must be performed at site.
CONFIDENTIAL
6.1.3 Bone DEXA scanning (hip and lumbar) will be performed in patients at
density by study sites at which DEXA scan equipment is available and has been
DEXA scanning approved for use in this study. Study participants will have this exam
at baseline (before randomization after the patient has been otherwise
confirmed as eligible and up to randomization visit), at week 52 and
then 2 years later as described in Table 1.
6.1.4 A liver biopsy (see Section 6.1.3.1 for recommendations) will be performed: For patients who consent to have liver biopsy samples collected, a liver
Histological • At baseline biopsy (see Section 6.1.4.1 for recommendations) will be performed:
assessment • At 52 weeks of treatment • During the Screening period (unless an historical liver
biopsy within 6 months before screening is available)
In addition, for any patient randomized in the study, a liver biopsy
can be requested at any time in case of suspicion of auto-immune
hepatitis or for safety monitoring at the discretion of the investigator
(section 6.3.2 & 6.3.3).
A Laboratory Manual will be provided to each study site. The manual will A Laboratory Manual will be provided to each study site. The manual will
outline the collection process, and shipping requirements for the specific outline the collection process, and shipping requirements for the specific
central laboratory. central laboratory.
6.1.4.2 Liver Histological changes from baseline to Week 52 will be evaluated. Liver biopsy samples will be sent to the central laboratory where they will
biopsy reading Liver biopsy samples will be sent to the central laboratory where they will be be stained and digitalized.
stained and digitalized. Liver biopsy slides will be assessed and scored by at least two
Liver biopsy slides will be assessed and scored by at least two pathologists. pathologists. Scores for fibrosis, bile duct, cholangitis activity, interface
Scores for fibrosis, bile duct, cholangitis activity, interface hepatitis activity, hepatitis activity, will be evaluated and agreed. A liver biopsy
will be evaluated and agreed. A liver biopsy management plan will detail the management plan will detail the process of management of the liver
process of management of the liver biopsy samples from collection to final biopsy samples from collection to final assessment. A liver biopsy
assessment. A liver biopsy assessment protocol will detail the reading assessment protocol will detail the reading methodology to be
methodology to be implemented. implemented.
CONFIDENTIAL
6.1.5 PK parameters (AUCss, clearance, volumes of distribution, etc.) will be PK parameters (AUCss, clearance, volumes of distribution, etc.) will be
Pharmacokinetic determined from elafibranor and GFT1007 plasma concentrations using a determined from elafibranor and GFT1007 plasma concentrations using a
assessment popPK model. A dedicated software for nonlinear mixed models will be used popPK model. A dedicated software for nonlinear mixed models will be
6.1.5.4 for the analysis. used for the analysis.
Description of The popPK analyses will be performed at Phinc Development. The population PK analyses will be described in a separate data
pharmacokinetic PK parameters of elafibranor and GFT1007 will be summarized by geometric analysis plan and reported in a standalone report.
evaluation mean, SD, coefficient of variation, minimum and maximum, and median. An exploratory analysis will be performed to assess the relationship
parameters between PK and PD (efficacy or safety endpoints). If a trend is shown,
an attempt to build a PKPD model using a population approach will
be performed. Those analyses (population PK and, if applicable,
population PKPD) will be described in a separate data analysis plan
and reported in a standalone report.
PK parameters of elafibranor and GFT1007 will be summarized by
geometric mean, SD, coefficient of variation, minimum and maximum,
and median.
6.1.6 Liver … …
stiffness by This assessment will be done the day of the visit. Failing this, it can be This assessment will be done the day of the visit. Failing this, it can be
transient performed within 7 days of the visit. performed within 7 days of the visit.
elastography To ensure reliability of the assessments patients must be in a fasted state for To ensure reliability of the assessments patients must be in a fasted state
(FibroScan®) at least 2 hours before the examination. Additional instructions will be for at least 3 hours before the examination. Additional instructions will be
provided in a separate manual. provided in a separate manual.
As presented in the paper from Corpechot et al [24], the threshold for
classification of cirrhosis is ≥ 16.9 KPa.
6.3 Important If at any visit during the treatment period, a patient experiences diffuse If at any visit during the treatment period, a patient experiences diffuse
Specific myalgia, muscle tenderness, and marked increase in muscle CPK values myalgia, muscle tenderness, and/or marked increase in muscle CPK
Biological between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), an additional visit and values between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), an additional
Considerations test must be performed within 48 to 72 hours, and an assessment of visit and test must be performed within 48 to 72 hours, and an assessment
And Patient myoglobinuria may be done locally. If, during that visit, the patient still of myoglobinuria/myoglobinemia should be done locally. If, during that
Discontinuation experiences diffuse myalgia, muscle tenderness and/or marked increase in visit, the patient still experiences diffuse myalgia, muscle tenderness
Rules muscle CPK values between 3 x and 5 x ULN (≥ 3 x ULN and ≤ 5 ULN), and/or marked increase in muscle CPK values between 3 x and 5 x ULN
6.3.1 Creatinine myopathy must be considered and the patient must be discontinued from (≥ 3 x ULN and ≤ 5 ULN), myopathy must be considered and the patient
Phosphokinase study treatment immediately and followed up as described in Section 5.2.1. must be discontinued from study treatment immediately and followed up
as described in Section 5.2.1
CONFIDENTIAL
6.3.2 Liver … …
Function In addition to management guideliens, the criteria used for reporting a In addition to management guidelines, the criteria used for reporting a
Monitoring potential DILI for adjudication are given below and correspond to the criteria potential DILI for adjudication are given below and correspond to the
leading to permanent study drug discontinuation. criteria leading to permanent study drug discontinuation.
For any suspicion of DILI or for any other liver related event, it is left
to the discretion of the investigator to request a liver biopsy in
accordance with the local clinical standards, in order to further assess
the case.
6.3.5 Ultrasonography of liver and analysis of AFP will be performed at visit V1, Ultrasonography of liver and analysis of AFP will be performed at
Monitoring of & then every year (V6, V8, LT3, LT5 , LT7, and LT9 if applicable). baseline, & then every year (V6, V8, LT3, LT5 , LT7, and LT9 if
hepatocellular applicable), AFP will be performed at LVDB, if applicable, as
and bladder described in Table 1 and Table 2.
cancer
6.3.5.1 Liver
monitoring
6.3.5.2 Bladder Ultrasonography of bladder and urinary tract will be performed at visit V1, Ultrasonography of bladder and urinary tract will be performed at
& urinary tract & then every year (V6, V8, LT3, LT5 , LT7, and LT9 if applicable). baseline, & then every year (V6, V8, LT3, LT5 , LT7, and LT9 if
monitoring applicable) as described in Table 1.
6.3.6 Safety Safety oversight will be implemented under the direction of a DSMB Safety oversight will be implemented under the direction of a DSMB
Review composed of five experienced physicians (an endocrinologist, cardiologist, composed of at least five experienced physicians (an endocrinologist,
oncologist, hepatologist and nephrologist) and one independent statistician, cardiologist, oncologist, hepatologist and nephrologist) and one
all independent from the conduct of the study. Members of the DSMB should independent statistician, all independent from the conduct of the study.
be free of conflicts of interest. The members of DSMB will review the Members of the DSMB should be free of conflicts of interest. The
progress of the study and perform a safety data review (including review of members of DSMB will review the progress of the study and perform a
the adjudication reports issued from the CEC) on a regular basis (at least safety data review (including review of the adjudication reports issued
every six months) to ensure patient safety and preserve study integrity. from the CEC) on a regular basis (at least every six months) to ensure
A DSMB charter will define the roles, responsibilities, rules and tasks of the patient safety and preserve study integrity.
DSMB. A DSMB charter will define the membership, roles, responsibilities, rules
and tasks of the DSMB.
CONFIDENTIAL
6.3.7 Clinical The CEC will conduct adjudication of the clinical outcomes (excluding The CEC will conduct adjudication of the clinical outcomes and DILI
Event progression to histological cirrhosis for non cirrhotic patients at baseline) and events. The CEC assessment and adjudication will occur in a blinded
Committee DILI events. The CEC assessment and adjudication will occur in a blinded (during DB period) and consistent and unbiased manner throughout the
(during DB period) and consistent and unbiased manner throughout the course of the study to determine whether the endpoint meets the protocol
course of the study to determine whether the endpoint meets the protocol specified criteria.
specified criteria. The CEC will be comprised of 3 hepatologists, all of them will be
The CEC will be comprised of 3 hepatologists, all of them will be independent from the conduct of the study.
independent from the conduct of the study.
CONFIDENTIAL
6.4 Guidance … …
for Investigators A Phase 3 study in subjects with NASH and fibrosis (Study GFT505-315-1) 2157 patients with NASH and fibrosis have been randomized in a Phase
6.4.1 Summary is ongoing. In this study, subjects are receiving 120 mg/day elafibranor or 3 study (Study GFT505-315-1) is ongoing. In this study, the subjects
of safety data placebo for up to 72 weeks during the first treatment period, followed by a were receiving 120 mg/day elafibranor or placebo for up to 72 weeks
long-term treatment period to assess efficacy on progression to cirrhosis, all- during the first treatment period, followed by a long-term treatment period
cause mortality and liver-related clinical outcomes as measured by the onset to assess efficacy on progression to cirrhosis, all-cause mortality and liver-
of any of the listed adjudicated events of portal hypertension/cirrhosis related related clinical outcomes as measured by the onset of any of the listed
events. adjudicated events of portal hypertension/cirrhosis related events. Given
the failure to meet the predefined primary surrogate efficacy
Based on the cumulative experience gathered to date, gastro-intestinal endpoint (i.e. NASH resolution without worsening of fibrosis) and
disorders (such as nausea, diarrhea and decreased appetite) and following further in-depth review of the efficacy dataset, despite
fatigue/asthenia are considered common and non-serious adverse reactions absence of safety issue, it was decided to prematurely terminate the
reasonably associated with elafibranor; most of them are of mild to moderate study in October 2020 following sponsor decision.
severity. Of note, these AEs are to be monitored as AESIs (see Section 8.1.2)
as well as other AESIs which could be considered as class effect AEs. Based on the cumulative experience gathered to date, gastro-intestinal
Regarding specific monitoring, although no signal for increase in CPK has disorders (nausea, vomiting) renal and urinary disorders, and pruritus
been observed in the clinical studies, given the known effects of PPAR are considered common non-serious adverse reactions reasonably
agonists on the increase of CPK enzyme, this parameter is monitored in associated with elafibranor; most of them are of mild to moderate severity.
clinical studies. For this reason, it is recommended that investigators review Of note, these AEs are to be monitored as AESIs (see Section 8.1.2) as
these lab results in the course of clinical studies. well as other AESIs which could be considered as class effect AEs.
Other known effects of PPAR agonists include the increase of creatinine, Regarding specific monitoring, although no signal for increase in CPK has
which was observed in our clinical studies, in a range of 1-10%. This increase been observed in the clinical studies, given the known effects of PPAR
was reversible at EOT. This should also be monitored in clinical studies. agonists on the increase of CPK enzyme, this parameter is monitored in
Liver enzymes will also be monitored in clinical studies, with specific clinical studies. For this reason, it is recommended that investigators
attention paid to DILI. review these lab results in the course of clinical studies.
Based on the findings of nonclinical reproductive and developmental toxicity Other known effects of PPAR agonists include the increase of creatinine,
studies performed to date, and in the absence of human pregnancy data, which was observed in our clinical studies, in a range of 1-10%. This
elafibranor may be classed in the “Possible human teratogenicity/fetotoxicity increase was reversible at EOT. This should also be monitored in clinical
in early pregnancy” risk category according to the Clinical Trial Facilitation studies.
Group (CTFG) document Recommendations related to contraception and Liver enzymes will also be monitored in clinical studies, with specific
pregnancy testing in clinical studies [32]. attention paid to DILI. In the elafibranor clinical development program
As such, all clinical studies with elafibranor including WOCBP request a to date, there has been no imbalance in DILI events in individuals who
negative pregnancy test before Randomization, effective contraceptive received elafibranor compared to individuals who received placebo.
measures throughout the study and mandatory study discontinuation upon Based on the findings of nonclinical reproductive and developmental
becoming pregnant. It is recommended to maintain the contraception up to 1 toxicity studies performed to date, and in the absence of human pregnancy
month after the last drug intake. Pregnancy tests should be repeated as stated data, elafibranor may be classed in the “Possible human
in the Table 2. teratogenicity/fetotoxicity in early pregnancy” risk category according to
CONFIDENTIAL
For further details, refer to the IB. the Clinical Trial Facilitation Group (CTFG) document Recommendations
related to contraception and pregnancy testing in clinical studies [33].
As such, all clinical studies with elafibranor including WOCBP request a
negative pregnancy test before Randomization, effective contraceptive
measures throughout the study and mandatory study discontinuation upon
becoming pregnant. Contraception should be maintained up to 1 month
after the last drug intake. Pregnancy tests should be repeated as stated in
the Table 2.
7. Treatments Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3- Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-

7.1 Description oxo-1(E)-propenyl] phenoxy]-2-methylpropanoic acid) will be supplied as 80 (methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-methylpropanoic
of Study mg white to off-white round coated tablets with no printed inscription. The acid) will be supplied as 80 mg white to off-white round coated tablets
Medications tablet contains elafibranor and inactive ingredients (microcrystalline with no printed inscription. The tablet contains elafibranor and inactive
cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium ingredients (microcrystalline cellulose, povidone, croscarmellose,
stearate, Opadry II HP 85F18422). anhydrous colloidal silica, magnesium stearate, Opadry II HP 85F18422).
Placebo tablets to match elafibranor 80 mg will be provided as a white to off- Placebo tablets to match elafibranor 80 mg will be provided as a white to
white round coated tablet with no printed inscription. off-white round coated tablet with no printed inscription. Of note, in the
Additional information can be found in the IB. placebo tablet formulation, lactose monohydrate is used for replacing
the active substance.
7.12 Other The following medications are permitted under the condition of steady dosage The following medications are permitted under the condition of steady
Medication prior to Screening: dosage prior to Screening:
7.12.3 Permitted • UDCA if taken for at least 12 months (and stable dose for ≥ 6 • UDCA if taken for at least 12 months (and stable dose for ≥ 3
Medication months) prior to SV months) prior to screening (SV1)
Under • Statins and ezetimibe provided the dosage is kept stable for at least • Statins and ezetimibe provided the dosage is kept stable for at
Conditions 2 months prior to randomization least 2 months prior to screening
• Colchicine provided the dosage is kept stable for at least 3 months • Colchicine provided the dosage is kept stable for at least 3
prior to Randomization. months prior to screening
• Medications for management of pruritus (e.g.,
cholestyramine, rifampin, naltrexone or sertraline) must be
on a stable dose for ≥ 3 months prior to screening.
CONFIDENTIAL
7.12.4 Permitted Any medications other than those listed above are permitted. However, the Any medications other than those listed above are permitted. However,
Medication dosage of a current medication for a chronic disease should remain the dosage of a current medication for a chronic disease should remain
unchanged as far as possible in order to reduce the risk of unknown DDIs. unchanged as far as possible in order to reduce the risk of unknown bias.
… …
CONFIDENTIAL
8. Adverse AESIs are treatment emergent AEs corresponding to the conceptual AESIs are treatment emergent AEs corresponding to the conceptual
Event and definition of: definition of:
Toxicity
Management • CPK elevations of severe intensity or leading to permanent study • CPK elevations of severe intensity or leading to permanent study
8.1 Definitions drug discontinuation drug discontinuation
8.1.2 Adverse • Muscle injury symptoms of severe intensity corresponding to: • Muscle injury symptoms of severe intensity corresponding to:
Events of o Muscle pain or Myalgia o Muscle pain or Myalgia
Special Interest o Muscle spasms or Tremor o Muscle spasms or Tremor
(AESIs) o Muscle weakness o Muscle weakness
• Transaminases elevations from baseline of severe intensity or • Transaminases elevations from baseline of severe intensity or
leading to permanent study drug discontinuation leading to permanent study drug discontinuation
• Autoimmune hepatitis • Autoimmune hepatitis
• Liver injury events of severe intensity corresponding to: • Liver injury events of severe intensity corresponding to:
o Hepatic impairment o Hepatic injury
o Hepatic failure o Hepatic impairment
• Gastrointestinal symptoms of severe intensity corresponding to: o Hepatic failure
o Abdominal pain • Gastrointestinal symptoms of severe intensity corresponding to:
o Constipation o Abdominal pain
o Diarrhea o Constipation
o Nausea o Diarrhea
o Decreased appetite o Nausea
o Vomiting o Decreased appetite
o Acute cholecystis o Vomiting
o Acute pancreatitis o Acute cholecystis
• Fatigue and Asthenia of severe intensity o Acute pancreatitis
• Serum creatinine elevations of severe intensity or leading to • Fatigue and Asthenia of severe intensity
permanent study drug discontinuation • Serum creatinine elevations of severe intensity or leading to
• Renal injury events of moderate or severe intensity corresponding permanent study drug discontinuation
to: • Renal injury events of moderate or severe intensity
o Renal failure corresponding to:
o Renal impairment o Renal injury
o Renal colic o Renal failure
• Neurological abnormalities of moderate to severe intensity o Renal impairment
corresponding to: o Renal colic
o Tremor • Neurological abnormalities of moderate to severe intensity
o Ataxia corresponding to:
o Fasciculations o Tremor
CONFIDENTIAL
• Parkinson’s Disease o Ataxia
• Peripheral edema of moderate to severe intensity o Fasciculations
• Weight gain of more than 5% from baseline • Parkinson’s Disease
• Major Adverse Cardiovascular Events corresponding to: • Peripheral edema of moderate to severe intensity
o Non-fatal myocardial infarction/unstable angina • Weight gain of more than 5% from baseline
o Non-fatal stroke • Major Adverse Cardiovascular Events corresponding to:
o Unstable Angina o Non-fatal myocardial infarction/unstable angina
o Hospitalization for Heart Failure o Non-fatal stroke
o Coronary Revascularization (bypass or percutaneous o Unstable Angina
coronary intervention ) o Hospitalization for Heart Failure
o Coronary Revascularization (bypass or percutaneous
Treatment emergent Pregnancy and outcomes of Pregnancy will be coronary intervention )
considered as AESIs, and are described in the Section 8.6.1.
Treatment emergent Pregnancy and outcomes of Pregnancy will be
considered as AESIs, and are described in the Section 8.6.1.
CONFIDENTIAL
9. Statistical … …
Methods and
Data Analysis • Key secondary estimands • Key secondary estimands
9.1 Estimands … …
Considerations Key-secondary endpoint: Change in pruritus from baseline through week 52 Key-secondary endpoint: Change in pruritus from baseline through week
based on PBC Worst Itch NRS score. 52 based on PBC Worst Itch NRS in patients with baseline PBC Worst
The hypothetical strategy assuming that patients who experienced an ICE Itch NRS score ≥4.
would have continued within their treatment arm will be applied. The hypothetical strategy assuming that patients who experienced an ICE
- A. Treatment condition: Administration of Elafibranor or Placebo on top would have continued within their treatment arm will be applied.
of UDCA or in subjects intolerant to UDCA, - A. Treatment condition: Administration of Elafibranor or Placebo on
- B. Population: Randomized patients with PBC and Inadequate Response top of UDCA or in subjects intolerant to UDCA,
or Intolerance to UCDA, - B. Population: Randomized patients with PBC and Inadequate
- C. Endpoint: Change from baseline through week 52 in PBC Worst Itch Response or Intolerance to UCDA,
NRS score, - C. Endpoint: Change from baseline through week 52 in PBC Worst
- D. Intercurrent events: Any outcome value collected after a treatment Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4,
discontinuation or use of rescue therapy will be considered as missing, - D. Intercurrent events: Any outcome value collected after a treatment
- E. Population-level summary: Between treatment group difference in discontinuation or use of rescue therapy will be considered as
mean changes from baseline. missing,
The key secondary estimand can be defined as the between treatment groups - E. Population-level summary: Between treatment group difference in
difference in PBC Worst Itch NRS mean change from baseline from all mean changes from baseline.
randomized patients through week 52 assuming they continued the assigned The key secondary estimand can be defined as the between treatment
treatment after they experienced an ICE. groups difference in PBC Worst Itch NRS mean change from baseline
As for the key binary endpoints, a tipping point analysis point analysis will from randomized patients with baseline PBC Worst Itch NRS score ≥4
be performed to explore several scenarios where missing outcomes through week 52 or week 24 assuming they continued the assigned
experienced after an ICE vary independently from Elafibranor and placebo treatment after they experienced an ICE.
groups. As for the key binary endpoints, a tipping point analysis point analysis
In addition, the treatment policy strategy will be investigated where all will be performed to explore several scenarios where missing outcomes
outcome values until week 52 will be used regardless of treatment experienced after an ICE vary independently from Elafibranor and
discontinuation or use of rescue therapy. placebo groups.
In addition, the treatment policy strategy will be investigated where all
outcome values until week 52 will be used regardless of treatment
Key-secondary endpoint: Change in pruritus from baseline through
week 24 based on PBC Worst Itch NRS in patients with baseline PBC
Worst Itch NRS score ≥4.
The estimand approach for the change in pruritus from baseline
through week 24 based on PBC Worst Itch NRS in patients with
CONFIDENTIAL
baseline PBC Worst Itch NRS score ≥4 will be the same as defined for
week 52.
CONFIDENTIAL
9.3 Endpoints Key Secondary Endpoints Key Secondary Endpoints

9.3.2 Secondary 1-Response to treatment based on ALP normalization at week 52. 1-Response to treatment based on ALP normalization at week 52.
Endpoints 2-Change in pruritus from baseline through week 52 in PBC Worst Itch NRS 2-Change in pruritus from baseline through week 52 on PBC Worst Itch
score. NRS in patients with baseline PBC Worst Itch NRS score ≥4.
3-Change in pruritus from baseline through week 24 based on PBC
Worst Itch NRS in patients with baseline PBC Worst Itch NRS score
≥4
Other Secondary Endpoints Other Secondary Endpoints

1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks 1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
2) ALP response defined as 10%, 20% and 40% ALP reduction from 2) ALP response defined as 10%, 20% and 40% ALP reduction from
baseline at week 52 baseline at week 52
3) Response to treatment at week 52 according to: 3) Response to treatment at week 52 according to:
a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN a. ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN
b) ALP < 3 x ULN, AST <2 x ULN and TB ≤ 1 mg/dL (Paris I) b. ALP < 3 x ULN, AST <2 x ULN and TB ≤ 1 mg/dL (Paris
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5 x ULN and TB ≤ 1mg/dL (Paris II) I)
d) TB response rate of 15% change c. ALP ≤ 1.5 x ULN, AST ≤ 1.5 x ULN and TB ≤ ULN (Paris
e) Normalization of abnormal TB and/or albumin (Rotterdam) II)
f) TB ≤ 0.6 x ULN d. TB response rate of 15% change
g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1] e. Normalization of abnormal TB and/or albumin (Rotterdam)
h) No worsening of TB defined as level of TB at week 52 < ULN or no f. TB ≤ 0.6 x ULN
increase from baseline of more than 0.1XULN at week 52 g. ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1]
4) PBC risk scores at week 52: UK PBC score and GLOBE score h. No worsening of TB defined as level of TB at week 52 <
5) Response based on the normalization of bilirubin at week 52 ULN or no increase from baseline of more than 0.1XULN at
6) Response based on the normalization of albumin at week 52 week 52
7) Change from baseline to week 52 in hepatobiliary injury and liver i. Complete biochemical response defined as normal ALP,
function as measured by AST, ALT, GGT, 5’ NT, total and conjugated TB, AST, ALT, albumin and INR
bilirubin, albumin, INR and ALP fractionated (hepatic) 4) PBC risk scores at week 52: UK PBC score and GLOBE score
8) Change from baseline to week 52 in biomarkers of inflammation as 5) Response based on the normalization of bilirubin at week 52
measured by hsCRP, fibrinogen, haptoglobin and TNF- 6) Response based on the normalization of albumin at week 52
9) Change from baseline to week 52 in immune response as measured by 7) Change from baseline to week 52 in hepatobiliary injury and liver
IgG and IgM function as measured by AST, ALT, GGT, 5’ NT, total and
10) Change from baseline to week 52 in biomarkers, non-invasive and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
invasive measures of hepatic fibrosis as measured by ELF (HA, PIINP, 8) Change from baseline to week 52 in biomarkers of inflammation as
TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and TE measured by hsCRP, fibrinogen, haptoglobin and TNF-
11) Change from baseline to week 52 in lipid parameters as measured by TC, 9) Change from baseline to week 52 in immune response as measured
LDL-C, HDL-C, calculated VLDL-C and TG by IgG and IgM
CONFIDENTIAL
12) Change from baseline to week 52 in FPG 10) Change from baseline to week 52 in biomarkers, and non-invasive
13) Change from baseline to week 52 in bile acids and biomarkers of bile measures of hepatic fibrosis as measured by ELF (HA, PIINP, TIMP-
acid synthesis as measured by bile acids, C4 and FGF-19 1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver stiffness
14) Proportion of patients with no worsening of pruritus at week 52 based on measured by TE (continuous)
PBC Worst Itch NRS 11) Change from baseline to week 52 in lipid parameters as measured by
15) Response in Worst Itch NRS defined as 30% reduction from baseline of TC, LDL-C, HDL-C, calculated VLDL-C and TG
NRS at week 52 in patients with a baseline NRS ≥ 4 12) Change from baseline to week 52 in FPG
16) Change from baseline to week 52 in 5D-Itch 13) Change from baseline to week 52 in bile acids and biomarkers of bile
17) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a acid synthesis as measured by bile acids, C4 and FGF-19
18) Change from baseline to week 52 in ESS 14) Proportion of responders in PBC Worst Itch NRS according to
19) Change from baseline to week 52 in PBC-40 clinically meaningful change; at least 30% reduction; and one
20) Change from baseline to week 52 in health utility as measured by EQ- point, two points or three points decrease in score from baseline
5D-5L through week 52 and through week 24 in patients with a baseline
21) Onset of clinical outcomes described as a composite endpoint composed NRS score ≥ 4
of: 15) Proportion of patients with no worsening of pruritus from
a) MELD-Na > 14 for patients with baseline MED-Na ≤12 baseline through week 52 and through week 24 measured by the
b) Progression to histological cirrhosis for non cirrhotic patients at PBC Worst Itch NRS
baseline 16) Change from baseline to week 52 in 5D-Itch
c) Liver transplant 17) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a
d) Uncontrolled ascites requiring treatment 18) Change from baseline to week 52 in ESS
e) Hospitalization for new onset or recurrence of any of the following: 19) Change from baseline to week 52 in PBC-40
i) variceal bleed 20) Change from baseline to week 52 in health utility as measured by EQ-
ii) hepatic encephalopathy defined as West-Haven/Conn of 2 or 5D-5L
more 21) Change from baseline to week 52 in serum markers of bone
iii) spontaneous bacterial peritonitis turnover and in bone mineral density (hip and lumbar) assessed
f) Death by DEXA scanning
22) Change from baseline in: the histological scores 22) Onset of clinical outcomes described as a composite endpoint
a) fibrosis stage according to Nakanuma scoring composed of:
b) Bile duct scores a. MELD-Na > 14 for patients with baseline MED-Na ≤12
c) Cholangitis activity b. Liver transplant
d) Interface Hepatitis activity c. Uncontrolled ascites requiring treatment
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct d. Hospitalization for new onset or recurrence of any of the
score) following:
f) Other exploratory scores (Fibrosis according to modified Ishak i. variceal bleed
(adapted to PBC) scoring, portal inflammation, ductular reaction, ii. hepatic encephalopathy defined as West-
cholestasis and concentric periductal fibrosis) Haven/Conn of 2 or more
23) Safety and tolerability as assessed by: iii. spontaneous bacterial peritonitis
e. Death
CONFIDENTIAL
a) SAE, AE, AESI, physical examination, vital signs, medical history, 23) Safety and tolerability as assessed by:
ECG a. SAE, AE, AESI, physical examination, vital signs, medical
b) Chemistry and hematology history, ECG
c) Liver markers b. Chemistry and hematology
d) Renal biomarkers (including urinalysis) c. Liver markers
e) Other biochemical safety markers d. Renal biomarkers (including urinalysis)
f) Histology e. Other biochemical safety markers
24) PK assessed by GFT505 and GFT2007 concentrations measurement in 24) PK assessed by GFT505 and GFT2007 concentrations measurement
plasma in plasma
Additionally, the same endpoints as for the DB period (except histology and Additionally, the same endpoints as for the DB period (except histology –
PK assessment) will be collected over the LTE period to assess the if applicable - and PK assessment) will be collected over the LTE period
maintenance of efficacy and safety of the treatment. The endpoints will be to assess the maintenance of efficacy and safety of the treatment.
described using descriptive statistics by DB treatment group and overall on
both ITT and PP sets.
9.3.3 1) Change from baseline in the histological scores:
Exploratory a) Fibrosis stage according to Nakanuma scoring
Endpoints b) Bile duct loss score
(related to c) Cholangitis activity
histological d) Interface Hepatitis activity
assessments) e) Stage of disease (Sum of Fibrosis stage by Nakanuma and
Bile duct loss score)
f) Other exploratory scores (Fibrosis according to Ishak
scoring, portal inflammation, ductular reaction, cholestasis
and concentric periductal fibrosis)
2) Correlation between histological fibrosis scores (Nakanuma and
Ishak scores) and non invasive markers of fibrosis (liver stiffness,
ELF test and ProC3)
CONFIDENTIAL
9.4 Analysis The following analysis sets will be used in this study: The following analysis sets will be used in this study:
Sets • Screened set: all patients who signed ICF. This set will be used to • Screened set: all patients who signed ICF. This set will be used
summarize disposition. to summarize disposition.
• ITT) set: all randomized subjects. This set will be used to summarize • ITT) set: all randomized subjects. This set will be used to
efficacy. summarize efficacy.
• PP set: all subjects from the ITT set without any major protocol • PP set: all subjects from the ITT set without any major protocol
deviation affecting the primary efficacy endpoint. deviation affecting the primary efficacy endpoint.
• SS: all subjects who were administered at least one dose of study • SS: all subjects who were administered at least one dose of study
drug. This set will be used to summarize safety. drug. This set will be used to summarize safety.
• PKS: All patients who were administered at least one dose of study • PKS: All patients who were administered at least one dose of
drug and have at least one post-dose PK sample. Moreover, patients study drug and have at least one post-dose PK sample. Moreover,
of the PK set must have data for time of dosing, time of sampling patients of the PK set must have data for time of dosing, time of
and amount of study drug administered. Placebo patients will be sampling and amount of study drug administered. Whereas all
removed from the analysis population. patients are sampled in order to maintain the blind, the
Patients in the ITT and PP sets will be analyzed based on randomized pharmacokinetics set applies only to patients under
treatment. Patients in the SS will be analyzed based on actual treatment elafibranor.
received. • Exploratory (Histological) set: All subjects from the ITT set
who consent to have liver biopsy samples collected at baseline
and/or week 52
Patients in the ITT and PP sets will be analyzed based on randomized

treatment. Patients in the SS will be analyzed based on actual treatment
received.
CONFIDENTIAL
9.5 Analysis of The null hypothesis for response to treatment based on the primary endpoint The null hypothesis for response to treatment based on the primary
Primary is that there is no difference in response rates between elafibranor and placebo endpoint is that there is no difference in response rates between elafibranor
Endpoint groups. The alternative hypothesis is that there is a difference in response and placebo groups. The alternative hypothesis is that there is a difference
rates between both groups. The null hypothesis will be tested at a two-sided in response rates between both groups. The null hypothesis will be tested
alpha of 0.01 (see Section 9.6). The efficacy analysis will be performed at the at a two-sided alpha of 0.05 (see Section 9.6). The efficacy analysis will
end of the common DB period (week 52) only, but descriptive statistics will be performed at the end of the common DB period (week 52) only, but
be provided over the entire DB period (up to week 104). descriptive statistics will be provided over the entire DB period (up to
The number and percentage of patients with favorable response to treatment week 104).
will be summarized by treatment group at the end of the 52 weeks of the The number and percentage of patients with favorable response to
common DB treatment period as well as at the end of the overall DB period treatment will be summarized by treatment group at the end of the 52
(either V6/V8/LVDB). The response rates (ALP < 1.67 x ULN and TB ≤ weeks of the common DB treatment period as well as at the end of the
ULN and ALP decrease ≥ 15%) at week 52 will be compared between the overall DB period (either V6/V8/LVDB). The response rates (ALP < 1.67
treatment groups using the exact Cochran-Mantel-Haentzel test stratified by x ULN and TB ≤ ULN and ALP decrease ≥ 15%) at week 52 will be
the randomization strata. The estimate of the odds ratio, its 99% CI and the compared between the treatment groups using the exact Cochran-Mantel-
corresponding p-value will be provided. The main analysis will be based on Haentzel test stratified by the randomization strata. The estimate of the
the ITT. To assess the robustness of the results, the same analysis will be odds ratio, its 95% CI and the corresponding p-value will be provided. The
replicated on the PP set. main analysis will be based on the ITT. To assess the robustness of the
… results, the same analysis will be replicated on the PP set.
…
CONFIDENTIAL
9.6 Other The number and percentage of patients with favorable response to treatment The number and percentage of patients with favorable response to
Statistical (according to ALP normalization) will be described at the end of the common treatment (according to ALP normalization) will be described at the end
Analysis DB treatment period and at the end of the overall DB period (either of the common DB treatment period and at the end of the overall DB
9.6.1 Key V6/V8/LVDB), and the same statistical methods as for the primary endpoint period (either V6/V8/LVDB), and the same statistical methods as for the
secondary will be applied to evaluate the treatment effect at week 52. primary endpoint will be applied to evaluate the treatment effect at week
endpoints The change from baseline in PBC Worst Itch NRS score through week 52 52.
will be summarized by treatment group using monthly scores computed every The change from baseline in PBC Worst Itch NRS score through week 52
28 days and will be compared using a MMRM with stratification factors as or through Week 24, in patients with baseline PBC Worst Itch NRS
fixed factors. The statistical model will be used to calculate the mean score ≥4, will be summarized by treatment group using monthly scores
treatment difference (elafibranor - placebo), 99% CI and the corresponding computed every 28 days and will be compared using a MMRM with
p-value. The main analysis assumes that patients who experienced an ICE stratification factors as fixed factors. The statistical model will be used to
would have continued within their treatment arm. A tipping point sensitivity calculate the mean treatment difference (elafibranor - placebo), 95% CI
analysis will evaluate the impact on imputing outcomes in both treatment and the corresponding p-value. The main analysis assumes that patients
arms independently. A supplementary analysis based on treatment policy will who experienced an ICE would have continued within their treatment arm.
use outcome values at week 52 regardless of treatment discontinuation or use A tipping point sensitivity analysis will evaluate the impact on imputing
of rescue therapy. Additionnally, the PBC Worst Itch NRS-Past week score outcomes in both treatment arms independently. A supplementary analysis
obtained during the variable DB period will be described. based on treatment policy will use outcome values at week 52 regardless
Both key secondary endpoints will be analysed on ITT and PP sets. of treatment discontinuation or use of rescue therapy. Additionally, the
PBC Worst Itch NRS-Past week score obtained during the variable DB
period will be described.
The same analyses as described above for the change from baseline in
PBC Worst NRS score through week 52 will be repeated for the
change from baseline in PBC Worst NRS score through week 24.
All key secondary endpoints will be analysed on ITT and PP sets.
CONFIDENTIAL
9.6.3 Subgroup Exploratory analyses of the primary and key secondary endpoints will be Exploratory analyses of the primary and key secondary endpoints will be
analyses done for the following subgroups: done for the following subgroups:
• Age (< or > 60 years) • Age (< or ≥ 65 years)
• Gender • Gender
• Race • Race
• UDCA treatment at baseline (Yes/No) • UDCA treatment at baseline (Yes/No)
• Prior OCA treatment (Yes/No) • Prior OCA treatment (Yes/No)
• ALP level at baseline (≤ or > 3 x ULN) • ALP level at baseline (≤ or > 3 x ULN)
• TB at baseline (≤ or > 1 x ULN) • TB at baseline (≤ or > 1 x ULN)
• TB at baseline > ULN or albumin at baseline < LLN (Yes/No) • TB at baseline > ULN or albumin at baseline < LLN (Yes/No)
• TB > 0.6 x ULN (Yes/No) • TB > 0.6 x ULN (Yes/No)
• Geographic region • Geographic region
• PBC Worst Itch NRS score ≥ 4 (Yes/No) • PBC Worst Itch NRS score ≥ 4 (Yes/No)
• ALP > 3 x ULN or TB > ULN (Yes/No) • ALP > 3 x ULN or TB > ULN (Yes/No)
Forest plots will be generated for each endpoint for patients in the ITT • Cirrhotic defined by Liver stiffness at baseline ≥ 16.9KPa at
population. Further details will be provided in the SAP. Fibroscan exam (Yes/No) and/or cirrhosis on histology
• Advanced disease stage defined as liver stiffness at baseline
>10 kPa at Fibroscan exam and/or bridging fibrosis or
Forest plots will be generated for each endpoint for patients in the ITT
population. Further details will be provided in the SAP.
9.7 Strategies The overall type I error for the primary and key secondary endpoints is two- The overall type I error for the primary and key secondary endpoints is
To Control Type sided α=0.01. two-sided α=0.05.
I Error The fixed-sequence testing approach will be used to control the overall type The fixed-sequence testing approach will be used to control the overall
I error rate at a two-sided 0.01 level. If the primary endpoint is statistically type I error rate at a two-sided 0.05 level. If the primary endpoint is
significant at a two-sided 0.01 level, the first key secondary endpoint (ALP statistically significant at a two-sided 0.05 level, the first key secondary
normalization) will be tested at the same level. If the first key secondary endpoint (ALP normalization) will be tested at the same level. If the first
endpoint is statistically significant at a two-sided 0.01 level, the second key key secondary endpoint is statistically significant at a two-sided 0.05 level,
secondary endpoint (change in pruritus) will be tested at the same level. the second key secondary endpoint (change in pruritus through week 24)
Statistical testing for other secondary endpoints will be of exploratory nature. will be tested at the same level. If the second key secondary endpoint is
statistically significant at a two-sided 0.05 level, the third key
secondary endpoint (change in pruritus through week 24) will be
tested at the same level.
Statistical testing for other secondary endpoints will be of exploratory
nature.
CONFIDENTIAL
9.8.1 Reduction … …
in ALP and TB One hundred and fifty patients (100 elafibranor and 50 placebo) allow to One hundred and fifty patients (100 elafibranor and 50 placebo) allow to
achieve at least 90% power to demonstrate a statistically significant between achieve at least 90% power to demonstrate a statistically significant
group difference of 35% (47% in elafibranor group vs 12% in placebo group) between group difference of 35% (47% in elafibranor group vs 12% in
in the response rate at week 52 of the primary efficacy endpoint with a two- placebo group) in the response rate at week 52 of the primary efficacy
sided alpha of 0.01 and using an exact Fisher test. endpoint with a two-sided alpha of 0.05 and using an exact Fisher test.
9.8.2 Assuming 1/50 (2.0%) patient in the placebo arm with ALP normalization at Assuming 1/50 (2.0%) patient in the placebo arm with ALP normalization
Normalization week 52 (key secondary endpoint), 150 patients (100 elafibranor vs 50 at week 52 (key secondary endpoint), 150 patients (100 elafibranor vs 50
in ALP placebo) provide at least 80% power to detect a statistically significant placebo) provide at least 80% power to detect a statistically significant
between group difference of 20.0% at a two-sided 0.01 alpha level. between group difference of 20.0% at a two-sided 0.05 alpha level.
9.8.3 Change in Assuming a pooled SD of 3 points, 150 patients (100 elafibranor vs 50 Assuming a pooled SD of 2.3 points, 60 patients (40 elafibranor vs 20
Pruritus placebo) provide at least 80% power to detect a statistically significant placebo) with baseline PBC Worst Itch NRS score ≥4 provide at
between group difference of 1.8 points in mean change from baseline in PBC approximately 80% power to detect a statistically significant between
Worst Itch NRS score at a two-sided 0.01 alpha level. group difference of 1.8 points in mean change from baseline in PBC Worst
Itch NRS score at a two-sided 0.05 alpha level. It is assumed that the
same assumptions would apply to the two key secondary endpoints
for pruritus (through week 52 and through week 24).
9.10 Descriptive statistics on the histological scores and the non invasive
Exploratory markers of fibrosis (liver stiffness, ELF test and ProC3) will be
Analysis provided by DB treatment groups and overall in the Exploratory
(related to (Histological) set.
histological Change over time on the histological scores will be described using
assessments) shift tables. In addition, the value at each visit as well as the change
from baseline will be described on the non invasive markers of
fibrosis.
For assessing the correlation between the histological fibrosis
endpoints (Nakanuma and Ishak scores) and the non invasive
markers of fibrosis, the correlation coefficients and their CIs will be
estimated depending on the nature and distribution of the endpoints
considered.
CONFIDENTIAL
10. Data The contract between the sponsor and their vendors, and study sites
Handling and specifies the responsibilities of the parties related to data protection,
Record Keeping including handling of data security breaches and respective
10.1 Data communication and cooperation of the parties.
Protection Information technology systems used to collect, process, and store
study-related data are secured by technical and organizational
security measures designed to protect such data against accidental or
unlawful loss, alteration, or unauthorized disclosure or access.
In the event of a potential data security breach concerning personal
data processed on behalf of the sponsor, the data protection officer
must be informed without undue delay and no later than 24 hours
from the discovery of the event. The data protection officer will
evaluate the event and notify the Data Protection Authorities within
72 hours, if required. Corrective actions and preventive actions will
be implemented to mitigate the possible adverse effects. Affected
study participants will be informed accordingly. Ipsen Data
Protection Officer can be contacted by email:
dataprivacy@ipsen.com.
CONFIDENTIAL
11. Quality It is the responsibility of the Investigator to ensure that the study is conducted It is the responsibility of the Investigator to ensure that the study is
Control and in accordance with the protocol, GCP (ICH topic E6 R2), applicable conducted in accordance with the protocol, GCP (ICH topic E6 R2),
Quality regulatory requirements, and the current Declaration of Helsinki and that applicable regulatory requirements, and the current Declaration of
Assurance valid data are entered into the eCRFs. Helsinki and that valid data are entered into the eCRFs.
11.1 Quality To achieve this objective, the Study Monitor’s duties are to aid the To achieve this objective, the Study Monitor’s duties are to aid the
Control & Investigator and, at the same time, the Sponsor in the maintenance of Investigator and, at the same time, the Sponsor in the maintenance of
Monitoring attributable, legible, and contemporaneously recorded, original or a true copy, attributable, legible, and contemporaneously recorded, original or a true
Procedures accurate (ALCOA), well-organized, and easily retrievable data. copy, accurate (ALCOA), well-organized, and easily retrievable data.
Before screening any patients in this study, the Study Monitor will review the Before screening any patients in this study, the Study Monitor will review
protocol, the IB, the eCRFs and instructions for their completion and return, the protocol, the IB, the eCRFs and instructions for their completion and
the procedure for obtaining informed consent, and all other study procedures return, the procedure for obtaining informed consent, and all other study
(e.g. the laboratory manual, electronic patient-reported outcomes [ePRO] procedures (e.g. the laboratory manual, electronic patient-reported
manual, IXRS manual, etc) including the reporting AEs and SAEs with the outcomes [ePRO] manual, IXRS manual, etc) including the reporting AEs,
Investigator. In addition, the Study Monitor will explain the Investigator’s AESIs and SAEs with the Investigator. In addition, the Study Monitor will
reporting responsibilities and all applicable regulations concerning the explain the Investigator’s reporting responsibilities and all applicable
clinical evaluation of the study drug. regulations concerning the clinical evaluation of the study drug.
The Investigator will permit the representatives of Sponsor to monitor the The Investigator will permit the representatives of Sponsor to monitor the
study as frequently as the Sponsor deems is necessary to determine that data study as frequently as the Sponsor deems is necessary to determine that
recording and protocol adherence are satisfactory. A Study Monitor from the data recording and protocol adherence are satisfactory. A Study Monitor
CRO will be responsible for monitoring this clinical study. To this end, the from the CRO will be responsible for monitoring this clinical study. To
Study Monitor will visit the study site at suitable intervals and be in frequent this end, the Study Monitor will visit the study site at suitable intervals
contact through verbal and written communication. The eCRFs and related and be in frequent contact through verbal and written communication. The
source documents, as well as drug accountability will be reviewed in detail eCRFs and related source documents, as well as drug accountability will
by the monitor, in accordance with relevant SOPs and GCP (ICH topic E6 be reviewed in detail by the monitor, in accordance with relevant SOPs
R2) regulations. This includes results of tests performed as a requirement for and GCP (ICH topic E6 R2) regulations. This includes results of tests
participation in this study and any other medical records required to confirm performed as a requirement for participation in this study and any other
information contained in the eCRFs, such as past medical history. medical records required to confirm information contained in the eCRFs,
Further details can be found in the monitoring plan. such as past medical history.
It is essential that the Study Monitor has access to all documents (related to In cases of emergency (e.g., pandemic, political strife, natural
the study and the individual subjects) at any time these are requested. In turn, disasters), to continue to ensure data monitoring, according to
the Study Monitor will adhere to all requirements for patient confidentiality national regulations and under the responsibility of the Investigator,
as outlined in the ICF. The Investigator and Investigator’s staff will be remote access to source documents can be provided to the Study
expected to cooperate with the Study Monitor, to be available during a portion Monitor to perfom remote Source Data Verification (SDV). Further
of the monitoring visit to answer questions, and to provide any missing details can be found in the monitoring plan.
information. It is essential that the Study Monitor has access to all documents (related
All monitoring activities will be reported and archived in the Trial Master to the study and the individual subjects) at any time these are requested.
File. In turn, the Study Monitor will adhere to all requirements for patient
confidentiality as outlined in the ICF. The Investigator and Investigator’s
CONFIDENTIAL
staff will be expected to cooperate with the Study Monitor, to be available
during a portion of the monitoring visit to answer questions, and to provide
any missing information.
All monitoring activities will be reported and archived in the Trial Master
File.
CONFIDENTIAL
12. Ethics and Written ICF for the study will be obtained from each patient before protocol- Written ICF for the study will be obtained from each patient before
Regulatory specific procedures are carried out. The ICF used by the Investigator for protocol-specific procedures are carried out. The ICF used by the
12.3 Patient obtaining the patient's informed consent must be reviewed and approved by Investigator for obtaining the patient's informed consent must be reviewed
Information and the Sponsor prior to submission to the appropriate ethics committee and approved by the Sponsor prior to submission to the appropriate ethics
Consent (IRB/IEC). The ICF will be approved (along with the protocol) by the committee (IRB/IEC). The ICF will be approved (along with the protocol)
IRB/IEC. by the IRB/IEC.
The Investigator or a person designated by the Investigator (according to The Investigator or a person designated by the Investigator (according to
applicable regulatory requirements), will explain the nature of the study and applicable regulatory requirements), will explain the nature of the study
the action of the study drug. The patients will be informed that participation and the action of the study drug. The patients will be informed that
is voluntary and that they can withdraw from the study at any time. In participation is voluntary and that they can withdraw from the study at any
accordance with 21 CFR 50, the informed consent process shall be time. In accordance with 21 CFR 50 local regulations, ICH guidelines,
documented by the use of a written ICF approved by the designated IRB/IEC privacy and data protection requirements, where applicable, the
and will be signed and personally dated by the patient or by the patient’s informed consent process shall be documented by the use of a written ICF
legally acceptable representative and by the person who conducted the approved by the designated IRB/IEC and will be signed and personally
informed consent discussion prior to protocol-specific procedures being dated by the patient and by the person who conducted the informed
performed. A separate consent form will be obtained for optional biomarker consent discussion prior to protocol-specific procedures being performed.
samples to be stored in the blood bank. A separate consent form will be obtained for optional biomarker
The Investigator must maintain the original, dated and signed ICF. A copy of samples to be collected and to be stored in the blood bank.
the signed ICF must be given to the patient. Participants to the optional research biobanking programme have the
right to withdraw their consent at any time and for any reason during
the study or during the period of sample storage (i.e. the entire 15
years during which samples are kept).
If a participant wishes to withdraw their consent for optional
biobanking and the samples are still at the investigator site or at the
central laboratory at the time, the investigator must inform the study
monitor in writing of the participant’s decision and destroy the
samples.
If the samples are at the sponsor’s repository (biobanking vendor),
the investigator must inform the sponsor directly using the e-mail
address: IpsenBiobanking@ipsen.com, mentioning only the
participant ID in this e-mail. The sponsor will ensure destruction of
the samples and all corresponding aliquots and issue confirmation of
the destruction, which will be forwarded to the investigator. Analyses
conducted before the withdrawal will not be affected.
In addition separate consent forms will be obtained for optional liver
biopsy sample collection, as well as for pregnant partner data
collection.
CONFIDENTIAL
The Investigator must maintain the original, dated and signed ICFs. A
copy of the signed ICFs must be given to the patient.
13. Financing Financial contracts will be signed between the Sponsor and the Financial contracts will be signed between the Sponsor and the
and Insurance Investigator/Institution before initiation of the study. Investigator/Institution before initiation of the study.
13.1 Financial Investigators and sub-investigators will provide the Sponsor with
Issues sufficient, accurate financial information as requested to allow the
Sponsor to submit complete and accurate financial certification or
disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial
interests during the course of the study and for one year after
14. Study The final report will be written in English upon completion of study and The final report will be written in English upon completion of study and
Results and statistical analysis according to ICH E3 guideline. The report or part of it statistical analysis according to ICH E3 guideline. The report or part of it
Publication must be submitted to relevant authorities if applicable. must be submitted to relevant authorities if applicable.
Policy The CRO will prepare an integrated Clinical Study Report (CSR). Prior to The Sponsor will prepare an integrated Clinical Study Report (CSR).
14.1 Study issuing the final CSR, the CRO will prepare a draft report for approval by the Prior to issuing the final CSR, the CRO will prepare a draft report for
Report Sponsor. The draft report will be submitted for Quality Control, the findings approval by the Sponsor and by the study Steering Committee. The draft
of which will be incorporated into the final version. report will be submitted for Quality Control, the findings of which will be
An electronic copy of the final CSR will be made available to the Sponsor. incorporated into the final version.
The CSR will be provided in PDF and MS Word formats unless agreed
otherwise by the CRO. Reports requiring specialized Sponsor
formats/alternative computer software packages may be possible on request
from the Sponsor but may involve extra time and cost. Electronic datasets
will also be provided to the Sponsor on issuance of the final report.
After review by the Sponsor, a final CSR will be submitted to the Sponsor
which incorporates the Sponsor’s comments.
CONFIDENTIAL
14.2 …. ….
Confidentiality Clinical study will be registered on the open access website Protocol information and (final/interim) study results will be made
and Ownership https://www.clinicaltrials.gov before the screening of the first patient in the publicly available on the US website (www.clinicaltrials.gov) and on
of Data, Use of study. the EU Clinical Trials Register (www.clinicaltrialsregister.eu) or EU
the Study It is the policy of the Sponsor to encourage the presentation and/or publication Clinical Trials Portal (https://euclinicaltrials.eu/home). The sponsor
Results and of the results of their studies, using only clean, checked, and validated data in also provides clinical trial information to other national clinical trial
Publication order to ensure the accuracy of the results. registries or databases according to local requirements/legislation. A
The publication of study results will be agreed between the Sponsor and the lay summary of the study will be made available on the EU Clinical
Investigators. Trials Portal (https://euclinicaltrials.eu/home) and/or Sponsor
At least 45 days in advance of proposed submission, the Investigator should website.
forward a copy of the manuscript or abstract for review by the Sponsor, and, It is the policy of the Sponsor to encourage the presentation and/or
if necessary, delay publication or communication for a limited time in order publication of the results of their studies, using only clean, checked, and
to protect the confidentiality or proprietary nature of any information validated data in order to ensure the accuracy of the results.
contained therein. The Sponsor may also request that the Sponsor’s name The study results may be published or presented at scientific meetings
and/or names of one or several of its employees appear or not appear in such after agreement between the Sponsor and the Investigators.
publication. If this is foreseen, the Investigator should discuss specific publication
concepts, including data to be covered, target congress/journal and
proposed authors, with the Sponsor for agreement before initiation.
The Sponsor may also request that the Sponsor’s name and/or names of
one or several of its employees appear or not appear in such publication.
The investigator agrees to submit all manuscripts or abstracts to the
Sponsor before submission. This allows the Sponsor to protect
proprietary information and to provide comments.
Page 293
Statistical Analysis Plan
Sponsor: Genfit
Protocol: GFT505B-319-1, IND number: 132202
Document Version No.: V1.0 Document Date: 28-JULY-2020
STATISTICAL ANALYSIS PLAN

(Double-Blind Period)
Protocol GFT505B-319-1
evaluate efficacy and safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with
Protocol Number: GFT505B-319-1, v0.7, IND number: 132202

(Version Date) July-2020
Name of Test Drug: Elafibranor
Phase: 3
Methodology: A Double-blind, Randomized, Placebo-Controlled Study and

Open-label Long Term Extension to evaluate efficacy and safety
of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis
with Inadequate Response or Intolerance to Ursodeoxycholic
Acid.
Sponsor: GENFIT
Parc Eurasanté
59120 LOOS, France, Phone: +33 320 16 40 38
CRS-BS-TP-000005 V 1.0
Page 1 of 86
Genfit / Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any
unauthorized person.
Page 294
Sponsor: Genfit
Document Version No.: 1.0 Document Date: 28-JULY-2020
Document Date: 28-July-2020
Document Version: vl.O
SIGNATURE PAGE
Protocol Title: A Double-blind, Randomized, Placebo-Controlled Study and

Open-label Long Term Extension to evaluate efficacy and
safety of Elafibranor 80 mg in Patients with Primary Biliary
Cholangitis with Inadequate Response or Intolerance to
Ursodeoxycholic Acid.
Sponsor: GENFIT
Parc Eurasanté
Protocol Number: GFT505B-319-1, IND number: 132202
Document Date/Version: 28-JULY-2020/vl.0
Cytel, Inc. Author:

PPD Signature:
Geneva Branch | Route de Prébois 20,
CFI-1215 Geneva Date:____
PPD Electronically signed by:
Signature
Reason: Approve PPD
Date: Jul29. 2020 10:00 GMT+2
Email: PPD
CRS-BS-TP-000005 V 1.0
Page 2 of 86
Genfit / Cvtel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any
Page 295
PPD
PPD
PPD
PPD
PPD
PPD
Page 296
Sponsor: Genfit
MODIFICATION HISTORY
Unique Date of SAP Author Changes from the Previous Version

Identifier for Version
SAP Version
Initial issuance of document

V 0.1 6-Nov-2019 PPD First draft of SAP
V 0.2 11-Nov-2019 PPD Updated version based on comments by Jean-loup on the
6Nov. Many sections are not updated because changes in
definitions and endpoints at the Protocol level are
happening on the Genfit side.
V 0.3 18-Nov-2019 PPD Third draft of SAP with changes due to Protocol update on
15-Nov-2019. The SAP v 0.3 has another date in the doc,
but it was sent to client on the 18th. Not all Protocol
changes have been incorporated.
V 0.4 19-Nov-2019 PPD All Protocol changes have been incorporated, missing
imputation section is incomplete-Cytel waiting for Genfit
expert to decide on the method to use. TLF list is
incomplete, links and references are incomplete as well.
V0.5 22-Nov-2019 PPD Added multiple imputation methodology suggested by
Genfit. Eliminated “non-reliable” data concept. Added
adjudicated analysis and CEC. Added UK-PBC score and
globe PBC score analysis. Added non parametric Ancova
macro. Added some SAS code. Changed CMH analysis to
exact univariate logistic regression to get exact p-values as
well as exact CI.
V0.6 25-Nov-2019 PPD Clean version without comments. Eliminated supportive
analysis definition, kept only sensitivity analysis of primary
and secondary endpoint and supplementary analysis
V0.7 03-JAN-2020 PPD Wording modifications, e.g. trial-study. Logistic regression
substituted with CMH as primary analysis. Layout
corrections. Table 1, Table 2 and Table 3 modified.
V0.8 4-May-2020 PPD Updates on SAP based on FDA comments: New key-
secondary EP: Change in pruritus (continuous). For the
primary efficacy endpoint, clarify how the OR from the
multiply imputed datasets will be combined.
V0.9 06-May-2020 PPD Inclusion of AESI analysis, modification of eDISH and
creatinine analyses.
Additional secondary endpoints (liver biopsy, PK, no
worsening of TB).
One supplementary analysis added for primary and key
secondary endpoints (treatment policy strategy).
Sections relative to sample size and multiplicity were
adjusted to take into account the new key secondary
endpoint added in v0.8.
V0.10 8-May-2020 PPD Minor corrections and added comments.
V0.11 12-May-2020 PPD Hyperlinks added and many track changes accepted
CRS-BS-TP-000005 V 1.0
Page 4 of 86
Page 297
Sponsor: Genfit

SAP Version

V0.12 24-July-2020 PPD Changes based on FDA comments of June 2020 and on
updated Protocol version 0.7, among others:
- Tipping point analysis
- PBC Worst itch NRS monthly average calculation
V1.0 28-July-2020 PPD Clean version
CRS-BS-TP-000005 V 1.0
Page 5 of 86
Page 298
Sponsor: Genfit
TABLE OF CONTENTS
MODIFICATION HISTORY .................................................................................................................. 4

1. INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 14
1.1. INTRODUCTION ............................................................................................................................. 14
1.2. OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 14
2. STUDY DESIGN ................................................................................................................... 15
2.1. SYNOPSIS OF STUDY DESIGN......................................................................................................... 15
2.2. SCREENING PERIOD....................................................................................................................... 15
2.3. BASELINE PERIOD (V1) .................................................................................................................. 17
2.4. DOUBLE BLIND (DB) TREATMENT PERIOD (WEEK 0 UP TO WEEK 104) ........................................ 17
2.5. LONG-TERM EXTENSION ............................................................................................................... 18
2.6. CLINICAL EVENT COMMITTEE (CEC) .............................................................................................. 18
2.7. OPTIONAL VISITS ........................................................................................................................... 19
2.8. EXPLORATORY/ANCILLARY SUB-STUDY ........................................................................................ 20
2.9. RANDOMIZATION METHODOLOGY .............................................................................................. 20
2.10. STOPPING RULES AND UNBLINDING............................................................................................. 21
2.11. STUDY PROCEDURES ..................................................................................................................... 22
2.12. EFFICACY, PHARMACOKINETIC, AND SAFETY VARIABLES ............................................................. 32
2.12.1. EFFICACY VARIABLES ................................................................................................... 32
2.12.2. PHARMACOKINETIC VARIABLES .................................................................................. 35
2.12.3. SAFETY VARIABLES ...................................................................................................... 35
3. SUBJECT POPULATIONS ...................................................................................................... 36
3.1. POPULATION DEFINITIONS ........................................................................................................... 36
3.2. PROTOCOL VIOLATIONS ................................................................................................................ 37
4. STATISTICAL METHODS ...................................................................................................... 39
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4.1. SAMPLE SIZE JUSTIFICATION ......................................................................................................... 39

4.2. GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 39
4.2.1. GENERAL METHODS .................................................................................................... 39
4.2.2. DATA CONVENTIONS .................................................................................................. 41
4.2.3. COMPUTING ENVIRONMENT ...................................................................................... 42
4.2.4. METHODS OF POOLING DATA .................................................................................... 42
4.2.5. ADJUSTMENTS FOR COVARIATES ............................................................................... 43
4.2.6. MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 43
4.2.7. SUBPOPULATIONS....................................................................................................... 43
4.2.8. WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP ................................................... 44
4.2.9. MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 44
4.2.10. VISIT WINDOWS .......................................................................................................... 46
4.2.11. DATA DERIVATION ...................................................................................................... 47
4.3. INTERIM ANALYSES ....................................................................................................................... 48
4.4. SUBJECT DISPOSITION ................................................................................................................... 48
4.5. DEMOGRAPHIC, SCREENING AND BASELINE CHARACTERISTICS .................................................. 49
4.5.1. DEMOGRAPHIC ........................................................................................................... 49
4.5.2. SCREENING DISEASE CHARACTERISTICS ..................................................................... 49
4.5.3. BASELINE DISEASE CHARACTERISTICS ......................................................................... 50
4.5.4. PRIOR MEDICATIONS .................................................................................................. 50
4.5.5. PRIOR PROCEDURES.................................................................................................... 51
4.6. EFFICACY EVALUATION ................................................................................................................. 51
4.6.1. PRIMARY EFFICACY ENDPOINT ANALYSIS ................................................................... 53
4.6.2. FIRST KEY SECONDARY EFFICACY ENDPOINT .............................................................. 61
4.6.3. SECOND KEY SECONDARY EFFICACY ENDPOINT ......................................................... 62
4.6.4. SUBGROUP ANALYSIS.................................................................................................. 65
4.6.5. OTHER SECONDARY ENDPOINTS ................................................................................ 65
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4.7. PHARMACOKINETIC EVALUATIONS .............................................................................................. 75

4.8. SAFETY ANALYSES ......................................................................................................................... 75
4.8.1. EXTENT OF EXPOSURE AND COMPLIANCE .................................................................. 75
4.8.2. ADVERSE EVENTS ........................................................................................................ 76
4.8.3. ADJUDICATED DILI....................................................................................................... 79
4.8.4. LABORATORY DATA..................................................................................................... 80
4.8.5. VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 82
4.8.6. ELECTROCARDIOGRAM ............................................................................................... 82
4.8.7. CONCOMITANT MEDICATIONS ................................................................................... 82
5. CHANGES TO PLANNED ANALYSES ...................................................................................... 83
6. REFERENCES ...................................................................................................................... 84
7. APPENDIX A ....................................................................................................................... 85
8.1. STATISTICAL OUTPUTS TO BE GENERATED ................................................................................... 86
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LIST OF IN-TEXT TABLES
Table Page
Table 1 Schedule of Assessments 22
Table 2 Schedule of Biological Assessments 27
Table 3 Schedule of Patient Reported Outcomes Questionnaires 31
Table 4 Evaluation Intervals for Efficacy Analysis 47
LIST OF IN-TEXT FIGURES
Figure 1 Study design overview 19
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ABBREVIATIONS
Abbreviation Definition
ACR Albumin to Creatinine Ratio
AE Adverse events
AESI Adverse events of specific interest
AKI Acute kidney injury
ALB Albumin
ALP Alkaline phosphatase
ALT Alanine transaminase
AST Aspartate transaminase
AT Aminotransferase
CEC Clinical event committee
CK-18 Cytokeratin-18
CI Confidence Interval
CMH Cochran-Mantel-Haenszel
CSR Clinical study report
C4 Serum 7 α-hydroxy-4-cholesten-3-one
DB Double blind
DILI Drug-induced Liver injury
DSMB Data Safety Monitoring Board
5D-Itch 5-D Pruritus Scale
ECG 12-lead Electrocardiogram
eDISH Evaluation of Drug-Induced Serious Hepatotoxicity
ELA Elafibranor
ELF Enhanced Liver Fibrosis test
EODB End of Double-Blind period
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EOS End of Study
EOT End of treatment
FGF-19 Fibroblast growth factor 19
FPFV First Patient First Visit
GCA Glycocholic acid
GGT Gamma-glutamyltransferase
HA Hyaluronic acid
Anti- HAV IgM Hepatitis A Antibody test
HBsAg Surface antigen of the hepatitis B virus (Australia antigen)
HCV Ab Hepatitis C antibody
HCV RNA Qualitative Detection of Hepatitis C Virus RNA
HDL-C High-Density Lipoprotein Cholesterol
HIV Ab I/II Rapid HIV antibody test
HRQoL Health-related Quality of Life
hsCRP high-sensitivity C-Reactive Protein
IgG Immunoglobulin G
IgM Immunoglobulin M
IL-6 Interleukin 6
INR International normalized ratio
IP Investigational Product
ITT Intent-to-treat
IxRS interactive voice/web response system
WI-NRS Worst Itch Numeric Rating Scale
KDIGO Kidney disease improving global outcomes
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LDL-C Low-Density Lipoprotein Cholesterol
LLT Lower limit of normal
M1, M2, M3 First Measure, Second Measure, Third Measure
MedDRA Medical Dictionary for Regulatory Activities
MELD-Na model end stage liver disease-Sodium
M30 measures caspase-cleaved CK18 produced during apoptosis
M65 measures the levels of both caspase-cleaved and intact CK18, total
cytokeratin
N/A Not applicable
5’ NT 5’-nucleotidase
OCA Ocaliva, obeticholic acid
PAI-1 Plasminogen activator inhibitor-1
PBC Primary Biliary Cholangitis
PBC-40 Quality of Life for Primary Biliary Cirrhosis
PGIC The Patient Global Impression of Change
PGIS patient global impression-severity
PIINP Procollagen III amino terminal peptide
PK Pharmacokinetic
PP Per Protocol
PRO Patient reported outcomes
Pro-C3 Plasma collagen type III
Pt prothrombin time
PT Preferred Term
Q1, Q3 First Quartile, Third Quartile
QTc corrected QT
R Randomization call
SAE Serious adverse events
SAP Statistical analysis plan
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SOC System/Organ/Class
SS Safety set
SV Screening visit
TC Total cholesterol
TB Total Bilirubin
TE Transient elastography
TEAE Treatment-emergent adverse event
TIMP-1 Tissue inhibitor of metalloproteinase 1
TG Thyroglobulin
TGF-β Transforming growth factor beta
TNF-α tumor necrosis factor alpha
UDCA Ursodexycholic acid
ULN Upper limit of normal
VLDL-C Very-low-density lipoprotein Cholesterol
V1 Randomization/baseline visit
V2-V6 Visit2-Visit6
WBC White cell blood count
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1. INTRODUCTION AND OBJECTIVES OF ANALYSIS
1.1. Introduction
This document describes the plan for the statistical analyses and reporting of the double-blind period of
the study GFT505B-319-1, which is a prospective, randomized, double-blind, placebo-controlled phase
3 study to demonstrate the efficacy of Elafibranor 80 mg versus Placebo in patients with Primary Biliary
Cholangitis (PBC) and inadequate response or intolerance to ursodexycholic acid (UDCA). Results of the
analyses described in this Statistical Analysis Plan (SAP) will be included in the Clinical Study Report
(CSR).
Additionally, the planned analyses identified in this SAP will be included in regulatory submissions or
future manuscripts. Any post-hoc or unplanned analyses related to the double-blind period and
performed to provide results for inclusion in the CSR but not identified in this prospective SAP will be
clearly identified in the CSR.
The information regarding the analyses of the open label long term extension period is not within the
scope of this SAP and will be described in a separate statistical analysis plan.
1.2. Objectives of Statistical Analysis
The primary objective of the study GFT505B-319-1, as stated in the protocol is to evaluate the effect of
Elafibranor (80 mg/day) on cholestasis and on pruritus over 52 weeks of treatment compared to
placebo.
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis of study
data in order to answer the study objective. Populations for analysis, data handling rules, statistical
methods, and formats for data presentation are provided in this SAP. The statistical analyses and
summary tabulations described in this SAP will provide the basis for the results sections of the clinical
study report (CSR) for this study.
This SAP will also outline any differences in the currently planned analytical objectives relative to those
planned in the study protocol.
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2. STUDY DESIGN
2.1. Synopsis of Study Design
This is a phase 3 double-blind (DB), randomized, placebo-controlled study evaluating Elafibranor (ELA)
80 mg once daily versus placebo in patients with PBC and inadequate response or intolerance to
ursodexycholic acid (UDCA).
2.2. Screening period
The study starts with a screening period, which must include at least one screening visit (SV) which
should be performed between 1 week to 12 weeks prior to randomization. At the SV, preliminary
entrance criteria will be reviewed.
For the purpose of establishing relevant baseline chemistries for suspected drug-induced liver injury
(DILI), repeated measures of AST, ALT and TB will be collected (see section 4.8.4) ONLY if the first
measure (M1) collected at SV1 is > ULN.
M1 and another value, either a historical value (M0), collected up to 12 weeks before SV1, or a second
measure (M2) will be collected at SV2 (4 to 6 weeks after SV1). This applies to only the analyte above
ULN.
• If variability between M1 and either M0 or M2 is > 40% a third measure (M3) will be collected
at SV3 (4 to 6 weeks after SV1 (if M0 compared) or after SV2 (if M2 compared)):
o If variability between M1 and M3 is > 40% the patient is ineligible for the study.
To assess the ALP eligibility criterion, two ALP values will be required. One value is the M1 collected at
SV1, and the other value is M0 collected up to 12 weeks before SV1 or M2 collected at SV2 (4 to 6
weeks after SV1).
• If M1 is < 1.67x ULN, the patient will be excluded, and no further assessment will be performed
• If M1 is ≥ 1.67x ULN, and the mean of M1 and either M0 or M2 is ≥ 1.67x ULN, and variability is
≤ 40%, the patient is eligible
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• If M1 is ≥ 1.67x ULN, and the mean of M1 and either M0 or M2 is < 1.67x ULN or variability is >
40%, M3 collected at SV3 (4 to 6 weeks after SV1 (if M0 compared) or after SV2 (if M2
compared)) will be required:
o If the mean of M1 and M3 is ≥ 1.67x ULN and variability is ≤ 40%, the patient is eligible
o If the mean of M1 and M3 is < 1.67x ULN or variability is > 40%, the patient is ineligible
for the study
NOTE: M2 and M3 values for AST, ALT, TB and ALP can be obtained locally. Comparison between M1
and local value(s) will be done on normalized values according to ULN.
The laboratory value used for the first stratification factor (see section 2.9) will be the ALP value and
total bilirubin value provided by the central lab at SV1.
Local laboratory assessments are allowed for repetition of assessment of ALT, AST, TB and ALP during
the screening period as well as for any required retest for liver function monitoring and assessment of
urinary myoglobin, when applicable.
At the screening period, the second stratification factor will be the PBC Worst Itch NRS. PBC Worst Itch
NRS will be recorded on an eDiary daily each evening; the PBC Worst Itch NRS score will be averaged
over the 7 days preceding Baseline (V1: Day 1) to determine stratification for randomization. The PBC
Worst Itch Score will be computed as an average of non-missing data falling in the 7 days window. At
least 4 values of the PBC Worst Itch NRS score of the 7 days prior to randomization visit are required for
randomizing the patients. If this number is not achieved, the screening period may be extended in
order to obtain the expected number of NRS values.
At Screening the availability of historic liver biopsy samples may be determined to support the
diagnosis of PBC. Liver biopsy is one of the criteria to help identify PBC subjects.
All inclusion and exclusion criteria will be reviewed. If eligibility is confirmed, the site will contact the
subject to confirm subject’s willingness to continue in the study.
Eligible patients will be asked if they agree to sign the ICF. Each patient who has signed the ICF will
perform procedures listed in Table 1.
During the screening period, the subject will receive no study drug.
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2.3. Baseline period (V1)
As per protocol, evaluations performed at the Study Day 1 visit V1 should be done before drug
administration and will be used for baseline values. Thus, baseline is defined as the last non-missing
assessment the day or prior to study drug start. If the assessment for ALP/AST/ALT/TB is not done at
the baseline visit, a previous assessment by the central lab during the screening period closest to the V1
may be used.
2.4. Double Blind (DB) treatment period (Week 0 up to Week 104)
Subject who satisfy all eligibility criteria and confirm participation, will be randomized (see section 2.9)
in a 2:1 ratio to one of two treatment groups:
- Elafibranor 80mg
- Placebo
In this DB Phase, study medication will be administered orally, once daily for up to 24 months. For any
patient, the DB period will last until the last completed Visit 6 (W52) or until a maximum of 104 weeks,
whatever happens first.
On the first day of the DB period the patient will receive the study drug after all baseline assessments
are completed. During the entire double-blind period, the laboratory assessments (at every visit) will be
done before study drug intake.
participation. During the Double-blind Period the patients will return to the site for visits every 13
weeks (±2 weeks) from the Randomization Visit (V1) to Visit 6 except for the Visit 2 (4 weeks after V1),
and if applicable every 26 weeks from Visit 6 to Visit 8 (W104). When the last V6 is performed, any
patient between Visit 6 and Visit 8 should perform a last visit DB (LVDB) within the next 13 weeks. In
case the LVDB occurs within the time window of the next scheduled visit, LVDB visit replaces the
scheduled visit. Between V6 and V8, safety contacts will be performed by phone call between on site
visits, every 26 weeks, to collect information related to AEs, concomitant medications, pregnancy, and
study drug compliance. The first phone safety contact will start 13 weeks after V6 as applicable. Patient
will be contacted at least 1 week before each visit to be reminded of procedures and study drug
administration.
In order to maintain the blind, ALP, GGT and 5’ nucleotidase obtained from blood samples from V2 to
V6 will be kept in blinded condition during the treatment period for each patient. Any blinded party will
not be informed of these values until the database freezing and the Sponsor authorization to unblind
the data at the end of the DB period.
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If a subject prematurely discontinues the study drug during the double-blind period, end of treatment
DB (EOT DB) Visit should be performed between 16 and 30 days after last drug intake. The follow-up of
the patients who discontinue the drug early will continue until W104, or until the last completed V6
whichever occurs first, and will complete all visit procedures except liver biopsy and PK (if already done
prior to study drug discontinuation) . The study procedures will be assessed as per the Table 1 and
Table 2. At the scheduled visit following early discontinuation/termination of the drug, the date and the
reason of the study drug withdrawal will be collected. In case the EOT visit occurs within the time
window of the next scheduled visit, EOT visit will be performed at the scheduled visit.
Only patients who completed the double-blind treatment period (excluding patients who permanently
stopped the study drug over the DB period) will be included into the open label LTE.
2.5. Long-Term extension
A second period of the study with an open-label long term extension (LTE) is planned. During this LTE
period, all patients will receive 80 mg of Elafibranor for up to 5 years. Apart for the first 2 visits in this
LTE period which will occur over a 13 weeks interval starting after V6, V8 or the last DB visit, patients
will return to the site every 26 weeks (+/-14 days) for procedures listed on Table 1 and Table 2, and
Safety Contacts will be performed, every alternating 26 weeks (+/-14 days), to collect information
related to AEs, concomitant medications, pregnancy, and study drug compliance. The Investigator may
subsequently decide to perform an unscheduled visit.
The statistical analyses of the LTE phase are not within the scope of this SAP and will be described in a
separate statistical analysis plan.
During the open label LTE, an EOT LTE visit will be performed between 16 to 30 days after the last drug
intake for any subject who discontinue study drug. No further follow-up will be required. The study
procedures will be assessed as per the Table 1 and Table 2.
2.6. Clinical event committee (CEC)
The CEC will conduct adjudication of the long-term clinical outcomes (excluding progression to
histological cirrhosis for non cirrhotic patients at baseline) and Drug-induced Liver injury (DILI) events.
The CEC assessment and adjudication will occur in a blinded (during DB period) and consistent and
unbiased manner throughout the course of the study to determine whether the event meets the
protocol specified criteria. The CEC will be comprised of 3 hepatologists, all of them will be independent
of the participants of the study.
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Figure 1. Study design overview
The statistical analyses of the Long-Term Extension

period are not covered in this SAP.

b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last
completed W52 / V6 (W52), whichever occurs first
c. The LTE duration is 5 years after end of the DB period or until the patient’s total treatment duration is 6
years, whichever occurs first
2.7. Optional Visits
2.7.1. Retesting and/or additional screening visits

• If CPK value is > 2xULN at SV1, it can be repeated within 1 to 2 weeks, but prior to V1.
• If HCV Ab test is positive at SV1, a patient’s HCV infection status needs to be confirmed by HCV
RNA testing prior to V1.
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical
Monitors.
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2.7.2 Unscheduled visits

An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation
timepoints where the patient is seen by study unit personnel, e.g., when follow-up assessments are
required for safety reasons or when repeat measurements are required out of the screening period
(either to confirm a measurement or in case of errors, measuring device failure, etc.).
2.8. Exploratory/Ancillary Sub-study
No Exploratory/Ancillary Sub-study is planned.
2.9. Randomization Methodology
Patients who satisfy all eligibility criteria will be randomized in a 2:1 ratio to one of the following
groups:
• Placebo
A central randomization system will be used (interactive voice/web response system [IxRS])
The randomization will be stratified at V1 (randomization/baseline visit = V1) on two factors, collected
during the screening period:
1. ALP > 3x ULN or bilirubin > ULN: Yes/No
and
2. PBC Worst Itch NRS averaged - over the 28 days preceding baseline - ≥ 4: Yes/No.
To ensure enrollment of a relevant ratio of patients with moderate disease stage:

- a minimum of 15 patients (i.e. at least 10% of the total randomized patients) will present a
total bilirubin (TBL) > ULN or Albumin < LLN (moderately advanced patients’ definition per
Rotterdam criteria)
AND
- a minimum of 30 patients (at least 20% of the total randomized patients) will present a total
bilirubin (TB) > 0.6 x ULN.
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2.10. Stopping Rules and Unblinding
An independent Data Safety Monitoring Board (DSMB) composed of relevant experts (an
endocrinologist, cardiologist, hepatologist and nephrologist) experienced in the management of
subjects with PBC and an independent biostatistician will oversee the study conduct. The DSMB will be
established in order to review on a regular basis during the study (at least every six months) the
progress of the study and the safety of the treatment in an unblinded manner, to protect patient
welfare and preserve study integrity. A first DSMB will be planned within the first 6 months after FPFV.
The Deputy CMO will be responsible for promptly reviewing the DSMB recommendations and
determining whether expedited reporting of any safety issues, amendments to the protocol, or changes
in study conduct are required.
The study blind may be broken for an individual subject only in the case of an emergency when
knowledge of the study drug is essential for the clinical management of the subject. The randomization
number allocated to the subject will allow any unblinded study personnel to identify the treatment
group to which the subject is randomized.
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2.11. Study Procedures
The schedule of assessments, as outlined in the study protocol, is provided in Table 1 and in Table 2.
Table 1 Schedule of Assessments

Study Period Screening applicabl Long-term Extension (LTE)
Common DB Variable DB e Safety contact in
variable DB &
S S S LTEa
Visit number V V V V1 V2 V3 V4 V5 V6 V7 V8 LVDBk EOT DBb LT1 LT2 to LTn EOT-LTEb
1 2 3
Safety DB period:
At max.
Follow- -Week 65 13 LT2 13 Safety Follow-
13 weeks
up: -Week 91 weeks weeks after up: 16 to 30
after last
Weeks -12 to -2 0 4 13 26 39 52 78 104 16 to 30 LTE: after LT1 then days after last
V6 for
days after - 13 weeks after last DB every 26 study drug
the last
last drug LT2 then every 26 visit weeks intake
patient
intake weeks
Week 65: 456 days LT2: 91 days

V6 or
Week 91: 638 days after LT1
V8 or
Days 1 29 92 183 274 365 547 729 NA NA LTE: 91 d after then every NA
LVDB
LT2 then every 182 182 days up
+ 91 d
d to 2185
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+/- +/- +/- +/- +/- +/-

14 14 14 14 14 14
STUDY PROCEDURESf
Medical and Disease History X
Physical Examination (Height

at SV1 only)
PROc questionnaires
PBC Worst Itch NRS Xd

X X X X X
Week
PGIS Xe X X X X X X X X X X X
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PROMIS Fatigue Short Form

7a
Transient Elastography (TE) X X X X X X
Liver Biopsy Xh X

X X X Xj
bladder)
PK Xi
Randomization X
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Treatment Assignment X
Dispense Study Drug X X X X X X X X Xg
Study Drug
X X X X X X X X X X
Footnotes:
a. Safety contact by phone call every alternating 26 weeks starting 13 weeks after V6 in the DB period and starting after LT2 during LTE to check AEs and concomitant
medications
b. If premature study drug discontinuation during DB period, end of treatment (EOT) DB Visit should be performed between 16 and 30 days after last drug intake, and patients
will continue in the study until V8, or until the last completed V6 whichever occurs first. In case the EOT DB visit occurs within the time window of the next scheduled visit,
EOT DB visit replaces the scheduled visit. If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after
last drug intake
c. Refer to Erreur ! Source du renvoi introuvable. (Schedule of PRO Questionnaires) for details
d. During the screening period and DB period up to week 52 (V6), the PBC Worst Itch NRS score will be collected every evening via an eDiary. The mean score of the 28 days
prior to randomization (V1) will be used for stratification. Patients must have at least 10 available values for PBC Worst Itch NRS during the 28 day intervals prior to V1
e. Patient Global Impression of Severity (PGIS) will be collected at SV1 only during the screening period
f. Procedures/assessments should be conducted in the following order during study visits: PROs (when completed at the study center), investigator
assessments, safety and laboratory assessments, administration of study drug
g. Drug dispensation will be done up to LT10. There will be no drug dispensation at LT11
h. Liver biopsy at inclusion to be done at any SV as long as it is completed at the latest 4 weeks prior to randomization visit
j. Ultrasound exam to be performed every year
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k. Last DB visit if prior to V8, is to be scheduled at the latest 13 weeks after the last V6 completed. It will allow switching the patients in a timely manner to LTE with open
label elafibranor. In case the last visit double blind (LVDB) visit occurs within the time window of the next scheduled visit, LVDB visit replaces the scheduled visit. The same
procedures as for V8 will be performed for LVDB.
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Table 2. Schedule of biological assessments
Double Blind (DB)

Study PeriodLC:L(7)C(18) Screening If applicable Long-term Extension (LTE)
SV SV SV
1 2 3
Safety
At max. 13
Follow-up:
10 16 to 30
4 days after
last drug
patient
intake
V6 or V8
LT2: 91 days after
18 27 36 54 72 or
Days 1 29 92 NA NA LT1 then every 182 NA
3 4 5 7 9 LVDB +
days up to 2185
91 d
+/- +/- +/- +/- +/- +/- +/-

7 14 14 14 14 14 14
Serum Hematology
reticulocytes/RBC
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Screening Serum Chemistry

ALP, ALT, AST, GGT, CPK, total and conjugated
bilirubin, albumin, creatinine, sodium, AFP, X
eGFR (MDRD formula & CKD-EPI formula),
MELD-Na
Serum Chemistry
amylase, TC, LDL-C, HDL-C, VLDL-C, TG,
CPK , FPG, eGFR, MELD-Na
Serology
X
Serum Bile Acids and Biomarkers of Bile
Acid Synthesis
Bile acids (cholic acid (CA), glycocholic acid

(GCA), taurocholic acid (TCA), chenodeoxycholic
acid (CDCA), glycochenodeoxycholic acid
(GCDCA), taurochenodeoxycholic acid X X X X X X
(TCDCA), deoxycholic acid (DCA),
glycodeoxycholic acid (GDCA), taurodeoxycholic
acid (TDCA), lithocholic acid (LCA),
glycolithocholic acid (GLCA), taurolithocholic
acid (TLCA)), C4, FGF-19
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Inflammation
HsCRP, fibrinogen, haptoglobin, TNF- , IL-6, X X X X X X
ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18
(M65 and M30), Pro-C3
Cystatin C, urine albumin to creatinine ratio X X X X X X
(urine ACR) , AFP
Immunoglobulins
X X X X X X
IgG, IgM
Urinalysis (dipstick)c,
Specific gravity, pH, protein, glucose, ketones, X X X X X X X X X X X X X X
bilirubin, urobilinogen, blood, nitrite, leukocytes
X X X X X X X X X X X X
gonadotropin (hCG) Pregnancy Testd,e
urinary myoglobin, serum IgG and SMA f X X X X X X X X X X X X
Biobankg X X X X X X
Footnotes:
a. Repeated measured for AST, ALT, ALP and TB to be collected (See section 2.2).
b. If premature study drug discontinuation during double blind period, EOT DB Visit should be performed between 16 and 30 days after last drug intake, and patients will
continue in the study until V8. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. If
premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake.
c. Microscopic evaluation will be performed if dipstick urinalysis indicated presence of any significant abnormality.
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d. Urine-based β-hCG pregnancy tests must be performed in all females of childbearing potential. If positive, a confirmatory pregnancy blood test must be performed at
the site.
e. A home pregnancy tests will be performed every 4 weeks, starting at V1.
f. Assessment of the presence of myoglobin in urine to be done locally only in case of clinically significant CPK elevation.
g. Additional blood samples will be collected from patients, who have given their consent, to be used to discover or validate biomarkers in PBC and related diseases.
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h.
Table 3: Schedule of Patient Reported Outcomes Questionnaires

Platform Assessment Frequency and Duration of Assessment Time of assessment
eDiary PBC Worst Itch NRS Once daily during screening and up to V6
a
Evening
eTablet PBC Worst Itch NRS Past Week At V7, V8, LVDB and each visit during the LTE During study visitb
period
eTablet PGIC At each visit during the DB period (starting at V2) During study visitb
and the LTE period
eTablet PGIS Throughout the screening period and at each visit During study visitb
during the DB period and the LTE period
eTablet 5-D Itch At each visit during the DB period and LTE period During study visitb
eTablet PROMIS Fatigue Short Form 7a At each visit during the DB period and LTE period During study visitb
eTablet ESS At each visit during the DB period and LTE period During study visitb
eTablet PBC-40 At each visit during the DB period and LTE period During study visitb
eTablet EQ5D-5L At each visit during the DB period and LTE period During study visitb
Footnotes:
a. The average of the PBC Worst Itch NRS score over the 14 days preceding V1 will be used for stratification. At least 4 values of the PBC Worst itch NRS during each of the 7 day intervals in the
14 days prior to randomization visit are required for randomizing the patients.
b. Administered on site.
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2.12. Efficacy, Pharmacokinetic, and Safety Variables
2.12.1. Efficacy Variables

The efficacy of Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated
considering the response to treatment in terms of:
ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52 (binary)
Furthermore, the following variables will be considered for the evaluation of efficacy:
Two key secondary endpoints:
- Response to treatment based on ALP normalization at week 52 (binary).

- Change in pruritus from baseline to week 52 in PBC Worst Itch NRS (continuous).

1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks (continuous)
2) ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52 (binary)
a) ALP < 1.5x ULN, ALP decrease from baseline≥ 40% and TB ≤ ULN (binary)
b) ALP < 3x ULN, AST <2x ULN and TB ≤ 1mg/dL (Paris I) (binary)
c) ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris II) (binary)
d) TB response rate of 15% change from baseline (binary)
e) Normalization of abnormal TB (TB ≤ ULN) and/or albumin (ALB ≥ LLN) (Rotterdam)
(binary)
f) TB ≤ 0.6x ULN (binary)
g) ALP ≤ 1.67x ULN and TB ≤ 1mg/dL (Mayo 2011) (binary)
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h) No worsening of TB defined as level of TB at week 52 ≤ ULN or no increase from

baseline of more than 0.1XULN at week 52
4) PBC risk scores at week 52: UK PBC score (Carbone_et_al_2016) and GLOBE score (a risk score
to predict transplantation-free survival at 5, 10 and 15 years. Lammers_et_al_2015)
5) Response to treatment based on the normalization of bilirubin (TB ≤ ULN) at week 52 (binary)
6) Response to treatment based on normalization of albumin (ALB ≥ LLN) at week 52 (binary)
(continuous)
8) Relative Change from baseline to week 52 in hepatobiliary injury and liver function as measured
by ALP, GGT, AST, ALT (continuous)
fibrinogen, haptoglobin and TNF-α (continuous)
(continuous)
11) Change from baseline to week 52 in biomarkers, non-invasive and invasive measures of hepatic
fibrosis as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3
and liver stiffness measured by Transient Elastography (continuous)
12) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C,
calculated VLDL-C and TG (continuous)
13) Change from baseline to week 52 in Fasting Plasma Glucose (continuous)
14) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as
measured by bile acids, C4 and FGF-19 (continuous)
15) No worsening of pruritus based on PBC Worst Itch NRS at week 52
16) Response to treatment defined as 30% reduction from baseline in PBC Worst Itch NRS at week
52 in patients with a baseline NRS score ≥ 4 (binary)
17) Change from baseline to week 52 in 5D-Itch (continuous)
18) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a (continuous)
19) Change from baseline to week 52 in ESS (continuous)
20) Change from baseline to week 52 in PBC-40 (continuous)
21) Change from baseline to week 52 in healthy utility as measured by the EQ5D-5L (continuous)
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22) Onset of clinical outcomes at week 52, described as a composite endpoint (binary) composed
of:
a) Meld-Na > 14 for patients with baseline MED-Na≤12
b) Progression to histological cirrhosis for non-cirrhotic patients at baseline
c) Liver transplant
i) Variceal bleed
ii) Hepatic encephalopathy defined as West-Haven/Conn of 2 or more
iii) Spontaneous bacterial peritonitis
f) Death
b) Bile duct scores
f) Portal inflammation
g) Ductular reaction
h) Cholestasis
i) Concentric periductal fibrosis
j) Fibrosis according to modified Ishak (adapted to PBC) scoring
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2.12.2. Pharmacokinetic Variables

The statistical considerations applicable to the popPK modeling, including the definition of the PK
population and the description of the statistical analyses, will be fully described in a dedicated Analysis
Plan (popPK SAP).
2.12.3. Safety Variables

The safety and tolerability profiles of Elafibranor (80mg/day) will be assessed from the recordings of:
a) Serious adverse events (SAE), adverse events (AE), adverse events of specific interest (AESI),
physical examination findings, including weight, vital signs, medical history, 12-lead
Electrocardiogram (ECG),
b) Serum chemistry (Sodium, potassium, chloride, calcium, albumin, BUN, creatinine, fasting
plasma glucose, total proteins, lipase, amylase, TC, LDL-C, HDL-C, VLDL-C, TG, CPK) and
hematology (Hemoglobin, hematocrit, WBC with differential, platelet count, PT),
c) Hepatobiliary injury and Liver function markers AST, ALT, GGT, 5’ NT, total and conjugated
bilirubin, albumin, INR and ALP fractionated (hepatic),
d) Renal biomarkers (including urinalysis: Specific gravity, pH, protein, glucose, ketones, bilirubin,
urobilinogen, blood, nitrite, leukocytes)
e) Other biochemical safety markers (Cystatin C, urine ACR, urinary myoglobin) and biomarkers of
inflammation (HsCRP, fibrinogen, haptoglobin, TNF-α, IL-6, ELF (HA, PIINP, TIMP-1), PAI-1, TGF-
β, CK-18 (M65 and M30), Pro-C3).
f) Histology
Additionally, these assessments (except histology and PK) will also be performed during the LTE period
to assess and maintain the efficacy and safety of the treatment. The planned statistical analyses related
to the open label LTE period are not within the scope of this SAP and will be described in a separate
SAP.
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3. SUBJECT POPULATIONS
3.1. Population Definitions
The following subject populations will be used for the analysis and the presentation of the data:
Screened Population: all patients who sign informed consent. This population will be used to
summarize disposition.
Intent-to-treat (ITT) Population: All randomized subjects. Patients will be analyzed according to
randomized treatment.
Per Protocol (PP) Population: All subjects from the ITT set without any major protocol deviation
affecting the primary efficacy endpoint (see Section 3.2).
Safety Population (SS): All subjects who were administered at least one dose of double-blind study
drug irrespective of the treatment received. Subjects will be analyzed according to the treatment
received. Patients who received any amount of active treatment, even by mistake and for one
intake, will be assigned to the active treatment group.
Pharmacokinetics set (PKS): All patients who were administered at least one dose of study medication
and have at least one post-dose PK sample. Patients of the PK set must have data for time of
dosing, time of sampling and amount of product administered. Placebo patients will be removed
from the analysis population.
The primary and secondary efficacy analyses will be performed primarily on the ITT population and
secondarily on the PP population.
Patients in the ITT and PP populations will be analyzed based on randomized treatment. Each efficacy
endpoint will be evaluated up to week 52. For patients who completed additional visits during the DB
period, descriptive statistics will be presented up to the end of the DB period.
The Safety Analysis population will be typically the primary analysis population for the analysis of safety
endpoints. Patients in the SS will be analyzed based on actual treatment received. Patients who
received any amount of active treatment, even by mistake and for one intake, will be assigned to the
active treatment group.
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3.2. Protocol Violations
Per International Council for Harmonization (ICH) E3 definition, protocol violations are defined as any
change, divergence, or departure from the study design or procedures defined in the protocol, unless
there is a description of elements that will not be considered as such.
The terms protocol violation and protocol deviation are sometimes used interchangeably to refer to a
significant departure from protocol requirements. The word “violation” may also have other meanings
in a regulatory context:
• A protocol deviation occurs when the activities during a study diverge from the Institutional Review
Board (IRB)-approved protocol and the applicable regulatory requirements, and then is considered as a
variance from protocol.
• A protocol violation occurs when there is divergence from the IRB-approved protocol and the
applicable regulatory requirements (a deviation) that also:
o Reduces the quality or completeness of the data, or
o Impacts a subject’s safety, rights, or welfare or affects the scientific integrity of the data.
All protocol deviations will be entered and managed in the Clinical Study Management System (CTMS)
and managed as per the Protocol Deviation Management Plan (PDMP) or detected via SAS
programming. They will be classified as minor or major based on their effect on the rights, safety, or
well-being of the subjects and/or the quality and integrity of the data, and the final rating of all
deviations will be confirmed on a case-by-case basis and prior to database lock (DBL). Some examples
of protocol deviations are given below:
 Missed study procedures (PROs collected through the eDiary, investigator assessments, safety
and laboratory assessments, administration of study drug), protocol deviations related to
Inclusion/Exclusion criteria (Ineligible subject randomized to the study)
 Randomization/drug dispensation errors (incorrect kit dispensed to a subject)
 Electronic diary (eDiary) non-compliance (≤36% overall compliance for the period between 2
visits (e.g., between screening and V1, V1 and V2 (Week 4), etc.)); eDiary provided to patients
at SV1 to record daily (each evening) the PBC Worst Itch NRS
 Questionnaires completed out of permitted window
 Use of prohibited concomitant treatments (see list of prohibited medications in protocol
Sections 4.2)
 Any other protocol deviations that may affect patient safety, data integrity, or future conduct
of the study.
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At the discretion of the sponsor, major protocol violations as determined by a review of the data prior
to unblinding of the study results and the conduct of statistical analyses may result in the removal of a
subject’s data and will therefore not be present in the PP population. The sponsor, or designee, will be
responsible for producing the final protocol violation file (formatted as a Microsoft Excel file), in
collaboration with Cytel and the data monitoring group as applicable, for determining in a blinded way
what kind of violations will be considered major and thus requiring the corresponding data to be
excluded from the PP population.
This file will include a description of the protocol violation, and clearly identify whether this violation
warrants exclusion from the PP population. This file will be finalized prior to hard database lock at the
end of the DB period and completed prior to the DB hard database lock for the primary endpoint
analysis.
No update will be allowed after the DB database lock on the data collected up to the patients last visit
performed during DB period (V6/V8/LVDB).
All protocol deviations/violations will be presented in data listings and all major deviations will be
summarized in a table.
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4. STATISTICAL METHODS
4.1. Sample Size Justification
study supporting the regulatory approval of OCA (10%) (Nevens, 2016),
• an expected response rate in the ELA group at least similar to OCA (47%).
estimated after imputation of missing data as non response.
One hundred and fifty patients (100 Elafibranor and 50 placebo) allow to achieve at least 90% power to
demonstrate a statistically significant between group difference of 35% (47% in Elafibranor group vs
12% in placebo group) in the response rate at week 52 of the primary efficacy endpoint with a two-
sided alpha of 0.01 and using an exact Fisher test.
Assuming 1/50 (2.0%) patients in the placebo arm with ALP normalization at week 52 (first key
secondary endpoint), 150 patients (100 Elafibranor vs 50 placebo) provide at least 80% power to detect
a statistically significant between group difference of 20.0% at a two-sided 0.01 alpha level.
Assuming a pooled standard deviation of 3 points, 150 patients (100 Elafibranor vs 50 placebo) provide
at least 80% power to detect a statistically significant between group difference of 1.8 points in mean
change from baseline in PBC worst itch NRS score (second key secondary endpoint) at a two-sided 0.01
alpha level.
4.2. General Statistical Methods and Data Handling
4.2.1. General Methods

All output will be incorporated into Rich Text Format (RTF) files, sorted and labeled according to the
International Conference on Harmonization (ICH) recommendations, and formatted to the appropriate
page size(s).
Statistical methods will focus on summarizing the data collected using appropriate graphical and
tabular presentations and on generation of inferential summaries.
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety parameters.
For measurements of continuous endpoints, summary statistics of absolute values and changes from
baseline, where appropriate, will be summarized and will include n, mean, standard deviation, median,
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25th percentile - 75th percentile (Q1-Q3), and minimum and maximum values. The number of missing
values will be displayed in parenthesis next to ‘N’. Mean, standard deviation, median, Q1 and Q3 will be
presented with one more decimal place compared to the raw data, and minimum and maximum will be
presented with the same number of decimal places as the raw data.
For categorical variables, summary tabulations of the number and percentage within each category of
the parameter will be presented (with a category for missing data). The total number of non-missing
subjects will be used as the denominator. Percentages will be rounded to one decimal place. Therefore,
there may be cases where for instance the total of the percentages does not exactly equal 100%.
Where applicable confidence intervals (99% CI for primary and key secondary endpoints, 95% CI for all
other secondary endpoints, 2-sided) will be presented, and they will be shown with 1 decimal place for
percentages, and with 2 decimal places for continuous measures.
Formal statistical hypothesis testing will be performed on the primary and key secondary efficacy
endpoints, with all tests conducted at the 2-sided, 0.01 level of significance. The fixed-sequence testing
approach will be used to control the overall type I error rate at a two-sided 0.01 level. Summary
statistics will be presented, as well as confidence intervals on selected parameters, as described in the
sections below.
The fixed-sequence testing approach implies that if the primary endpoint is statistically significant at a
two-sided 0.01 level, the first key secondary endpoint (ALP normalization) will be tested at the same
level. If the first key secondary endpoint is statistically significant at a two-sided 0.01 level, the second
key secondary endpoint (change in pruritus) will be tested at the same level. If the primary endpoint is
NOT statistically significant, none of the key secondary endpoints will be tested. If the primary endpoint
is statistically significant and the first key secondary is NOT statistically significant, the second key
secondary endpoint will not be tested.
Statistical testing for other secondary endpoints will be of exploratory nature and will be performed at
the two-sided 0.05 level of significance.
All summarized data will be listed in addition to the analyses and summaries described below. Any data
present in the final locked database which are not summarized or analyzed according to the plans
below will be listed only.
Analyses described in this SAP will be dependent on the availability of the data collected. Additional
exploratory analyses may be performed as well as those described below, if suggested by inspection of
the final database.
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4.2.2. Data Conventions

In the context of this SAP, we will consider 4 periods (max. 12 weeks screening, max. 104 weeks DB,
max. 260 weeks LTE, 4 weeks follow-up; only the statistical analyses of the first two periods are detailed
in this SAP):
1) Screening period, defined as the period prior to Study Visit 1 (before first study drug dispensation),
which could last from 2 to 12 weeks.
2) Treatment period 1 for the double-blind period of the study, defined as the time between Study Visit
1 (first study drug intake) and the last study drug intake for the DB period (i.e. one day before week
52/LVDB/week 104 visit).
3) Treatment period 2 for the long-term extension period of the study, defined as the time between the
Week 52/LVDB/week 104 visit and the Week 312 weeks visit (max. 260 weeks for the LTE period)
4) Follow-up period, defined as the period beyond the Week 312 visit or beyond the study treatment
discontinuation happening during LTE period (follow-up period allowing 4 weeks for safety follow-up).
The study period will end after approximately 6 years from SV1, but this SAP only provides the details
for the DB (12 weeks of screening and up to 104 weeks of DB period) analyses.
The week 0 Visit 1 (V1) is defined as the first treatment visit, where the subject is randomized and given
the study Treatment carton (kit) for the first time.
Treatment day 1 is defined as the date of first administration of any of the following study drugs:
Placebo or Elafibranor 80mg.
End of Treatment DB (EOT DB) visit (in case of study drug discontinuation during the DB period), is
defined as the safety visit date recorded during Treatment period 1.
Either V6, LVDB or V8 can be defined as the latest visit date recorded during Treatment period 1, as
well as the first date of Treatment period 2, depending on when the last V6 is performed. This date
corresponds to the end of the double-blind period (EODB). The patient will be assessed in a fasting
status and then take the first study drug for the LTE period on that same day.
The Week 312 visit (LT9/LT10/LT11) is defined as the latest date from any panel of Treatment period 2.
End of Treatment LTE (EOT LTE) visit date is defined as the last recorded visit date from any panel of
the Follow-up period.
The following conversion factors will be used to convert days to months or years, or Fahrenheit to
Celsius, where applicable:
• 1 month = 30.4375 days
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• 1 year = 365.25 days

• 1 week = 7 days
• °C = (°F - 32)/1.8.
Additional data handling rules are as follows:
• Age (years) = (date of informed consent – date of birth + 1) / 365.25, rounded to the lowest whole
number.
• Weight values recorded in pounds will be converted to kilograms using the following formula:
kilograms = pounds/2.2046.
• Height values recorded in inches will be converted to centimeters using the following formula:
centimeters = inches*2.54.
• Duration on study (weeks) = (Last visit date – randomization date + 1) / 7.
• Duration on treatment (weeks) = (Last study drug intake date – first study drug intake date + 1) / 7.
• (Absolute) Change from baseline = Value at the time point – Baseline value.
• Relative change from baseline = [(Value at the time point – Baseline value) / Baseline value] x 100.
As a general rule of thumb, each laboratory value below/above the limit of quantification will be
imputed numerically to the nearest value below/above the limit, respecting the same number of
decimal places than numerical values (e.g. if the number of decimal places=0, subtract/add 1 to the
limit of quantification; if the number of decimal places=1, subtract/add 0.1 to the LOQ, etc.).
4.2.3. Computing Environment

All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4 or later),
unless otherwise noted. Medical history and adverse events will be coded on an ongoing basis using
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 and (if necessary) updated to the
most recent version at the time of database lock. Concomitant medications will be coded in the same
way using current World Health Organization (WHO) Drug dictionary version B3 WHO DDE - Mar 2017.
4.2.4. Methods of Pooling Data

N/A.
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4.2.5. Adjustments for Covariates

The randomization will be stratified across two factors: (ALP > 3x ULN or bilirubin > ULN (Yes/No) and
PBC Worst Itch NRS score averaged - over the 14 days preceding baseline - value ≥ 4) (Yes/No) at
baseline (V1) (see section 2.9).
All the categorical endpoints will be analyzed using the exact Cochran-Mantel-Haenszel test stratified
by the randomization factors.
The sensitivity analysis to the statistical model (see section 4.6.1.2.) performed on the primary endpoint
and the first key secondary endpoint will be analyzed using an exact logistic regression model with
treatment group and randomization strata as factors, on both ITT and PP population populations.
The continuous endpoints will be compared between treatment groups using the Mixed effect Model
with Repeated Measurement (MMRM) with stratification factors as fixed factors.
4.2.6. Multiple Comparisons/Multiplicity

Multiplicity will be dealt with through the Fixed-sequence Testing Procedure that implies a pre-
specified sequence of hypotheses testing. In this study the first key secondary endpoint will only be
tested if the primary endpoint is statistically significant and the second key secondary endpoint will
only be tested if the first key secondary endpoint is statistically significant (see section 4.2.1.).
4.2.7. Subpopulations
Exploratory analyses of the primary (ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥
15% at week 52) and the two key secondary endpoints (Response to treatment based on ALP
normalization at week 52 and Change from baseline to week 52 in PBC Worst Itch NRS) will be done for
the following subgroups:
• Age at consent (<= 60 years and > 60 years)
• Sex (Female, Male)
• Race (White, African Americans, Asians, Others)
• ALP level at baseline > 3x ULN (Yes/No)
• TB at baseline > ULN (Yes/No)
• TB at baseline > ULN or ALB at baseline < LLN (Yes/No)
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• TB at baseline > 0.6x ULN (Yes/No)

• Geographic region (Europe, North America, Latin America, Asia, Others)
 ALP > 3x ULN or TB > ULN at screening (Yes/No)
 PBC Worst Itch NRS score (averaged - over the 14 days preceding baseline – value ≥ 4) at
screening (Yes/No)
4.2.8. Withdrawals, Dropouts, Loss to Follow-up

Discontinued subjects who received the study drug were not to be replaced.
Over the DB period, follow-up of the patients who discontinue early the study drug will continue until
the end of the DB period (V8 or until last V6 performed). The study procedures will be assessed as per
Table 1 and Table 2.
To limit the occurrence of intercurrent events such as study treatment discontinuations due to lack of
efficacy and/or use of rescue medication such as OCA, the treatment allocation as well as values of ALP,
GGT and 5’NCTD will remain blinded for the Investigator and for the subject up to the DB database lock.
4.2.9. Missing, Unused, and Spurious Data

The patient's outcomes will be considered censored at the time of an intercurrent event (ICE) (study
treatment discontinuation or use of rescue therapy) and any data observed more than 1 day after the
occurrence of this event will not be considered for the statistical analyses. Instead, this unused data will
be handled as missing data.
For the binary/categorical endpoints (including the primary and the first key secondary endpoints),
patients who stopped prematurely the study treatment will be considered as non-responders. In
addition, for the primary and the first key secondary (ALP normalization) endpoints, three
supplementary and sensitivity analyses will be performed using relevant multiple imputation methods
(see Section 4.6.1.3). One will assume Missing At Random (MAR) and use multiple imputation to
impute values as if subjects would follow their initial treatment. A second one will impute values using
the information from the placebo group. The third one will be a tipping point analysis to explore a
number of scenarios about the missing outcomes.
A fourth sensitivity analysis will use outcome value at week 52 regardless of treatment discontinuation
or use of rescue therapy
Missing values for continuous efficacy endpoints with repeated measurements will be handled within
the analysis itself via mixed model repeated measures with the assumption that the model specification
will be correct, and that the data will be missing at random.
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Unless otherwise specified, there will be no substitutions made to accommodate missing data points.
All data recorded on the CRF will be included in data listings that will accompany the clinical study
report.
Partially missing dates for AEs will be imputed. Of note, imputation of missing/partial AE dates will be
done only to identify treatment-emergent AEs.
AE onset dates
• Partially missing onset dates will be imputed as follows:
o When only Day is missing:
 If Month & Year of the onset date are the same as Month & Year of the first
administration date, the imputed onset date will be imputed as the minimum
of the first administration date and the AE resolution date (imputed if needed).
 Otherwise, the missing day will be replaced by “1.”
o When Day & Month are missing:
 If Year of the onset date is the same as Year of the first administration date, the
imputed onset date will be imputed as the minimum of the first administration
date and the AE end date (imputed if needed).
 Otherwise, the missing Day & Month will be replaced by “01 JAN.”
• Completely missing onset dates for AEs will be imputed by the first administration date and the
AE will be considered as treatment-emergent, unless the end date of the AE (imputed if
needed) or the end year of the AE (if day and month are missing) is entered and is before the
first administration date. If the end date is before the first administration date, the AE will not
be considered as treatment-emergent.
AE end dates
• If Day only is missing, incomplete end dates will be replaced by the last day of the month if it is
not resulting in a date later than the date of the subject's death. In the latter case, the date of
death will be used to impute the incomplete end date.
• If Day & Month are missing, Day & Month will be replaced by 31DEC if it is not resulting in a
date later than the date of the subject's death. In the latter case, the date of death will be used
to impute the incomplete end date.
• In all other cases the incomplete end date will not be imputed.
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All data recorded in the electronic Case Report Form (eCRF) will be included in data listings that will
accompany the Clinical Study Report.
Concomitant medication dates imputation:

- End date: Missing day will be imputed as the last day of the month, and missing month will be
imputed as December.
- Start date: Missing day will be imputed as the first day of the month, and missing month will be
imputed as January.
If the start date is completely missing, then:
• If the end date is prior to the date of first administration of the study drug, then the
medication is considered as prior
• If the end date is prior to the date of last administration of the study drug, then the
medication is considered as prior and concomitant
• If the end date is completely missing or after the date of last administration of the
study drug, then the medication is considered as prior, concomitant and post.
4.2.10. Visit Windows

For all analyses, the visit dates as collected in the eCRF will be used. However, the visits will be checked
for accuracy according to protocol-specified intervals (Table 4) and sensitivity analyses may be deemed
necessary considering this derivation, in particular for Week 52 comparative analyses.
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Table 4 Evaluation Intervals for Efficacy Analysis

Evaluation Protocol-Specified Interval
Screening Day -84 to day -14
Baseline (V1) Day 1
Visit 2 (V2) Day 29 (±7 days)
Visit 7 (V7) - optional Day 547 (±14 days)

Visit 8 (V8) - optional Day 729 (±14 days)
Last visit DB (LVDB) – optional Within 91 days after last V6 performed
Safety Contact – DB period Day 456 and day 638 (±14 days)
Long term visit 1 (LT1) 91 days after V6/V8/LVDB (±14 days)
Long term visit 2 (LT2) 91 days after LT1 (±14 days)
Safety Contact – LTE period Every 182 days, starting 91 days after LT2
(±14 days)
LT3 to LT11 Every 182 days, starting 182 days after
LT2 (±14 days)
EOT/EOS- Safety follow-up 16 to 30 days after last study drug intake
4.2.11. Data Derivation

Baseline and postbaseline average number of PBC Worst Itch NRS for a patient within an analysis
window will be calculated based on data available and prorated to 14 and 28 days respectively using
the following formula as the monthly average for analyses based on monthly windows:
Baseline 14-days average PBC Worst Itch NRS:
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[Sum (efficacy endpoint data during the period)/Number of Days with assessments recorded
during the period ] X 14
Postbaseline monthly weighted average PBC Worst Itch NRS:

[Sum (efficacy endpoint data during the period)/Number of Days with assessments recorded during the
period ] X 28
Note: For baseline value, patients must have at least 4 values of the PBC Worst Itch NRS during each of
the 7 day intervals in the 14 days prior to V1 to be randomized. After V1, for patients who have less
than 10/28 values in an analysis window the monthly average PBC Worst Itch NRS will be considered as
missing.
4.3. Interim Analyses
No interim analysis is planned for this study.

A full analysis will be performed after all subjects have completed Week 52. Previous treatment
allocation will remain blinded for the Investigator and the subject up to the final database lock (see
section 2.4).
4.4. Subject Disposition
All subjects screened will be summarized.

All subjects screened, randomized, and treated will be accounted for in this study.
Patient disposition will be tabulated and will include the number of subjects treated, the number in
each analysis population, the number who discontinued from treatment and reason(s) for
discontinuation from treatment, and the number who discontinued from the study and reason(s) for
discontinuation from study.
Summary data will be presented by treatment group and overall. The denominator for all percentages
is the total number in each dose group.
The following by-subject data listings will be presented:
 Study completion information including the reason for premature study discontinuation, if
applicable;
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 Inclusion/exclusion criteria;
 Patient inclusion in each of the analysis populations [ITT and Safety Analysis populations].
 Patients excluded from the Efficacy analysis (i.e. from the ITT population)
 Protocol Deviations.
4.5. Demographic, Screening and Baseline Characteristics
All collected demographic, screening, baseline characteristics, and medical history data will be provided
in data listings. The demographic, screening, baseline characteristics and medical history data will also
be summarized.
The baseline characteristics will be presented by treatment group for the ITT. No formal statistical
comparisons will be performed.
4.5.1. Demographic
Demographic data will be presented for the ITT and for the Safety population, as follows:
• Demographic characteristics (age at SV1, weight (kg), height (cm), Body Mass Index (BMI)
(kg/m2)), vital signs (i.e., systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate
(beats/minute)) and ECG (i.e., QTc interval (Fridericia) (ms)) at Screening will be summarized using
descriptive statistics.
• Demographic characteristics (age at consent, weight (kg), Body Mass Index (BMI) (kg/m2)), vital
signs (i.e., systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats/minute))
and ECG (i.e., QTc interval (Fridericia) (ms)) at Baseline will be summarized using descriptive statistics.
4.5.2. Screening Disease characteristics

Screening Disease characteristics data will be summarized for the ITT and for the Safety population by
treatment group and overall. For the screening laboratory parameters, the summaries will be provided
by visit where applicable. The following will be summarized:
 Duration since diagnosis of PBC in years defined as (randomization date – date of diagnosis +
1)/365.25.
 Screening PBC Worst Itch NRS over the 14 days preceding Baseline (V1).
 Screening PGIS at SV1.
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 Screening laboratory measures of ALP, AST, GGT, CPK, total and conjugated bilirubin, albumin,
creatinine, sodium, AFP, eGFR, MELD-Na.
 Screening serum hematology measures of hemoglobin, hematocrit, WBC with differential,
platelet count, PT, INR.
 Screening serology measures of HIV Ab I/II, Anti- HAV IgM, HBsAg, HCV Ab, HCV RNA.
 Screening urinalysis (dipstick) measures of specific gravity, pH, protein, glucose, ketones,
bilirubin, urobilinogen, blood, nitrite, leukocytes.
 Screening urine-based β-hCG pregnancy test for all women of childbearing potential.
Concomitant drug use and medication during 30 days before screening and at screening (including
nonprescription medications and herbal and dietary supplement preparations), alcohol use,
recreational drug use, and special diets will be listed.
Data collected at screening will be also included in the corresponding listings.
4.5.3. Baseline Disease Characteristics

Baseline disease characteristics will be summarized separately for the ITT population and for the Safety
population, by treatment group and overall.
 Baseline medical history coded using Medical Dictionary for Regulatory Activities (MedDRA) will
be summarized per System Organ Class (SOC) and Preferred Term (PT). Medical history includes
past and/or ongoing diseases or surgeries recorded in the Medical History eCRF. Reported
terms will be coded on an ongoing basis using MedDRA version 23.0 and (if necessary) updated
to the most recent version at the time of database lock.
 Concomitant medications at baseline will be summarized and will be coded in the same way
using current World Health Organization (WHO) Drug dictionary version B3 WHO DDE - Mar
2017.
 Frequency and percentage of the randomization factors: 1) ALP > 3x ULN or Total bilirubin >
ULN-(Yes/No) and 2) PBC Worst Itch NRS score (averaged over the 14 days preceding baseline
value ≥ 4 Yes/No) as collected in the eCRF will be provided as per IxRS.
4.5.4. Prior Medications

Refer to Section 4.8.7.
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4.5.5. Prior Procedures

N/A.
4.6. Efficacy Evaluation
The primary objective of the study is to evaluate the effect of Elafibranor (80 mg/day) on cholestasis
As detailed below, in line with ICH E9 (R1) addendum; five attributes (treatment condition, population,
endpoint, intercurrent events and population level summary) have been specified to translate the
primary objective into treatment effect that is to be estimated (estimands):
• Primary estimand:
The composite strategy imputing non response for patients who experienced intercurrent events (ICE)
prior to week 52 will be applied.
intolerant to UDCA
- B. Population: Randomized patients with PBC and inadequate response or intolerance to UDCA,
- C. Endpoint: Response to treatment (binary variable) indicating a successful response at week
52 for a subject with ALP < 1.67x ULN, TB ≤ ULN and ALP decrease from baseline ≥15%, and who does
not stop prematurely the study treatment nor uses any rescue therapy,
The primary estimand can be defined as the between treatment group difference in proportions of
patients, from all randomized patients, achieving response at week 52 (defined as: ALP < 1.67x ULN, TB
≤ ULN and ALP decrease ≥ 15%), and not stopping prematurely the study treatment nor using rescue
therapy.
In addition, two strategies will be explored as supplementary and sensitivity analyses:
- the hypothetical strategy will be investigated comparing the potential outcomes that would
have been observed at week 52 between the treatment arms as if:
o The patients who experienced an ICE would follow their initial randomized treatment,
o The patients who experienced an ICE from both arms would continue on placebo,
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In addition, a tipping point analysis will explore various scenarios among the hypothetical
strategy where missing outcomes experienced after an ICE vary independently from Elafibranor
and placebo groups
- the treatment policy strategy will be investigated where patients are classified as responders
based on their outcome value at week 52 regardless of treatment discontinuation or use of
rescue therapy.
(see section 4.2.9 and section 4.6.1.3).
• First Key secondary estimand (ALP normalization)

be applied.
intolerant to UDCA
- C. Endpoint: Response to treatment (binary variable) indicating a successful normalization of
ALP at week 52 without stopping prematurely the study treatment nor using any rescue therapy,
The first key secondary estimand can be defined as the between treatment group difference in
proportions of patients from all randomized patients who successfully normalize their ALP at week 52
and who do not prematurely stop the study treatment nor use any rescue therapy.
In addition, the same hypothetical and treatment policy strategies used for the primary estimand will
be applied as supplementary and sensitivity analyses of the first key secondary estimand (see section
4.2.9 and section 4.6.1.3).
 Second key secondary estimand (Change in pruritus)

intolerant to UDCA
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- C. Endpoint: Change from baseline to week 52 in PBC Worst Itch NRS (continuous),
- D. Intercurrent events: Any outcome value after a treatment discontinuation or use of rescue
therapy will be considered as missing,
- E. Population-level summary: Between treatment group difference in means of PBC Worst itch
NRS.
The second key secondary estimand can be defined as the between treatment group difference in
mean change from baseline from all randomized patients at week 52 assuming they continued the
assigned treatment after they experienced an ICE.
In addition, the treatment policy strategy will be investigated where all outcome values until week 52
will be used regardless of treatment discontinuation or use of rescue therapy (see section 4.6.1.3.2)
All efficacy analyses will be based on the ITT population. To assess the robustness of the results, the
same analyses will be replicated on the PP population.
4.6.1. Primary Efficacy endpoint analysis

4.6.1.1. Main Analysis
The efficacy of Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated
ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52 (binary: YES/NO)
The null hypothesis for response to treatment based on the primary endpoint is that there is no
difference in response rates between the Elafibranor and the placebo group. The alternative hypothesis
is that there is a difference in response rates between both groups. The null hypothesis will be tested at
a two-sided alpha of 0.01.
Patients who stopped prematurely the study treatment will be considered as non-responders.
The number and percentage of patients with favorable response to treatment at the end of the 52
weeks of the DB treatment period will be summarized by treatment group and overall.
Forest plots including will be generated for the ITT population.
The analysis of the primary efficacy endpoint will be conducted as follows:
The response proportions at week 52 will be compared between the treatment groups using the exact
Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata. The estimate of the odds
ratio and the corresponding 99% exact confidence interval and exact p-value will be provided.
Sample SAS code (SAS code will be fully validated at the analysis stage):
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Exact Cochran-Mantel-Haenszel (CMH)

PROC FREQ data=dataset noprint;
Exact COMOR;
Tables randstrata*treatment*response / alpha= 0.01;
Run;
The treatment and response should be labelled so that the labels are alphabetically sorted in a given
order (treatment: active treatment, placebo; response: event, no event).
4.6.1.2. Sensitivity analysis to the statistical model

A sensitivity analysis, in addition to the exact CMH, will be performed (on both ITT and PP populations),
using an exact logistic regression model with treatment group and randomization strata as factors.
Exact PROC LOGISTIC (SAS Institute) will be used for the statistical analysis
proc logistic data = dataset desc;
class treatment(ref=placebo) randstrata;
Model response (event = ”Yes”) = randstrata treatment;
exact treatment / estimate = both alpha=0.01;
run;
4.6.1.3. Supplementary and other sensitivity analyses

4.6.1.3.1 Hypothetical strategy
The first supplementary analyses strategy using three relevant multiple imputation methods of the
primary endpoint [ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52]
will be performed imputing outcomes experienced after an ICE at Week 52 (see section 4.2.9).
The imputations will be based on patients completing the week 52 treatment period and relevant
baseline covariates.
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Three relevant multiple imputation scenarios/assumptions will be modeled:

1) Outcomes imputed assuming that patients would follow their initial treatment (rather than
switching to placebo after discontinuation). This scenario assumes Missing At Random (MAR) where
missingness is independent of unobserved outcomes given observed data. The multiple imputation
method will impute values as if subjects would follow their initial treatment, conditional on baseline
and pre-withdrawal data included in the analysis. Therefore, the treatment arm will be included in the
imputation model as a covariate.
Missing values for ALP and TB until week 52 will be imputed multiple times to account for the
uncertainty about the true values to impute. In case of non-monotone missingness, firstly the Markov
Chain Monte Carlo (MCMC) method will be used for completing data to a monotone pattern and
secondly a monotone regression will be applied with m imputed datasets.
To consider the correlation between ALP and TB, both parameters will be jointly imputed using the
basal ALP and TB as covariates.
For this multiple imputation analysis, a separate random seed between 1 and 10000 will be generated.
1000 imputed datasets will be generated.
proc mi data=DATAIN out=DATAIN_MONO nimpute=1000 seed=1234;
var treatment ALP TB;
mcmc chain=multiple impute=monotone;
run;
proc sort data=DATAIN_MONO;

by _Imputation_ treatment;
run;
proc mi data=DATAIN_MONO out=DATAIN_REG seed=465 nimpute=1000;

by _Imputation_;
class treatment;
monotone regression;
run;
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data DATAIN_REG1;
set DATAIN_REG;
by _Imputation_;
if [ALP < 1.67x ULN (at V6) and TB ≤ ULN (at V6) and ([ALP (at V6)- ALP (at V1)]/ALP (at V1)) ≥
15%)] then response= 1;
else response =0;
run;
proc sort data=DATAIN_REG1;

by _Imputation_;
run;
PROC FREQ data= DATAIN_REG1;

Exact COMOR;
Tables randstrata*treatment*response / alpha= 0.01;
ODS OUTPUT CommonOddsRatioCL= lgsparms;
by _Imputation_;
Run;
After calculation of the response to treatment (primary endpoint) based on imputed ALP and TB, the m
imputed datasets will be used separately in the statistical analysis model (exact CMH stratified on the
stratification factors of the randomization) and the resulting log (odds ratios) will be combined via
Rubin’s rules (using PROC MIANALYZE) to provide a global estimate of the odds ratio. Furthermore, the
p-values from exact CMH tests based on the m imputed sets will be transformed into a Z statistic by
applying the inverse normal cumulative distribution function. Since the resulting Z statistics are
normally distributed and have unit variances, they can be combined using standard Rubin's
combination rules across the multiply imputed sets.
PROC MIANALYZE PARMS (CLASSVAR=CLASSVAL) = lgsparms;

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CLASS treatment;
MODELEFFECTS treatment;
ODS OUTPUT PARAMETERESTIMATES=mian_ lgsparms;
RUN;
2) Outcomes imputed for both placebo and treatment dropouts as if they would continue on
placebo (using placebo-based multiple imputation (PBI)): The PBI method assumes the statistical
behavior of placebo- and drug-treated patients after dropout is the statistical behavior of placebo-
treated patients.
Thus, missing values for ALP and TB will be imputed using a pattern mixture model. This analysis will
use the placebo group as the basis for imputation of any missing values. To implement this approach,
the MNAR statement of PROC MI will be used along with the monotone regression (similarly to the
imputation strategy described above).
Non-monotone missing data are being imputed using the MCMC method:
proc mi data=DATAIN out=DATAIN_MONO nimpute=1000 seed=1234;
mcmc chain=multiple impute=monotone;
run;
The general logic of such a strategy is as follows (see PharmaSUG2011 - Paper SP04: Implementation of
Pattern-Mixture Models Using Standard SAS/STAT Procedures):
i. With each call to PROC MI, impute only one time-point. That is, include only one variable
corresponding to the time-point that needs to be imputed in the VAR statement (plus
predictors), while respecting the order in which PROC MI would have done it in a single call (all
time-points in chronological order).
j. When imputing missing values for time-point t, the input dataset should include all control
subjects, but only those subjects from the experimental arm that have values at time-point t
missing (only those that need imputation at time-point t). Since subjects from the experimental
arm with non-missing values at time-point t are not included in the input dataset, they will not
contribute to the estimation of an imputation model for time-point t. Imputation model will be
estimated using control subjects only, while this call to PROC MI will impute missing data at
time-point t for all subjects who need imputation at that time-point. This way, subjects from
experimental arm will be imputed based on the control subjects’ model. Note that treatment
arm should not be included as an effect in this model.
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k. Repeat (i) for all other time-points sequentially. Subjects whose missing values were imputed in
the last call to PROC MI will be included in the input dataset for the next call to PROC MI. Thus,
data for time-point t, filled in during the last call, will be used for predictor variables in the next
call to PROC MI (for time-point t+1), which is consistent with the internal workings of a single
call to PROC MI to impute all time-points automatically.
The proposed pattern-mixture analysis imputes missing values for ALP and TB using the basal ALP and
TB as covariates.
3) Outcomes imputed for both placebo and treatment dropouts under a number of scenarios about the
missing outcomes (delta-adjusted imputation or tipping point analysis).
Multiple imputation will be conducted to impute the missing ALP and TB values following an ICE at
week 4, week 13, Week 26 and Week 39 via sequential Bayesian regression with the stratification factor
as well as baseline and earlier post-baseline values of ALP and TB included as covariates. Non-
monotone missingness will be imputed via MCMC for multivariate normal data using the same variables
to complete the data to a monotone pattern. If needed, ALP and TB may be transformed to make their
distribution more symmetric and multivariate normal model more attainable (it is known from the
multiple imputation literature that the multivariate normal model works well under mild departures
from normality). The final binary response at week 52 will be imputed using a Bayesian logistic
regression model with for the clinical response with the stratification factor as well as baseline and
earlier post-baseline values of ALP and TB included as covariates.
Imputations will be conducted within each treatment arm and represent values expected under a
hypothetical estimand that patients who experienced an ICE would have continued their assigned
treatment despite the ICE under the assumption of missingness at random (MAR). The sensitivity
analysis will stress-test the MAR assumption by assuming two sensitivity parameters, and , for the
Elafibranor and placebo arms, respectively, representing an adjustment to the probability of clinical
response at week 52 compared to that expected under MAR on the log-odds scale. For details refer to
Appendix A.
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The sensitivity analysis will be implemented via PROC MI with the MNAR option and ADJUST statement.
The analysis of 1000 multiply imputed data sets will be conducted by using the same CMH statistic as in
the main analysis, which will be subsequently transformed into Z scores by an appropriate
transformation. The final analysis will be conducted via Rubin’s combination rules (PROC MIANALYZE)
with these Z scores from the multiply imputed sets (assuming unit standard errors). The resulting p-
values will be shown on a two-dimensional plane as functions of the sensitivity parameters and , or
their exponentiated values (odds ratios). The regions on the plane when the significance of the primary
analysis will be overturned will be highlighted, and their clinical plausibility will be interpreted.
The proposed delta-adjusted imputation will be implemented using PROC MI. Code snippets are
presented below (here Z is the binary response at week 52 and basALP, basTB, w4ALP, w4TB, w13ALP,
w13TB, w26ALP, w26TB, w39ALP and w39TB denote the appropriate values of ALP and TB, for example,
w4ALP is ALP at week 4).
/* Complete the data to a monotone pattern under MAR, separately by treatment arm using MCMC*/
proc MI DATA= ex SEED=1214 OUT=outmi NIMPUTE=1000;
by treatment;
var basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB;
MCMC impute=monotone;
run;
/* MNAR imputation using delta adjustment, separately by treatment arm*/
proc MI DATA= outmi (where=(treatment=1)) SEED=1214 OUT=outmi_1 NIMPUTE=1;
class treatment Z;
by _Imputation;
var basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB Z;
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monotone reg ; /* imputing all variables except Z using sequential Bayesian regression */
monotone logistic (Z = basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB);
mnar adjust(Z (event= '1')/ delta==&delta1 adjustobs=(treatment=1)); /* Elafibranor */
run;
proc MI DATA= outmi (where=(treatment=2)) SEED=1214 OUT=outmi_2 NIMPUTE=1;
class treatment Z;
by _Imputation;
var basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB Z;
monotone reg ; /* imputing all variables except Z using sequential Bayesian regression */
monotone logistic (Z = basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB);
mnar adjust(Z (event= '1')/ delta=&delta2 adjustobs=(treatment=2)); /* Placebo */
run;
/* combine the complete data in the Elafibranor and placebo arms */
data outmi_all;
set outmi_1 outmi_2;
run;
The delta-adjusted imputation for the continuous outcome (second key secondary endpoint) will be
implemented using PROC MI. Code snippets are presented below (here d1NRS through dnNRS denote
the daily NRS scores).
/* Complete the data to a monotone pattern under MAR, separately by treatment arm using MCMC */
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by treatment;
var basNRS d1NRS - dnNRS;
run;
/* MAR imputation applied to the monotone data using sequential Bayesian regression, separately by
treatment arm*/
proc MI DATA= outmi SEED=1214 OUT=completed NIMPUTE=1;
by _Imputation treatment;
run;
/* transform the completed data to the original scale (if imputation was done on transformed scores)
and add delta1 and delta2 to the imputed daily scores up to week 52 in the Elafibranor and placebo
arms */
/* compute the average outcomes at week 52 based on the observed and delta-adjusted imputed daily
measures */
4.6.1.3.2 Treatment policy strategy

The second supplementary analysis strategy will be investigated using outcome values at week 52
regardless of treatment discontinuation or use of rescue therapy to classify subjects as responders or
non-responders. The same model than the one described in section 4.6.1.1 will be applied.
The results of these supplementary analyses will allow assessing the robustness of the findings and
conclusions based on the primary analysis by changing the level of quality of the measure.
4.6.2. First Key Secondary Efficacy Endpoint

The response to Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated
A successful normalization of ALP at week 52 (ALP ≤ ULN) - (binary: YES/NO).
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The null hypothesis for response to treatment based on the first key secondary endpoint is that there is
no difference in response rates between the Elafibranor and the placebo group. The alternative
hypothesis is that there is a difference in response rates between both groups. The null hypothesis will
be tested at a two-sided alpha of 0.01, only if the primary endpoint is statistically significant (see
section 4.2.1).
Patients who stopped prematurely the study treatment or took a rescue therapy will be considered as
non-responders.
The number and percentage of patients with response to treatment at the end of the 52 weeks of the
DB treatment period will be summarized by treatment group and overall.
The analysis of the first key secondary efficacy endpoint will be conducted similarly to the primary
endpoint (see section 4.6.1). In particular, a sensitivity analysis to the statistical model, a hypothetical
strategy and a treatment policy strategy will be implemented the same way as for the primary efficacy
endpoint.
For the supplementary analyses with multiple imputation of the first key secondary endpoint, only the
ALP will be imputed and not the TB (see section 4.6.1.3.1).
4.6.3. Second Key Secondary Efficacy Endpoint

The response to Elafibranor (80 mg/day) compared to placebo on pruritus will be evaluated considering
the response to treatment in terms of:
Change in pruritus from baseline to week 52 in PBC Worst Itch NRS (continuous)
The null hypothesis for response to treatment based on the second key secondary endpoint is that
there is no difference in mean change of Worst Itch score between the Elafibranor and the placebo
group. The alternative hypothesis is that there is a difference in mean change of Worst Itch score
between both groups. The null hypothesis will be tested at a two-sided alpha of 0.01, only if the
primary endpoint and the first key secondary endpoint are statistically significant (see section 4.2.1).
Outcome values for patients who stopped prematurely the study treatment or took a rescue therapy
will be considered as missing.
The mean change from baseline in Worst Itch score at the end of the 52 weeks of the DB treatment
period will be summarized by treatment group and overall.
Mean Worst Itch NRS values (13 months including baseline) and change from baseline for each month
(see section 4.2.11) will be summarized by treatment group (Elafibranor 80mg/day and Placebo).
Change from baseline at each month over time will also be plotted as well as the mean Worst itch NRS
over time using the least squares mean (LsMean) + 99% CI. Additionally, Worst Itch NRS past week
values at V7, V8 and LVDB as well as the change from baseline will be summarized only.
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The analysis of the second key secondary efficacy endpoint will be conducted modeling the change
from baseline values over the entire duration of the W52 period via a mixed model of repeated
measures adjusting for baseline Worst Itch NRS and the stratification factor [ALP > 3x ULN or Total
bilirubin > ULN-(Yes/No)] as possible covariate effects (see section 4.2.7). Please refer to the methods
specified in section 4.6.5.1 for the verification of the dependency structure modelled if needed.
The estimated least squares means, treatment differences, together with the 99% CIs and p value will
be presented.
Months [1,2, …, 12] will be included as fixed effects along with baseline Worst Itch NRS value. The
comparison between Elafibranor and placebo will be based on a weighted average of the monthly LS
Means.
Missing values will be handled within the analysis itself with the assumption that the model
specification will be correct and that the data will be missing at random (see section 4.2.9). No
supplementary analysis with multiple imputation will be applied in case of model non-convergence.
Months will be considered as a repeated variable within a subject. The treatment by month and
baseline by month interactions will be included in the model.
proc mixed data=dataset;
class usubjid month treatment strata;
model change = Baseline strata treatment month Treatment*month baseline*month /
ddfm=kenwardroger;
repeated month / subject=usubjid;
lsmeans treatment treatment*month/ pdiff cl;
ODS OUTPUT ConvergenceStatus = ConvergenceStatus;
ods output lsmeans = lsm; * contains the adjusted means;
ods output diffs = dif; * contains treatment differences;
run;
A sensitivity tipping point analysis for the second key secondary endpoint based on the NRS score will
be performed in a similar way than described in section 4.6.1.3.1 with appropriate modifications. In
particular, imputation will be applied to impute the missing daily NRS scores following an ICE with the
stratification factor as well as the baseline and earlier post-baseline values of the NRS score included as
covariates. Non-monotone missingness will be imputed via MCMC for multivariate normal data using
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the same variables to compete data to monotone. If needed, the NRS scores may be transformed to
make their distribution more symmetric. The sensitivity parameters δ1 and δ2 specified within
clinically plausible ranges, including both positive and negative values, will be added to the imputed
NRS daily scores within week 52 (transformed to the original scale) in the Elafibranor and placebo arms,
respectively, in each completed data set. Then analysis of covariance (ANCOVA) will be performed on
the monthly averages for week 52. The resulting treatment effect p-values based on Rubin’s
combination rules will be plotted as functions of δ1 and δ2 .
implemented using PROC MI. Code snippets are presented below (here d1NRS through dnNRS denote
the daily NRS scores).
/* Complete the data to a monotone pattern under MAR, separately by treatment arm using MCMC */
by treatment;
run;
/* MAR imputation applied to the monotone data using sequential Bayesian regression, separately by
treatment arm*/
proc MI DATA= outmi SEED=1214 OUT=completed NIMPUTE=1;
by _Imputation treatment;
run;
/* transform the completed data to the original scale (if imputation was done on transformed scores)
and add delta1 and delta2 to the imputed daily scores up to week 52 in the Elafibranor and placebo
arms */
/* compute the average outcomes at week 52 based on the observed and delta-
adjusted imputed daily measures */
A supplementary analysis based on treatment policy will be investigated using the same SAS code as
above but considering outcome values at week 52 regardless of treatment discontinuation or use of
rescue therapy.
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4.6.4. Subgroup Analysis

The primary endpoint and first key-secondary endpoint will also be analyzed within subgroups using the
exact CMH. This model will be stratified by the randomization strata in the analyses for all subgroups
defined in section 4.2.7 excluding the analyses for the randomization strata subgroups themselves. The
second key secondary endpoint will be analyzed within subgroups using the MMRM.
Additionally, all secondary endpoints corresponding to response to treatment according to TB and/or
ALP (see section 2.12.1) will also be analyzed in the subgroups of patients with moderately severe
disease defined as follows (see section 4.2.7):
Within each subgroup, the treatment effect will be analyzed comparing treatment to placebo by
presenting the estimate of the odds ratio and the corresponding 95% exact confidence intervals as well
as the exact p-value.
Corresponding forest plots for odds ratios by subgroup and overall will be presented. If the subgroup
includes ≥ 95% or ≤ 5% of the overall population, the analysis will be omitted.
4.6.5.1. Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks (continuous)
Mean ALP values and change from baseline at each visit (baseline [V1], V2, V3, V4, V5 and V6 [if
applicable]) will be summarized by treatment group (Elafibranor 80mg/day and Placebo). Change from
baseline over time will also be plotted as well as the mean ALP over time using the least squares mean
(LsMean) + 95% CI.
To assess treatment effect on data collected up to week 52, change from baseline in ALP will be
compared between treatment and placebo using the MMRM with stratification groups as fixed factors.
Visit will be included as a fixed effect along with baseline ALP value.
Missing values will be handled within the analysis itself with the assumption that the model
specification will be correct and that the data will be missing at random (see section 4.2.9).
Visit will be considered as a repeated variable within a subject. The treatment by visit and baseline by
visit interactions will be included in the model.
The treatment will be compared to placebo at week 52. As a first intention, the unstructured variance-
covariance structure will be applied to model the within-patient errors. If there is no convergence, the
following structures will be tested until the model succeeds to converge: heterogeneous Toeplitz
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structure (TOEPH), heterogeneous autoregressive(1) (ARH(1)), heterogeneous compound symmetry

(CSH), Toeplitz structure (TOEP), autoregressive(1) (AR(1)), and compound symmetry.
The model will be fitted using the Restricted Maximum Likelihood method (REML). Denominator
degrees of freedom will be estimated using Satterthwaite’s approximation. The statistical model will be
used to estimate the mean treatment difference and its 95% confidence interval.
The estimated least squares means, treatment difference, together with the 95% CIs and p-value will be
presented.
PROC MIXED (SAS Institute) will be used for the statistical analysis.
Mixed Model Repeated Measures
proc mixed data=dataset;
class usubjid visit treatment;
model value = Baseline strata treatment visit treatment*visit / ddfm=kenwardroger;
repeated visit / subject=usubjid;
lsmeans treatment / pdiff cl;
ods output lsmeans = lsm; * contains the adjusted means;
ods output diffs = dif; * contains treatment differences;
run;
4.6.5.2. ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
(binary)
ALP response rates at 52 weeks will be classified as:
1) ≥ 10% decrease from baseline (Yes/No),
3) ≥ 40% decrease from baseline (Yes/No).
These categories will be summarized descriptively at each visit ([V2, V3, V4, V5, V6] by treatment group
and overall.
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The analysis will be conducted similar to the main analysis for the primary efficacy endpoint but with
95% CI (see section 4.6.1.1).
4.6.5.3. Response to treatment according to ALP < 1.5x ULN, ALP decrease from baseline ≥ 40%
and TB ≤ ULN at week 52 (binary)
The analysis on this endpoint will be conducted the same way as the analysis described in section
4.6.1.1.
4.6.5.4. Response to treatment according to ALP < 3x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris
I) at week 52 (binary)
4.6.1.1.
4.6.5.5. Response to treatment according to ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL
(Paris II) at week 52 (binary)
4.6.1.1.
4.6.5.6. Response to treatment according to TB response rate of 15% change from baseline at
week 52 (binary)
4.6.1.1.
4.6.5.7. Response to treatment according to normalization of abnormal TB (TB ≤ ULN) and/or

albumin (ALB ≥ LLN) (Rotterdam) at week 52 (binary)
4.6.1.1.
4.6.5.8. Response to treatment according to TB ≤ 0.6x ULN (binary)

4.6.1.1.
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4.6.5.9. Response to treatment according to ALP ≤ 1.67x ULN and TB ≤ 1mg/dL (Mayo 2011) at
week 52 (binary)
4.6.1.1.
4.6.5.10. No worsening of TB defined as TB ≤ ULN at week 52 or no increase from baseline of more

than 0.1x ULN at week 52 (binary)
4.6.1.1.
4.6.5.11. Response to treatment according to UK-PBC risk score at week 52 (continuous)

The continuous PBC risk score will be calculated at week 52 based on the UK-PBC score. This will be
calculated at each of the 3 survivor functions, detailed below.
UK-PBC: 1-baseline survival functionêxp(0.0287854*(alpEPxuln-1.722136304) -
0.0422873*(((altastEPxuln/10)^-1) - 8.675729006) + 1.4199 * (LN(bilEPxuln /10)+2.709607778) -
1.960303*(albxlln -1.17673001)-0.4161954*( pltxlln -1.873564875))
Where:
Baseline survivor function=0. 982 (at 5 years); 0. 941 (at 10 years); 0.893 (at 15 years).
alpEPxuln=ALP at EndPoint/Upper Level Normal ALP
altastEPxuln=(ALT, AST or TA) at EndPoint/upper level normal of the value
bilEPxuln=bilirubin at EndPoint/upper level normal bilirubin
albxlln=alb at baseline/alb lower level normal
pltxlln=plt at baseline/ plt lower level normal
Only descriptive statistics at week 52 will be provided on the continuous PBC risk score.
4.6.5.12. Response according to GLOBE PBC score at week 52 (continuous)

The GLOBE score free survival at 5, 10 and 15 years will be calculated as follows:
GLOBE score = (0.044378 * age at start of UDCA therapy + 0.93982 * LN(bilirubin times the upper
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limit of normal (ULN) at 1 year follow-up)) + (0.335648 * LN(alkaline phosphatase times the ULN at 1
year follow-up)) – 2.266708 * albumin level times the lower limit of normal (LLN) at 1 year follow-up
– 0.002581 * platelet count per 109/L at 1 year follow-up) + 1.216865.
The baseline survival curve at the mean GLOBE score S0(t) was: 0.9385, 0.8429, 0.7361 at 5-, 10- and
15-year follow-up respectively. The survival S(t) for any given patients was then calculated by S(t) =
S0(t) exp(GLOBE score).
Only descriptive statistics at week 52 will be provided on the continuous GLOBE PBC score.
4.6.5.13. Response to treatment based on the proportion of patients who normalized bilirubin (TB
≤ ULN) at week 52 (binary)
4.6.1.1.
4.6.5.14. Response to treatment based on the proportion of patients who normalized albumin
(ALB ≥ LLN) at week 52 (binary)
4.6.1.1.
4.6.5.15. Change from baseline to week 52 in hepatobiliary injury and liver function as measured
by AST, ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP
fractionated (hepatic) (continuous)
4.6.4.1.
4.6.5.16. Relative change from baseline to week 52 in hepatobiliary injury and liver function as
measured by ALP, GGT, AST and ALT (continuous)
Mean ALP, GGT, AST and ALT values and relative change from baseline at each visit (baseline [V1], V2,
V3, V4, V5 and V6 [if applicable]) will be summarized by treatment group (Elafibranor 80mg/day and
Placebo).
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The relative change ALP, GGT, AST, ALT from baseline to week 52 will be compared between Elafibranor
and placebo using a nonparametric randomization-based Analysis of Covariance method (LaVange et al,
2005). This methodology uses weighted least squares on the treatment differences of outcome and
covariate means. The resulting model estimates give the treatment effects for the outcomes, adjusting
for the covariates added into the model.
The method will be applied using the SAS NParCov4 macro (©Zinc and Koch, 2001), adjusting for
baseline ALP (or GGT, AST and ALT) level as a covariate.
Macro example for ALP relative change from baseline:
The macro will be applied to compare the relative change from baseline in ALP (PCTCHG) between the
active treatment and placebo, adjusting for baseline ALP (BASE).
Assumptions for this model are minimal:
• Randomization to treatment
• Subjects in the study are a simple random sample
The macro will be applied in the following steps:

1. Create a dataset DATAIN. The dataset should include one observation per subject and include the
variables TRTPN (1 denotes placebo, 2 denotes Elafibranor 80mg), BASE (baseline ALP) and PCTCHG
(relative change at endpoint in ALP from baseline) calculated as described above. Restrict DATAIN to
subjects with TRTPN=1 and TRTPN=2.
2. Apply the macro as shown: %NPARCOV4(OUTCOMES=PCTCHG, COVARS=BASE, C=0, HYPOTH=NULL,
STRATA=NONE, TRTGRPS=TRTP, TRANSFORM=NONE, COMBINE=NONE, DSNIN=DATAIN,
DSNOUT=DATAOUT)
3. Dataset _OUTDAT_COVTEST contains the evaluation of the covariate imbalance. P-value > 0.05
indicates random imbalance for the distribution of covariates between the 2 treatments.
4. Extract the relevant data from the output datasets. Dataset _OUTDAT_DEPTEST gives the estimate
(beta), standard error (sebeta) and p-value (pvalue) for the treatment difference and dataset
_OUTDAT_CI gives a 95% CI for this treatment estimate. The model compares TRTPN 2 vs 1.
Note: The variance under the null (HYPOTH=NULL) will be the structure for producing p-values, while
the variance under the alternative (HYPOTH=ALT) will be used for computing confidence intervals.
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4.6.5.17. Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP,

4.6.4.1.
For the hsCRP, before computing the model, the hsCRP value will be log-transformed. After back
transformation, the estimate of the between group geometric mean ratio and the corresponding 95%
CI and p-value will be displayed.
4.6.5.18. Change from baseline to week 52 in immune response as measured by IgG and IgM
(continuous)
4.6.4.1.
4.6.5.19. Change from baseline to week 52 in biomarkers, non-invasive and invasive measures of
hepatic fibrosis as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and
M30), Pro-C3 and liver stiffness measured by Transient Elastography (continuous)
The analysis on these measures will be conducted the same way as the analysis described in section
4.6.4.1.
4.6.5.20. Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C,
4.6.4.1.
4.6.5.21. Change from baseline to week 52 in Fasting Plasma Glucose (continuous)

4.6.4.1.
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4.6.5.22. Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as
4.6.4.1.
4.6.5.23. No worsening of pruritus based on PBC Worst Itch NRS at week 52 (binary)
The analysis on this measure will be conducted the same way as the analysis described in section
4.6.1.1.
4.6.5.24. Response to treatment according to PBC Worst Itch NRS reduction from baseline of 30%
at week 52 in patients with a baseline NRS score ≥ 4 (binary)
4.6.1.1.
4.6.5.25. Change from baseline to week 52 in 5D-Itch (continuous)

The analysis on the 5D-Itch sum score measure will be conducted the same way as the analysis
described in section 4.6.4.1.
4.6.5.26. Change from baseline to week 52 in PROMIS Fatigue Short Form 7a (continuous)
The analysis on the total PROMIS Fatigue Short Form 7a score will be conducted the same way as the
analysis described in section 4.6.4.1.
4.6.5.27. Change from baseline to week 52 in ESS (continuous)

4.6.4.1.
4.6.5.28. Change from baseline to week 52 in PBC-40 (continuous)

The analysis on the PBC-40 measure will be conducted by domain (Symptoms, Itch, Fatigue, Cognition,
Social, Emotional) the same way as the analysis described in section 4.6.4.1.
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4.6.5.29. Change from Baseline to week 52 in health utility as measured by the EQ5D-5L
(continuous)
4.6.1.1.
4.6.5.30. Onset of clinical outcomes described as a composite endpoint of Progression to

histological cirrhosis, Meld-Na, Liver transplant, Uncontrolled ascites requiring
treatment, Hospitalization for Variceal bleed, for Hepatic encephalopathy and for
spontaneous bacterial peritonitis, death at week 52 (Binary)
Only descriptive analyses will be conducted on these measures where number and percentage of
patients will be summarized by treatment group and overall.
4.6.5.31. Change from baseline in fibrosis stage according to Nakanuma scoring scoring
(continuous)
The analysis on the fibrosis stage according to Nakanuma scoring or modified Ishak will be conducted
the same way as the analysis described in section 4.6.5.1. The Nakanuma scoring can take the values 0,
1, 2 or 3.
4.6.5.32. Change from baseline in bile duct scores (continuous)

The analysis on the bile duct scores will be conducted the same way as the analysis described in section
4.6.5.1. The bile duct scores can take the values 0, 1, 2 or 3.
4.6.5.33. Change from baseline in cholangitis activity (continuous)

The analysis on the cholangitis activity will be conducted the same way as the analysis described in
section 4.6.5.1. The cholangitis activity can take the values 0, 1, 2 or 3.
4.6.5.34. Change from baseline in interface hepatitis activity (continuous)

The analysis on the interface hepatitis activity will be conducted the same way as the analysis described
in section 4.6.5.1. The hepatitis activity can take the values 0, 1, 2 or 3.
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4.6.5.35. Change from baseline in stage of disease (continuous)

Stage of disease must be computed based on the sum of fibrosis stage by Nakanuma and bile duct
score so that:
Stage 1 corresponds to a sum of 0
Stage 2 corresponds to a sum of 1 or 2
Stage 3 corresponds to a sum of 3 or 4
Stage 4 corresponds to a sum or 5 or 6.
The analysis will be conducted the same way as the analysis described in section 4.6.5.1.
4.6.5.36. Change from baseline in portal inflammation (continuous)

The analysis on the portal inflammation will be conducted the same way as the analysis described in
section 4.6.5.1.
4.6.5.37. Change from baseline in ductular reaction (continuous)

The analysis on the ductular reaction will be conducted the same way as the analysis described in
section 4.6.5.1.
4.6.5.38. Change from baseline in cholestasis (continuous)

The analysis on the cholestasis will be conducted the same way as the analysis described in section
4.6.5.1.
4.6.5.39. Change from baseline in concentric periductal fibrosis (continuous)

The analysis on the concentric periductal fibrosis will be conducted the same way as the analysis
described in section 4.6.5.1.
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4.6.5.40. Change from baseline in Fibrosis according to modified Ishak (adapted to PBC) scoring
(continuous)
The analysis on the fibrosis stage according to modified Ishak will be conducted the same way as the
4.7. Pharmacokinetic Evaluations
The statistical considerations applicable to the popPK modeling, will be fully described in a dedicated
Analysis Plan (popPK SAP).
4.8. Safety Analyses
Exposure to Study treatment will be summarized for the ITT and for the Safety population.
The analysis of the extent of exposure and compliance to treatment will be conducted using the ITT and
Safety Analysis populations. Safety analyses of adverse events, laboratory parameters, and vital signs
will be conducted using the Safety Analysis population.
4.8.1. Extent of Exposure and Compliance

4.8.1.1. Extent of Exposure
Duration of treatment (weeks) from Study Visit 1 to the EODB visit will be summarized by treatment
group and overall (see section 4.2.2.).
The first date of study treatment administration and the last date of drug intake as recorded on the
eCRF for those subjects who discontinue before EODB will be used to calculate the duration of
treatment.
4.8.1.2. Compliance
The subject should take 1 tablet of Elafibranor (80 mg/day) or placebo every day:
While the patient is being treated with the study drug, the patient will be directed to bring back all used
and unused cartons and blisters at baseline and at subsequent visits. Compliance will be checked by the
Investigator during those visits and recorded on the electronic case report form (eCRF). The total
number of days treatment was interrupted during the treatment period will be summarized using
summary statistics for continuous variables for estimation of drug compliance. Treatment interruptions
will be recorded on the eCRF and percentage compliance will be calculated as:
100 * actual tablets taken/expected tablets taken
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where
actual tablets taken is defined as the sum of the tablets taken and
expected tablets taken is defined as (date of last dose – date of first dose) + 1.
The number and percentage of compliant patients will be presented for the SS, where compliant is
defined as percentage compliance between 80.0% and 120.0% inclusive. The following percentage
compliance categories will be presented :<80.0%; ≥80.0% to ≤120.0%; >120.0%.
Exposure and compliance data will be summarized until V6 and until the EODB period.
Exposure and compliance data will also be listed.
4.8.2. Adverse Events

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and
displayed in tables and listings using System Organ Class (SOC) and Preferred Term (PT).
Analyses of adverse events will be performed for those events that are considered treatment emergent
adverse event (TEAE), where treatment emergent is defined as any adverse event with onset on or
after the date of first administration of study treatment and up to 30 days after the EODB date or any
event with start date prior to first dose of treatment whose severity worsened in intensity on or after
the date of first dose of study treatment.
An overview of AEs will be provided displaying the number of events along with the number and
percentage of patients with at least one:
• AE
• TEAE by severity
• TEAE related to study medication
• Serious TEAE
• Serious TEAE related to study medication
• TEAE leading to treatment discontinuation
• TEAE related to study medication leading to treatment discontinuation
• Serious TEAE leading to treatment discontinuation
• Serious TEAE related to study medication leading to treatment discontinuation
• Serious TEAE leading to death
• Serious TEAE related to study medication leading to death.
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Adverse events (AE) are summarized giving the total number of events as well as by subject incidence
rates, therefore, in any tabulation, a subject contributes only once to the count for a given adverse
event (SOC or preferred term). For summaries by maximum severity, patients with multiple AEs within
a particular SOC or PT will be counted under the category of their most severe AE within that SOC or PT.
The number of events along with the number and percentage of subjects with any AE will be
summarized by treatment group and overall.
The number of events along with the number and percentage of subjects with any TEAE by severity
(mild, moderate, severe) and TEAE related to study medication (unlikely related, possibly related,
unlikely related, not related and not assessable) will be summarized by treatment group and overall.
Relationship to study medication is not expected to be missing after data cleaning; however, if
relationship is confirmed as missing, the AE will be considered as treatment related.
The number of events along with the number and percentage of subjects with any serious TEAE and
with any serious TEAE related to study medication will be summarized by treatment group and overall.
The number of events along with the number and percentage of subjects with any TEAE leading to
treatment discontinuation and with any TEAE related to study medication leading to treatment
discontinuation will be summarized by treatment group and overall.
The number of events along with the number and percentage of subjects with any serious TEAE leading
to treatment discontinuation and with any serious TEAE related to study medication leading to
treatment discontinuation will be summarized by treatment group and overall.
The number of events along with the number of events along with the number and percentage of
subjects with any serious TEAE leading to death and with any serious TEAE related to study medication
leading to death will be summarized by treatment group and overall.
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or the
most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the
number of episodes.
No formal hypothesis-testing analysis of adverse events incidence rates will be performed.
All adverse events (more especially, death, serious TEAEs, non-treatment emergent SAEs, TEAEs leading
to withdrawal or temporary withdrawal of study drug) occurring on study will be listed in subject data
listings.
AEs of special interest (AESI) are TEAEs which are defined according to categories and sub-categories as
follows:
 CPK elevations of severe intensity or leading to permanent study drug discontinuation
 Muscle injury symptoms of severe intensity corresponding to:
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o Muscle weakness
 Transaminases elevations from baseline of severe intensity or leading to permanent study drug
discontinuation
 Autoimmune hepatitis
 Liver injury events of severe intensity corresponding to:
o Hepatic failure
 Gastrointestinal symptoms of severe intensity corresponding to:
o Abdominal pain
o Constipation
o Diarrhea
o Nausea
o Vomiting
o Acute cholecystis
 Fatigue and Asthenia of severe intensity
 Serum creatinine elevations of severe intensity or leading to permanent study drug
discontinuation
 Renal injury events of moderate or severe intensity corresponding to:
o Renal failure
o Renal impairment
o Renal colic
 Neurological abnormalities of moderate to severe intensity corresponding to:
o Tremor
o Ataxia
o Fasciculations
 Parkinson’s Disease
 Peripheral edema of moderate to severe intensity
 Weight gain of more than 5% from baseline
 Major Adverse Cardiovascular Events corresponding to:
o Non-fatal stroke
o Unstable Angina
 Coronary Revascularization (bypass or percutaneous coronary intervention)
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 Treatment emergent Pregnancy and outcomes of Pregnancy
All of the above categories, with the exception of the pregnancy AESIs, will be identified via a list of
MedDRA queries of PT codes. Pregnancy AESIs will be identified using positive pregnancy assessment
and reported in the pregnancy report form.
For each of the AESI categories and subcategories defined above, besides treatment emergent
Pregnancy, the number and percentage of patients with at least one event and the corresponding
number of events will be summarized for any:
 AESIs
 Treatment related AESIs
 Serious AESIs
 AESIs leading to death
 AESIs leading to treatment discontinuation
In addition, the total number and percentage of patients with at least one AESI (with the exception of
treatment emergent Pregnancy), and the corresponding number of events will be summarized for the
five categories above.
A between-group comparison will be performed using the exposure-adjusted incidence rates (EAIR) of
AEs and AESIs. The comparison will be summarized using the EAIR difference, that will be accompanied
by a 95% confidence interval. The 95% CI for the risk difference will be computed using the He and al
method (He et al, 2015).
For Pregnancy, the number and percentage of patients with at least one event and the corresponding
number of events will be summarized. The outcomes of Pregnancy will also be summarized by SOC and
PT.
4.8.3. Adjudicated DILI

DILI events will be adjudicated by the CEC.
The total number of adjudicated DILI events along with the number and percentage of patients with at
least one adjudicated DILI events will be summarized by treatment group. As for AEs, a between-group
comparison will be performed using the exposure-adjusted incidence rates (EAIR) of DILI (see section
4.8.2).
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4.8.4. Laboratory Data

Clinical laboratory evaluations include hematology, chemistry and urinalysis. Clinical laboratory values
will be expressed using conventional respective units for each parameter. All analyses will be done on
the central laboratory data.
In the event of repeated post-baseline values, the first non-missing value per study day/time will be
used.
Serum hematology and serum chemistry, (see Table 2) assessed from blood and urine samples taken at
baseline, V2, V3, V4, V5 and V6 will be summarized by treatment group and overall. If applicable, values
obtained at V7, V8 and LVDB will also be summarized by treatment group.
Biobank samples (see Table 2) collected from additional blood samples from patients, who have given
their consent, at baseline, V2, V3, V4, V5 and V6 - and if applicable at V7, V8, LVDB - will be summarized
by treatment group and overall.
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots will present the concomitant values of
aminotransferase (ALT or AST) and total bilirubin at the visit corresponding to the peak of
aminotransferase.
Distinct plots will be produced separately with regards to the peaks of ALT and AST. For each subject
and for both ALT and AST, the strategy is as follows:
 Among all the visits, identify the maximum value of aminotransferase
 If the peak value occurs at just one visit, keep the value of total bilirubin at the visit
corresponding to the peak of aminotransferase
 If the peak value occurs at more than one visit, keep the highest value of total bilirubin at any
of the visits corresponding to the peak of aminotransferase
 If the peak value occurs at a visit / visits with no corresponding value/values of total bilirubin,
keep the value of bilirubin closest to the corresponding visit / any of the corresponding visits. In
the event of equidistant time from the peak value visit / visits, keep the highest value of total
bilirubin at any of the visits equidistant from the corresponding visit/visits of peak
aminotransferase
 Classify subjects into two subgroups: baseline value of ALT < ULN or baseline value of ALT ≥
ULN.
o If baseline value of ALT < ULN, express total bilirubin in xULN on the y-axis and
aminotransferase in xULN on the x-axis. Add horizontal and vertical lines corresponding
to total bilirubin = 2 ULN and aminotransferase = 3 ULN respectively.
o If baseline value of ALT ≥ ULN, present two plots:
 Express total bilirubin in xBaseline on the y-axis and aminotransferase in
xBaseline on the x-axis. Add horizontal and vertical lines corresponding to total
bilirubin = 2xBaseline and aminotransferase = 3xBaseline respectively. For total
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bilirubin values > 2xBaseline, values identified as > 2 ULN will be plotted
differently than values ≤ 2 ULN.
 Express total bilirubin in xULN on the y-axis and aminotransferase in xBaseline
on the xaxis. Add horizontal and vertical lines corresponding to total bilirubin =
2 ULN and aminotransferase = 3xBaseline respectively.
Occurrence of aminotransferases (ALT and AST) increase will be presented separately according to the
baseline level (normal or abnormal). The classes of aminotransferase increase considered are:
• > 3x ULN and ≤ 5x ULN, > 5x ULN and ≤ 10x ULN, > 10x ULN if the baseline level of
aminotransferase is normal (i.e. < ULN). The worst on treatment classification will be retained.
• > 3x Baseline and ≤ 5x Baseline, > 5x Baseline if the baseline level of aminotransferase is
abnormal (i.e. ≥ ULN). The worst on treatment classification will be retained.
The increase in serum creatinine will be presented as:

• Occurrence of at least one post baseline value > ULN (only on the subset of subjects with
baseline value ≤ ULN)
• Change from baseline in creatinine presented in classes according to KDIGO (Kidney Disease
Improving Global Outcomes) AKI (Acute Kidney Injury) stages. Among all visits, the worst case
will be retained:
o ≥ 1.5xBaseline and < 2.0xBaseline, or ≥ 0.3 mg/dL increase
o ≥ 2.0xBaseline and < 3.0xBaseline
o ≥ 3.0xBaseline or ≥ 4 mg/dL.
Transient elastography (TE), serum bile acids and biomarkers of bile acid synthesis, biomarkers of
hepatic fibrosis and/or inflammation, additional kidney safety markers and immunoglobulins (see Table
2) at baseline, V4 and V6, will be summarized by treatment group and overall.
All laboratory data will be provided in data listings.
A subset listing will be presented for all abnormal laboratory values.
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4.8.5. Vital Signs and Physical Examinations

The actual value and change from Baseline to each on study visit evaluation (baseline, V2, V3, V4, V5,
V6, and if applicable V7, V8, LVDB) for vital signs (continuous) will be summarized by treatment group
and overall.
By-subject listings of vital sign measurements will be presented in data listings.
Physical examination results at baseline, V2, V3, V4, V5, V6 and if applicable V7, V8, LVDB will be
summarized by treatment group and overall; shifts from Baseline in physical examination findings to
each on study visit will also be presented.
All physical examination findings will be presented in a data listing.
4.8.6. Electrocardiogram
12-lead ECG results will be summarized descriptively, including the number and percent of subjects
with normal, abnormal and clinically significant abnormal results at Baseline, V4, V6 and if applicable
V8.
All ECG data for each subject will be provided in data listings.
4.8.7. Concomitant Medications

Concomitant medications will be coded using the WHO Drug dictionary. Results will be summarized by
Anatomical Therapeutic Chemical Classification (ATC), Therapeutic Subgroup (ATC level 2), Chemical
Subgroup (ATC level 4) and preferred term.
The use of concomitant medications will be included in by-subject data listing.
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5. CHANGES TO PLANNED ANALYSES
As of this date, there have been no changes between the protocol-defined statistical analyses and
those presented in this statistical plan.
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6. REFERENCES
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term
prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-7.
Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to
treatment and prediction of long-term outcome. J Hepatol 2011;55:1361-7.
Dmitrienko, A, D’Agostino, RB, Huque, MF. (2013). Key multiplicity issues in clinical drug development.
Statistics in Medicine. 2013;32:1079-1111.
He X, Chen L, Lei L, Xia HA, Lee MLT (2015) A Simple Method for Estimating Confidence Intervals for
Exposure Adjusted Incidence Rate and Its Applications to Clinical Trials. J Biom Biostat 6: 238.
doi:10.4172/2155-6180.1000238
Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis
that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009;136:1281-7.
Carbone M et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term
prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016; VOL.63, NO.3.
ICH E9 (R1) addendum on estimands and Sensitivity Analysis in Clinical Trials to the guideline on
statistical principles for clinical trials EMA/CHMP/ICH/436221/2017.
Lammers WJ, Hirschfield GM, Corpechot C, et al. on behalf of the Global PBC Study Group.
Development and validation of a scoring system to predict outcomes of patients with primary biliary
cirrhosis receiving ursodeoxycholic acid. Therapy, Gastroenterology (2015), doi:
10.1053/j.gastro.2015.07.061.
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are
surrogate end points of outcomes of patient with primary biliary cirrhosis: an international follow-up
study. Gastroenterology. 2014;147:1338-49.
Lipkovich I, O’Kelly M. Combining Analysis Results from Multiply Imputed Categorical Data. PharmaSUG
2013 - Paper SP03.
Ratitch B, O’Kelly M. Implementation of Pattern-Mixture Models Using Standard SAS/STAT Procedures.
PharmaSUG 2011 - Paper SP04.
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7. APPENDIX A
Tipping point analysis:
The sensitivity analysis will stress-test the MAR assumption by assuming two sensitivity parameters,
and , for the Elafibranor and placebo arms, respectively, representing an adjustment to the probability
of clinical response at week 52 compared to that expected under MAR on the log-odds scale.
Specifically, values of will represent a departure from MAR towards higher odds of response,
and will indicate lower odds of response. A two-dimensional sensitivity analysis will report
outcomes for and each varying independently within a plausible range. Typically, and
represent scenarios when dropouts from the Elafibranor arm have worse outcomes than
dropouts from the placebo arm. The assumed values of the sensitivity parameters will be applied to the
individual probabilities of response drawn from the posterior distributions at week 52 based on the
Bayesian logistic regression defined above, resulting in the adjusted probabilities , where
. Returning to a probability scale,
Then missing binary outcomes will be imputed separately by treatment arm via sampling from a
Bernoulli distribution with the adjusted probabilities, , obtained as explained above using the arm-
specific sensitivity parameters, i.e., and .
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8.1. Statistical Outputs to be Generated
Sample tables, listings and figures will be provided in a separate document.
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Document Version No.: 4.0 Document Date: 10-May-2023
STATISTICAL ANALYSIS PLAN

(Double-Blind Period)
Protocol GFT505B-319-1
evaluate efficacy and safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with
Protocol Number: GFT505B-319-1, v4.0, IND number: 132202

(Version Date) 20-September-2022
Name of Test Drug: Elafibranor
Phase: 3
Methodology: A Double-blind, Randomized, Placebo-Controlled Study and

Open-label Long Term Extension to evaluate efficacy and safety
of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis
with Inadequate Response or Intolerance to Ursodeoxycholic
Acid.
Sponsor: GENFIT
Parc Eurasanté
Document Date: 10-May-2023
Document Version: 4.0
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SIGNATURE PAGE
Protocol Title: A Double-blind, Randomized, Placebo-Controlled Study and

Open-label Long Term Extension to evaluate efficacy and
safety of Elafibranor 80 mg in Patients with Primary Biliary
Cholangitis with Inadequate Response or Intolerance to
Ursodeoxycholic Acid.
Sponsor: GENFIT
Parc Eurasanté
Protocol Number: GFT505B-319-1, IND number: 132202
Document Date/Version: 10-May-2023/v4.0
Cytel, Inc. Author:

Signature:
PPD PPD Electronically signed by:
PPD
Date: Signature:
Reason: Approve
Date: May 10, 2023 14:45 GMT+2
Principal Biostatisticians
Email: PPD
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Sponsor Approval
By signing this document, I acknowledge that I have read the document and approve of the planned
statistical analyses described herein. I agree that the planned statistical analyses are appropriate for this
study, are in accordance with the study objectives, and are consistent with the statistical methodology
described in the protocol, clinical development plan, and all applicable regulatory guidance’s and
guidelines.
I have discussed any questions I have regarding the contents of this document with the biostatistical author.
I also understand that any subsequent changes to the planned statistical analyses, as described herein, may
have a regulatory impact and/or result in timeline adjustments. All changes to the planned analyses will be
described in the clinical study report (CSR).
Sponsor Signature :
GENFIT
Date :
885, Avenue Eugène Avinée, 59120 Loos,
France
ronically signed by:
PPD P PP
PPD Statistician Signature:
Date : on: Approve P D
Date: May 10, 2023 15:33 GMT+2
Email: PPD D
Electronically signed by: p
PPD , VP Biometrics PPD PP
Date : Signature: PP
Reason: Approve
PGMPT+2
Date: May 10, 2023 14:57
D
Email: PPD DD
PP Electronically signed by:
PPD
PPD , CMO Signature: D Reason: Approve
Date : Date: May 10, 2023 11:11 EDT
Email: PPD
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MODIFICATION HISTORY

SAP Version

V1.0 28-July-2020 PPD First signed version. Based on protocol version 0.7,
15-July- 2020.
V2.0 16-September- PPD Addressing FDA’s feedback; adding the optimal

2021 weighting scheme as proposed in Song et al. (2013).
V3.0 27-October- PPD Updates based on protocol version 4.0, 20Sept22;

2022 Addressing FDA’s feedback in the Informational
Request and Writing Response Only; Change
analysis population for the 2nd key secondary
endpoint related to pruritus; addition of 3rd key
secondary endpoint (change in NRS through week
24)
V4.0 10-May-2023 PPD Update based on FDA’s feedback in the Informational

Request and Writing Response Only on February 17th,
2023.
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TABLE OF CONTENT
1. INTRODUCTION AND OBJECTIVES OF ANALYSIS......................................................................................... 15

1.1 Introduction ...................................................................................................................................... 15
1.2 Objectives of Statistical Analysis ...................................................................................................... 15
2. STUDY DESIGN ............................................................................................................................................ 16
2.1 Synopsis of Study Design .................................................................................................................. 16
2.2 Screening period............................................................................................................................... 16
2.3 Baseline period (V1) ......................................................................................................................... 17
2.4 Double-Blind period (Week 0 up to Week 104)................................................................................ 18
2.5 Long-Term extension ........................................................................................................................ 19
2.6 Clinical event committee (CEC) ........................................................................................................ 19
2.7 Optional Visits .................................................................................................................................. 20
2.7.1 Retesting and/or additional screening visits .............................................................................. 20
2.7.2 Unscheduled visits ...................................................................................................................... 21
2.8 Exploratory/Ancillary Sub-study ....................................................................................................... 21
2.9 Randomization Methodology ........................................................................................................... 21
2.10 Stopping Rules and Unblinding ........................................................................................................ 22
2.11 Study Procedures.............................................................................................................................. 23
2.12 Efficacy, Pharmacokinetic, and Safety Variables .............................................................................. 34
2.12.1 Efficacy Variables ........................................................................................................................ 34
2.12.2 Pharmacokinetic Variables ......................................................................................................... 36
2.12.3 Safety Variables .......................................................................................................................... 36
2.12.4 Exploratory Variables (related to histological assessment) ........................................................ 37
3. SUBJECT POPULATIONS .............................................................................................................................. 38
3.1 Population Definitions ...................................................................................................................... 38
3.2 Protocol Deviations .......................................................................................................................... 40
4. STATISTICAL METHODS .............................................................................................................................. 41
4.1 Sample Size Justification ................................................................................................................... 41
4.2 General Statistical Methods and Data Handling............................................................................... 41
4.2.1 General Methods........................................................................................................................ 41
4.2.2 Data Conventions ....................................................................................................................... 42
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4.2.3 Computing Environment ............................................................................................................ 44
4.2.4 Methods of Pooling Data ............................................................................................................ 44
4.2.5 Adjustments for Covariates ........................................................................................................ 44
4.2.6 Multiple Comparisons/Multiplicity ............................................................................................. 45
4.2.7 Subpopulations ........................................................................................................................... 45
4.2.8 Withdrawals, Dropouts, Loss to Follow-up ................................................................................ 46
4.2.9 Missing, Unused, and Spurious Data .......................................................................................... 46
4.2.10 Visit Windows ............................................................................................................................. 50
4.2.11 Data Derivation .......................................................................................................................... 51
4.3 Interim Analyses ............................................................................................................................... 52
4.4 Subject Disposition ........................................................................................................................... 53
4.5 Demographic, Screening and Baseline Characteristics ..................................................................... 53
4.5.1 Demographics ............................................................................................................................. 54
4.5.2 Screening Characteristics ............................................................................................................ 54
4.5.3 Baseline Disease Characteristics ................................................................................................. 55
4.5.4 Prior Medications ....................................................................................................................... 56
4.5.5 Prior Procedures ......................................................................................................................... 56
4.6 Efficacy Evaluation ............................................................................................................................ 56
4.6.1 Estimand Framework for Primary and Key Secondary Endpoints .............................................. 56
4.6.2 Primary Efficacy endpoint analysis ............................................................................................. 62
4.6.2.1 Main Analysis ...................................................................................................................... 62
4.6.2.2 Sensitivity analysis to the statistical model ........................................................................ 64
4.6.2.3 Supplementary analyses..................................................................................................... 64
4.6.2.3.1 Composite strategy with missing data as non-responders............................................... 64
4.6.2.3.2 Hypothetical strategy ....................................................................................................... 64
4.6.2.3.3 Treatment policy strategy ................................................................................................ 72
4.6.2.3.4 COVID-19 .......................................................................................................................... 74
4.6.3 First Key Secondary Efficacy Endpoint ........................................................................................ 74
4.6.4 Second Key Secondary Efficacy Endpoint ................................................................................... 75
4.6.4.1 Main Analysis ...................................................................................................................... 75
4.6.4.2 Supplementary analysis ...................................................................................................... 76
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4.6.4.2.1 Tipping point analysis ....................................................................................................... 76
4.6.4.2.2 Other supplementary analysis.......................................................................................... 78
4.6.5 Third Key Secondary Efficacy Endpoint ...................................................................................... 80
4.6.6 Subgroup Analysis ...................................................................................................................... 81
4.6.7 Other secondary endpoints ........................................................................................................ 82
4.6.7.1 Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks (continuous) ......................... 82
4.6.7.2 ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
(binary) 83
4.6.7.3 Response to treatment according to ALP < 1.5x ULN, ALP decrease from baseline ≥ 40%
and TB ≤ ULN at week 52 (binary) .......................................................................................................... 83
4.6.7.4 Response to treatment according to ALP < 3x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
at week 52 (binary)................................................................................................................................. 83
4.6.7.5 Response to treatment according to ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris
II) at week 52 (binary) ............................................................................................................................ 84
4.6.7.6 Response to treatment according to TB decrease of 15% change from baseline at week 52
(binary) 84
4.6.7.7 Response to treatment according to normalization of abnormal TB (TB ≤ ULN) and/or ALB
(ALB ≥ LLN) (Rotterdam) at week 52 (binary) ........................................................................................ 84
4.6.7.8 Response to treatment according to TB ≤ 0.6x ULN at week 52 (binary) ........................... 84
4.6.7.9 Response to treatment according to ALP ≤ 1.67x ULN and TB ≤ 1mg/dL (Momah/Lindor
criterion, 2011) at week 52 (binary) ...................................................................................................... 84
4.6.7.10 No worsening of TB defined as TB ≤ ULN at week 52 or no increase from baseline of more
than 0.1x ULN at week 52 (binary) ........................................................................................................ 84
4.6.7.11 Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin, and INR at
week 52 (binary) ..................................................................................................................................... 85
4.6.7.12 UK-PBC score at week 52 (continuous) .............................................................................. 86
4.6.7.13 GLOBE PBC score at week 52 (continuous) ........................................................................ 86
4.6.7.14 Response to treatment based on the proportion of patients who normalized bilirubin (TB
≤ ULN) at week 52 (binary) ..................................................................................................................... 87
4.6.7.15 Response to treatment based on the proportion of patients who normalized albumin (ALB
≥ LLN) at week 52 (binary) ...................................................................................................................... 87
4.6.7.16 Change from baseline to week 52 in hepatobiliary injury and liver function as measured by
AST, ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
(continuous) ........................................................................................................................................... 88
4.6.7.17 Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP,
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fibrinogen, haptoglobin and TNF-α (continuous) ................................................................................... 89
4.6.7.18 Change from baseline to week 52 in immune response as measured by IgG and IgM
(continuous) ........................................................................................................................................... 89
4.6.7.19 Change from baseline to week 52 in biomarkers, non-invasive measures of hepatic fibrosis
as measured by ELF test (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver
stiffness measured by Transient Elastography (continuous) .................................................................. 89
4.6.7.20 Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C,
calculated VLDL-C and TG (continuous) ................................................................................................. 89
4.6.7.21 Change from baseline to week 52 in Fasting Plasma Glucose (continuous) ....................... 89
4.6.7.22 Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as
measured by bile acids, C4 and FGF-19 (continuous)............................................................................. 90
4.6.7.23 No worsening of pruritus based on PBC Worst Itch NRS through week 52 and through week
24 (binary) 90
4.6.7.24 Proportion of responders in PBC Worst Itch NRS score according to clinically meaningful
change; at least 30% reduction; and one point, two points or three points decrease in score from
baseline through week 52 and through week 24 in patients with baseline PBC Worst Itch NRS score ≥
4 90
4.6.7.25 Proportion of participants achieving sustained improvement in PBC Worst Itch NRS
(binary) 91
4.6.7.26 PGIC and PGIS ..................................................................................................................... 91
4.6.7.27 Change from baseline to week 52 in 5-D Itch (continuous) ............................................... 92
4.6.7.28 Change from baseline to week 52 in PROMIS Fatigue Short Form 7a (continuous) 92
4.6.7.29 Change from baseline to week 52 in Epworth Sleepiness Scale (continuous) .................... 93
4.6.7.30 Change from baseline to week 52 in PBC-40 (continuous)................................................. 93
4.6.7.31 Change from Baseline to week 52 in health utility as measured by the EQ-5D-5L
(continuous) ........................................................................................................................................... 94
4.6.7.32 Onset of clinical outcomes described as a composite endpoint of MELD-Na; Liver
transplant; Uncontrolled ascites requiring treatment; Hospitalization for Variceal bleed, for Hepatic
encephalopathy and for spontaneous bacterial peritonitis; death until week 52 (Binary) .................... 94
4.6.7.33 Change from baseline to week 52 in serum markers of bone turnover and in bone mineral
density (hip and lumbar) assessed by DEXA scanning (continuous) ....................................................... 95
4.7 Pharmacokinetic Evaluations ........................................................................................................... 96
4.8 Safety Analyses ................................................................................................................................. 96
4.8.1 Extent of Exposure and Compliance ........................................................................................... 96
4.8.1.1 Extent of Exposure.............................................................................................................. 96
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4.8.1.2 Compliance ......................................................................................................................... 97
4.8.2 Adverse Events ........................................................................................................................... 97
4.8.3 Adjudicated events ................................................................................................................... 102
4.8.4 Laboratory Data........................................................................................................................ 103
4.8.5 Transient elastography ............................................................................................................. 106
4.8.6 Vital Signs and Physical Examinations ...................................................................................... 107
4.8.7 Electrocardiogram .................................................................................................................... 107
4.8.8 Concomitant Medications ........................................................................................................ 108
4.8.9 Concomitant Procedures .......................................................................................................... 108
4.9 Exploratory analyses (related to histological assessments)............................................................ 109
5. CHANGES TO PLANNED ANALYSES ........................................................................................................... 111
6. REFERENCES ............................................................................................................................................. 112
7. APPENDIX A .............................................................................................................................................. 114
8. APPENDIX B .............................................................................................................................................. 115
9. APPENDIX C .............................................................................................................................................. 116
10. APPENDIX D .............................................................................................................................................. 119
11. APPENDIX E .............................................................................................................................................. 124
12. APPENDIX F............................................................................................................................................... 126
13. STATISTICAL OUTPUTS TO BE GENERATED............................................................................................... 136
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LIST OF IN-TEXT TABLES
Table 1: Schedule of Assessments .......................................................................................................................... 23

Table 2: Schedule of Biological Assessments .......................................................................................................... 28
Table 3: Schedule of Patient Reported Outcomes Questionnaires ........................................................................ 32
Table 4: Missing Severity and Definition of Treatment-emergent ......................................................................... 50
Table 5: Evaluation Intervals for Efficacy and Safety Analysis ................................................................................ 50
Table 6: Histological Endpoints..............................................................................................................................109
Table 7: PROMIS Fatigue short form 7a Conversion table ....................................................................................116
Table 8: The six domains and 40 questions of the PBC-40 ....................................................................................117
Table 9: Laboratory Test Toxicity Grades ..............................................................................................................119
Table 10: Classification of worst value for laboratory parameters of interest ......................................................124
Table 11: List of PT defining Hepatic Failure .........................................................................................................126
Table 12: List of PT defining Hepatic Injury ...........................................................................................................128
LIST OF IN-TEXT FIGURES
Figure 1: Study Design Overview ............................................................................................................................ 20
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ABBREVIATIONS
ACR Albumin to Creatinine Ratio
AE Adverse event
AESI Adverse event of specific interest
AKI Acute kidney injury
ALB Albumin
ALP Alkaline phosphatase
ALT Alanine transaminase
ANCOVA Analysis of covariance
AST Aspartate transaminase
AT Aminotransferase
BDRM Blind Data Review Meeting
CEC Clinical event committee
CK-18 Cytokeratin-18
CI Confidence Interval
CMH Cochran-Mantel-Haenszel
CMO Chief Medical Officer
CSR Clinical study report
C4 Serum 7 α-hydroxy-4-cholesten-3-one
DB Double-blind
DEXA Dual-Energy X-ray Absorptiometry
DILI Drug-induced Liver injury
DSMB Data Safety Monitoring Board
5D-Itch 5-D Pruritus Scale
ECG 12-lead Electrocardiogram
eCRF electronic Case Report Form
eDiary Electronic diary
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eDISH Evaluation of Drug-Induced Serious Hepatotoxicity
ELF Enhanced Liver Fibrosis
EODB End of the Double-Blind period
EOS End of Study
EOT End of treatment
FGF-19 Fibroblast growth factor 19
GCA Glycocholic acid
GGT Gamma-glutamyltransferase
HA Hyaluronic acid
Anti- HAV IgM Hepatitis A Antibody test
HBsAg Surface antigen of the hepatitis B virus (Australia antigen)
HCV Ab Hepatitis C antibody
HCV RNA Qualitative Detection of Hepatitis C Virus RNA
HDL-C High-Density Lipoprotein Cholesterol
HIV Ab I/II Rapid HIV antibody test
HRQoL Health-related Quality of Life
hsCRP high-sensitivity C-Reactive Protein
IgG Immunoglobulin G
IgM Immunoglobulin M
IL-6 Interleukin 6
INR International normalized ratio
ITT Intent-to-treat
IxRS interactive voice/web response system
KDIGO Kidney disease improving global outcomes
LDL-C Low-Density Lipoprotein Cholesterol
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LLN Lower limit of normal
LSM Least Squares Means
LVDB Last Visit Double-Blind
M1, M2, M3 First Measure, Second Measure, Third Measure
M30 measures caspase-cleaved CK18 produced during apoptosis
M65 measures the levels of both caspase-cleaved and intact CK18, total
cytokeratin
MAR Missing At Random
MedDRA Medical Dictionary for Regulatory Activities
MELD-Na model end stage liver disease-Sodium
MMRM Mixed effect Model for Repeated Measures
N/A Not applicable
5’ NT 5’-nucleotidase
OCA Ocaliva (obeticholic acid)
PAI-1 Plasminogen activator inhibitor-1
PBC Primary Biliary Cholangitis
PBC-40 Quality of Life for Primary Biliary Cirrhosis
PDP Protocol Deviation Plan
PGIC Patient Global Impression of Change
PGIS patient global impression-severity
PIINP Procollagen III amino terminal peptide
PK Pharmacokinetic
PP Per Protocol
PRO Patient reported outcomes
Pro-C3 Plasma collagen type III
PCSA Potentially clinically significant abnormality
Pt prothrombin time
PT Preferred Term
Q1, Q3 First Quartile, Third Quartile
QTc corrected QT
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RIM Risk and Issue Management System
SAE Serious adverse event
SAP Statistical analysis plan
SOC System Organ Class
SV Screening visit
TC Total cholesterol
TB Total Bilirubin
TE Transient elastography
TEAE Treatment-emergent adverse event
TIMP-1 Tissue inhibitor of metalloproteinase 1
TG Triglycerides
TGF-β Transforming growth factor beta
TNF-α tumor necrosis factor alpha
UDCA Ursodeoxycholic acid
ULN Upper limit of normal
US Ultrasound exam
VLDL-C Very-low-density lipoprotein Cholesterol
V1 Randomization/baseline visit
V2-V6 Visit2-Visit6
WBC White cell blood count
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1. INTRODUCTION AND OBJECTIVES OF ANALYSIS
1.1 Introduction
This document describes the plan for the statistical analyses and reporting of the double-blind (DB) period
of the study GFT505B-319-1, which is a prospective, randomized, double-blind, placebo- controlled phase
3 study to demonstrate the efficacy of Elafibranor 80 mg versus Placebo in patients with Primary Biliary
Cholangitis (PBC) and inadequate response or intolerance to ursodeoxycholic acid (UDCA). Results of the
analyses described in this Statistical Analysis Plan (SAP) will be included in the Clinical Study Report (CSR).
Additionally, the planned analyses identified in this SAP will be included in regulatory submissions or future
manuscripts. Any post-hoc or unplanned analyses related to the DB period and performed to provide results
for inclusion in the CSR but not identified in this prospective SAP will be clearly identified in the CSR.
The information regarding the analyses of the open label long term extension (LTE) period is not within the
scope of this SAP and will be described in a separate SAP.
1.2 Objectives of Statistical Analysis

The primary objective of the study GFT505B-319-1, as stated in the protocol is to evaluate the effect of
Elafibranor (80 mg/day) on cholestasis over 52 weeks of treatment compared to placebo.
The key secondary objectives of the study are to evaluate the effect of Elafibranor (80 mg/day) over 52
weeks of treatment compared to placebo based on ALP normalization, and through 52 weeks and through
24 weeks on pruritus.
This SAP is designed to outline the methods to be used in the analysis of study data in order to address the
study objectives. Populations for analysis, data handling rules, statistical methods, and formats for data
presentation are provided in this SAP. The statistical analyses and summary tabulations described in this
SAP will provide the basis for the results sections of the CSR for this study.
This SAP will also outline any differences in the currently planned analytical objectives relative to those
planned in the study protocol.
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2. STUDY DESIGN
2.1 Synopsis of Study Design

This is a phase 3 DB, randomized, placebo-controlled study evaluating Elafibranor 80 mg once daily versus
placebo in patients with PBC and inadequate response or intolerance to UDCA.
2.2 Screening period

The study starts with a screening period, which must include at least one screening visit (SV) which should
be performed between 2 to 12 weeks prior to randomization. At the SV1, preliminary eligibility criteria will
be reviewed.
For the purpose of establishing relevant baseline chemistries for suspected drug-induced liver injury (DILI),
repeated measures of aspartate transaminase (AST), alanine transaminase (ALT) and total bilirubin (TB) will
be collected (see section 4.8.4) ONLY if the first measure (M1) collected at SV1 is > upper limit of normal
(ULN).
M1 and another value, either a historical value (M0), collected at least 4 weeks and up to 12 weeks apart
before SV1, or a second measure (M2) will be collected at SV2 (4 to 6 weeks after SV1). This applies to only
the analyte above ULN.
• If variability between M1 and either M0 or M2 is > 40% a third measure (M3) will be collected at SV3
(4 to 6 weeks after SV1 (if M0 compared) or after SV2 (if M2 compared)):
o If variability between M1 and M3 is > 40% the patient is ineligible for the study.
To assess the alkaline phosphatase (ALP) eligibility criterion, two ALP values will be required. One value is
the M1 collected at SV1, and the other value is M0 collected at least 4 weeks and up to 12 weeks apart
before SV1 or M2 collected at SV2 (4 to 6 weeks after SV1).
• If M1 is < 1.67x ULN, the patient will be excluded, and no further assessment will be performed.
• If M1 is ≥ 1.67x ULN, and the mean of M1 and either M0 or M2 is ≥ 1.67x ULN, and variability is ≤ 40%,
the patient is eligible
• If M1 is ≥ 1.67x ULN, and the mean of M1 and either M0 or M2 is < 1.67x ULN or variability is > 40%,
M3 collected at SV3 (4 to 6 weeks after SV1 (if M0 compared) or after SV2 (if M2 compared)) will be
required:
o If the mean of M1 and M3 is ≥ 1.67x ULN and variability is ≤ 40%, the patient is eligible
o If the mean of M1 and M3 is < 1.67x ULN or variability is > 40%, the patient is ineligible for the
study
NOTE: M2 and M3 values for AST, ALT, TB and ALP can be obtained locally. Comparison between M1 and
local value(s) will be done on normalized values according to ULN.
The laboratory value used for the first stratification factor (see section 2.9) will be the ALP value and TB
value provided by the central lab at SV1.
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Local laboratory assessments are allowed for repeated assessment of ALT, AST, TB, ALP, and CPK during
the screening period as well as for any required retest for liver function monitoring. Assessments of urinary
myoglobin are to be done locally only in case of clinically significant CPK elevation.
At the screening period, the second stratification factor will be the PBC Worst Itch NRS score. PBC Worst
Itch NRS score will be recorded on an electronic diary (eDiary) daily each evening; the PBC Worst Itch NRS
score will be averaged over the 14 days preceding Baseline (V1: Day 1) to determine stratification for
randomization. The PBC Worst Itch Score will be computed as an average of non-missing data falling in the
14-day window. At least 4 values of the PBC Worst Itch NRS score from each of the two 7-day intervals in
the 14 days prior to randomization visit are required for randomizing the patients. If this number is not
achieved, the screening period may be extended in order to obtain the expected number of NRS values.
At Screening the availability of historic liver biopsy samples may be determined to support the diagnosis of
PBC. Liver biopsy is one of the three criteria to help identify PBC patients, along with two non-biopsy
criteria. A minimum of two out of three criteria must be met in order to meet eligibility criteria (see
protocol, inclusion criterion 3).
As a first step, patients will be asked if they agree to participate in the study and sign the Informed Consent
Form (ICF). Each patient who has signed the ICF will perform procedures listed in Table 1. All inclusion and
exclusion criteria will be reviewed. If eligibility is confirmed, the site will contact the patient to confirm the
patient’s willingness to continue in the study. In case of ineligibility, the patient should be contacted as
soon as possible.
During the screening period, the patient will not receive study drug.
2.3 Baseline period (V1)

As per protocol, evaluations performed at the Study Day 1 visit (V1) should be done before drug
administration and will be used for baseline values. Thus, baseline is defined as the last non-missing
assessment the day of or prior to study drug start. If the assessment for ALP/AST/ALT/TB is not done at the
baseline visit, a previous assessment by the central lab during the screening period closest to V1 may be
used.
Note that the baseline of laboratory parameters assessed by central laboratory will be the last non-missing
central assessment the day of or prior to study drug start.
Note that the baseline PBC Worst Itch NRS average will be calculated based on available data within 14 days
prior the day of randomization.
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2.4 Double-Blind period (Week 0 up to Week 104)

Patients who satisfy all eligibility criteria and confirm participation, will be randomized (see section 2.9) in
a 2:1 ratio to one of two treatment groups:
• Elafibranor 80mg
• Placebo
In this DB period, study medication will be administered orally, once daily for up to 24 months. For any
patient, the DB period will last until the last patient completes Visit 6 (W52) or until a maximum of 104
weeks, whichever happens first.
On the first day of the DB period the patient will receive the study drug after all baseline assessments are
completed. During the entire double-blind period, the laboratory assessments (at every visit) will be done
before study drug intake.
participation. During the DB period the patients will return to the site for visits every 13 weeks (±2 weeks)
from the Randomization Visit (V1) to Visit 6 except for the Visit 2 (4 weeks after V1), and if applicable every
26 weeks from Visit 6 to Visit 8 (W104). When the last V5 is performed, any patient between Visit 6 and
Visit 8 should perform a last visit DB (LVDB) within the next 13 weeks. For patients who have not yet had
V6 at the time the last patient completes his/her V5, LVDB will be scheduled at the latest 13 weeks after
the date on which V5 was completed for the last patient. For those patients, LVDB will coincide with V6,
and patients will complete V6 and associated procedures.
Patients who have not yet had V6 completed at the time the last patient completes his/her V5, will complete
LVDB at the next scheduled visit (either V7 or V8) within the next 13 weeks. LVDB will replace V7 or V8. The
same procedures as for V8 will be performed for LVDB (except US exam).
Between V6 and V8, safety contacts will be performed by phone call between on-site visits, every 26 weeks,
to collect information related to AEs, concomitant medications, pregnancy, and study drug compliance. The
first phone safety contact will start 13 weeks after V6 as applicable. Patients will be contacted at least 1
week before each visit to be reminded of procedures and study drug administration.
In order to maintain the blind, ALP, gamma-glutamyltransferase (GGT) and 5’ nucleotidase obtained from
blood samples from V2 to LVDB will be kept in blinded condition during the Double-blind period for each
patient. Any blinded party will not be informed of these values until the database freezing and the Sponsor
authorization to unblind the data at the end of the DB period.
If a patient prematurely discontinues the study drug during the DB period, end of treatment (EOT) DB Visit
should be performed between 16 and 30 days after last drug intake. The follow-up of the patients who
discontinue the drug early will continue until W104, or until the last completed V6 whichever occurs first,
and will complete all visit procedures except liver biopsy and PK (if already done prior to study drug
discontinuation). The study procedures will be assessed as per Table 1 and Table 2. At the scheduled visit
following early discontinuation/termination of the study drug, the date and the reason of the study drug
discontinuation will be collected. In case the EOT visit occurs within the time window of the next scheduled
visit, EOT visit will be performed at the scheduled visit.
Only patients who completed the DB period (excluding patients who permanently stopped the study drug
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during the DB period) will be included into the open label LTE.
2.5 Long-Term extension

The second study period is an open-label LTE. During this LTE period, all patients will receive 80 mg of
Elafibranor for up to 5 years, so that the total duration of study participation for a patient is up to 6 years.
Apart from the first two visits in this LTE period, which will occur over a 13-week interval starting after V6,
V8 or the LVDB, patients will return to the site every 26 weeks (+/-14 days) for procedures listed on Table
1 and Table 2, and safety contacts will be performed by phone call between on-site visits, every alternating
26 weeks (+/-14 days), to collect information related to AEs, concomitant medications, pregnancy, and
study drug compliance. The Investigator may subsequently decide to perform an unscheduled visit.
The statistical analyses of the LTE phase are not within the scope of this SAP and will be described in a
separate SAP. The LTE data will be included in the SDTM domains but will not be part of the ADAM datasets
nor the statistical outputs of the double-blind period.
During the open label LTE, an EOT LTE visit will be performed between 16 to 30 days after the last drug
intake for any patient who discontinue study drug. No further follow-up will be required. The study
procedures will be assessed as per Table 1 and Table 2.
2.6 Clinical event committee (CEC)

The CEC will conduct adjudication of the clinical outcomes and DILI events. The CEC assessment and
adjudication will occur in a blinded (during DB period) and consistent and unbiased manner throughout the
course of the study to determine whether the event meets the protocol specified criteria. The CEC will be
comprised of 3 hepatologists, and all of them will be independent of the conduct of the study.
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Figure 1: Study Design Overview
Footnotes:
The statistical analyses of the Long-
Term Extension period are not
covered in this SAP.
a. If receiving UDCA at randomization, continue throughout studyparticipation
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last completed W52 / V6 (W52),
whichever occurs first
c. The LTE duration is 5 years after end of the DB period or until the patient’s total treatment duration is 6 years, whichever occurs
first
2.7 Optional Visits
2.7.1 Retesting and/or additional screening visits
• If creatine phosphokinase (CPK) value is > 2xULN at SV1, it can be repeated within 1 to 2 weeks,
but prior to V1.
• If HCV Ab test is positive at SV1, a patient’s HCV infection status needs to be confirmed by HCV
RNA testing prior to V1.
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical
Monitors.
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2.7.2 Unscheduled visits
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for safety
reasons or when repeat measurements are required out of the screening period (either to confirm a
measurement or in case of errors, measuring device failure, etc.).
2.8 Exploratory/Ancillary Sub-study

No Exploratory/Ancillary Sub-study is planned.
2.9 Randomization Methodology

Patients who satisfy all eligibility criteria will be randomized in a 2:1 ratio to one of the following groups:
• Placebo
A central randomization system will be used (interactive voice/web response system [IxRS]).
The randomization will be stratified at V1 (randomization/baseline visit = V1) on two factors, collected
during the screening period:
• ALP > 3x ULN or Total bilirubin > ULN: Yes/No, and
• PBC Worst Itch NRS averaged - over the 14 days preceding randomization - ≥ 4: Yes/No.
To ensure inclusion of a relevant ratio of patients with moderate disease or increased risk of progression:
• approximately 10% of the total randomized patients will present with a TB > ULN or Albumin (ALB)
< lower limit of normal (LLN) (definition of moderately advanced patients per Rotterdam
criteria))
and
• approximately 20% of the total randomized patients will present with a TB > 0.6 x ULN.
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2.10 Stopping Rules and Unblinding

An independent Data Safety Monitoring Board (DSMB) composed of relevant experts (an endocrinologist,
cardiologist, hepatologist and nephrologist) experienced in the management of patients with PBC and an
independent biostatistician will oversee the study conduct. The DSMB will be established in order to review
on a regular basis during the study (at least every six months) the progress of the study and the safety of
the treatment in an unblinded manner, to protect patient welfare and preserve study integrity. A first DSMB
will be planned within the first 6 months after First Patient randomized First Visit.
The Chief Medical Officer (CMO) will be responsible for promptly reviewing the DSMB recommendations
and determining whether expedited reporting of any safety issues, amendments to the protocol, or changes
in study conduct are required.
The study blind may be broken for an individual patient only in the case of an emergency when knowledge
of the study drug is essential for the clinical management of the patient. The randomization number
allocated to the patient will allow any unblinded study personnel to identify the treatment group to which
the patient is randomized.
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2.11 Study Procedures

The schedule of assessments, as outlined in the study protocol, is provided in Table 1 and in Table 2.
Table 1: Schedule of Assessments
Double-Blind (DB) If
Study Period Screening applicab Long-term Extension (LTE)
Common DB Variable DB le Safety contact in
variable DB &
S S S LTEl
EOT
Visit number V V V V1 V2 V3 V4 V5 V6 V7 V8 LVDBj LT1 LT2 to LTn EOT-LTEk
1 2 3 DBk
At max. Safety
13 Follow-
weeks up: DB period:
13 LT2 13 Safety
after last 16 to 30 -Week 65
weeks weeks after Follow-up:
V5 for days -Week 91
after LT1 then 16 to 30
Weeks -12 to -2 0 4 13 26 39 52 78 104 the last after last LTE:
last every 26 days after
patient drug - 13 weeks after
DB weeks last study
intake LT2 then every
visit drug intake
26 weeks
Week 65: 456 V6 or

LT2: 91
days V8 or
days after
Days 1 29 92 183 274 365 547 729 NA NA Week 91: 638 LVD NA
LT1 then
days B+
every 182
LTE: 91 d after 91 d
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LT2 then every days up to

182 d 2185
+/- +/- +/- +/- +/- +/-

Tolerances (Days) +/- 7 14 14 14 14 14 14 NA NA +/- 14 +/- 14 +/- 14 NA
STUDY PROCEDURES a
Medical and Disease

History X
Physical Examination
(Height at SV1 only) X X X X X X X X X X X X X X
PRO questionnairesb
PBC Worst Itch NRS Xf
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Week X X X X X
PGIS Xg X X X X X X X X X X X
PROMIS Fatigue Short

Form 7a X X X X X X X X X X X
Transient Elastography
X X X X X X X
(TE) (Fibroscan)
Liver Biopsy (optional) Xh X

X X X X
bladder) c
Hip and lumbar DEXA

X X X
scanning d
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PK Xi
Randomization X
Treatment Assignment e X X
Dispense Study Drug X X X X X X X X Xm
Study Drug
Accountability/Compliance X X X X X X X X X X X
Footnotes:
a. Procedures/assessments should be conducted in the following order during study visits: PROs (when completed at the study center), investigator assessments, safety and
laboratory assessments, administration of study drug
b. Refer to Table 3 (Schedule of PRO Questionnaires) for details
c. At baseline, US exam can be performed before randomization after the patient has been otherwise confirmed as eligible and up to randomization visit. Ultrasound exam to
be performed every year and for any visit post baseline US exam can be performed with a tolerance of +/ 7 days around the planned visit date.
d. Hip and lumbar DEXA scanning to be performed in all patients where the exam is accessible to sites at baseline, at V6, and then 2 years later. At baseline, the exam can be
performed before randomization after the patient has been otherwise confirmed as eligible and up to randomization visit. For exam post baseline, DEXA exam can be
performed with a tolerance of +/ 7 days around the planned visitdate.
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e. The switch to elafibranor treatment will happen either at V8 or at LVDB (either V7 or V8, depending on when the last patient in the study completes his/her V5).
f. During the screening period and DB period up to week 52 (V6), the PBC Worst Itch NRS score will be collected every evening via an eDiary. The mean score of the 14 days
prior to randomization (V1) will be used for stratification. Patients must have at least 4 available values for PBC Worst Itch NRS during each of the 7-day intervals in the 14-
day intervals prior to V1, for a total of at least 8 values in the 14 days prior to V1.
g. Patient Global Impression of Severity (PGIS) will be collected at SV1 only during the screening period.
h. For patients who have consented to have liver biopsy samples collected, Liver biopsy at inclusion to be done at any SV preferably in patients already confirmed as eligible
and if at all possible 2 to 4 weeks prior to randomization. LB at week 52 can be performed with a tolerance of +/- 2 weeks around the planned visit V6.
i. PK assessment will include the following timepoints: pre-dose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h.
j. Until the last patient in the study completes his/her V5, patients between V6 and V8, will complete LVDB according to Table 1 General Assessment Schedule. After the last
patient in the study completes his/her V5, patients between V6 and V8, will complete LVDB at the next scheduled visit (either V7 or V8). LVDB will replace V7 or V8. The
same procedures as for V8 will be performed for LVDB (except US exam). For patients who have not yet had V6 at the time the last patient completes his/her V5, LVDB will
be scheduled at the latest 13 weeks after the date on which V5 was completed for the last patient. For those patients, LVDB will coincide with V6, and patients will complete
V6 and associated procedures to facilitate transition to the open-label elafibranor treatment phase in the long-term extension study, in a timely manner.
k. Safety contact by phone call every alternating 26 weeks starting 13 weeks after V6 in the DB period and starting after LT2 during LTE to check AEs and concomitant
medications
l. If premature study drug discontinuation during DB period, EOT DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue in the
study until V8, or until the last completed V6 whichever occurs first. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces
the scheduled visit. If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake
m. Drug dispensation will be done up to LT10. There will be no drug dispensation at LT11
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Table 2: Schedule of Biological Assessments
Double-Blind (DB)
If
applicable
Visit number SV1 SV2 SV3 V1 V2 V3 V4 V5 V6 V7 V8 LVDB EOT DBi LT1 LT2 to LTn EOT-LTEb
At max. Safety
13 Follow- 13
weeks up: weeks
after last 16 to 30 after Safety Follow-
last LT2 13 weeks up: 16 to 30 days
Weeks -12 to -2 0 4 13 26 39 52 78 104 V5 for days after after LT1 then
the last last drug DB after last study
visit every 26 weeks drug intake
patient intake
V6 or LT2: 91 days
Days 1 29 92 183 274 365 547 729 NA NA V8 or after LT1 then NA
LVDB every 182 days
+ 91 d up to 2185
+/- +/- +/- +/- +/- +/- +/-

7 14 14 14 14 14 14
Serum Hematology
Hemoglobin, hematocrit, WBC with X X X X X X X X X X X X X X
differential, platelet count, prothrombin
time (Pt), INR, reticulocytes/RBC
Screening Serum Chemistry a X
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ALP, ALT, AST, GGT, CPK, total and

conjugated bilirubin, albumin, creatinine,
sodium, AFP, eGFR (MDRD formula &
CKD-EPI formula), MELD-Na
Screening serum hCG pregnancy test b X
Serum Chemistry
Sodium, potassium, chloride, calcium,
albumin, BUN, creatinine, TB,
conjugated bilirubin, AST, ALT, ALP, X X X X X X X X X X X X X
GGT, 5’ NT, total proteins, lipase,
amylase, TC, LDL-C, HDL-C, VLDL-C,
TG, CPK, FPG, eGFR, MELD-Na
Serology
X
HIV Ab I/II, Anti- HAV IgM, HBs, HCV
Serum Bile Acids and Biomarkers of
Bile Acid Synthesis
Bile acids (cholic acid (CA), glycocholic
acid (GCA), taurocholic acid (TCA),
chenodeoxycholic acid (CDCA),
glycochenodeoxycholic acid (GCDCA),
taurochenodeoxycholic acid (TCDCA), X X X X X X X
deoxycholic acid (DCA), glycodeoxycholic
acid (GDCA), taurodeoxycholic acid
(TDCA), lithocholic acid (LCA),
glycolithocholic acid (GLCA),
taurolithocholic acid (TLCA)), C4, FGF-
19
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Biomarkers of Hepatic Fibrosis

and/or Inflammation
HsCRP, fibrinogen, haptoglobin, TNF-α, X X X X X X X
IL-6, ELF (HA, PIINP, TIMP-1), PAI-1,
TGF-β, CK-18 (M65 and M30), Pro-C3
X X X X X X X X X
Cystatin C, urine albumin to creatinine
ratio (urine ACR), AFP c
Immunoglobulins
X X X X X X X
IgG, IgM
Serum Bone markers d
CTX, P1NP X X X X
Urinalysis (dipstick)e
Specific gravity, pH, protein, glucose, X X X X X X X X X X X X X X
ketones, bilirubin, urobilinogen, blood,
nitrite, leukocytes
gonadotropin (hCG) Pregnancy Test f
urinary myoglobin, serum IgG and
X X X X X X X X X X X X X
SMA g
Biobank (optional) h X X X X X X X
Footnotes:
a. Repeated measured for AST, ALT, ALP and TB to be collected (See section 2.2).
b. Serum pregnancy test must be performed at screening in all females of childbearing potential and may be repeated within one month prior to randomization in case the
screening period lasts more than 4 weeks.
c. AFP to be valuated at V1, V6, and then everyyear, as well as at LVDB, if applicable.
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d. Serum bone markers to be assessed at baseline, week 13, week 26, and week 52
e. Microscopic evaluation will be performed if dipstick urinalysis indicated presence of any significant abnormality.
f. In all females of childbearing potential, urine-based β-hCG pregnancy tests at any site visits from V1. In between site visits, a home pregnancy test is to be performed every 4
weeks, starting after V1. If the urine-based test is positive, a confirmatory serum pregnancy test must be performed at site.
g. Assessment of presence of myoglobin in urine to be done locally only in case of clinically significant CPK elevation; assessment of IgG and SMA to be done locally in case of
suspicion of AIH
h. Additional blood samples will be collected from patients, who have given their consent, to be used to discover or validate biomarkers in PBC and related diseases.
i. If premature study drug discontinuation during double-blind period, EOT DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue
in the study until V8. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. If premature study drug
discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake.
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Table 3: Schedule of Patient Reported Outcomes Questionnaires
Platform Assessment Frequency and Duration of Assessment Time of

assessment
eDiary PBC Worst Itch NRS Once daily during screeninga and the Common DB period (up to V6) Evening
eTablet PBC Worst Itch NRS Past Week Throughout the Variable DB and LTE periods During study
visitb
eTablet PGIC Throughout the DB (starting at V2) and LTE periods During study
visitb
eTablet PGIS Throughout the screening, DB, and LTE periods During study
visitb
eTablet 5-D Itch Throughout the DB and LTE periods During study
visitb
eTablet PROMIS Fatigue Short Form 7a Throughout the DB and LTE periods During study
visitb
eTablet ESS Throughout the DB and LTE periods During study
visitb
eTablet PBC-40 Throughout the DB and LTE periods During study
visitb
eTablet EQ-5D-5L Throughout the DB and LTE periods During study
visitb
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Footnotes:
a. The mean PBC Worst Itch NRS score of the 14 days prior to randomization (V1) will be used for stratification. Patients must have at least 4 available values for PBC
Worst Itch NRS during each of the 7 day intervals in the 14 days prior to V1, for a total of at least 8 values in the 14 days prior to V1.
b. Administered on site.
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2.12 Efficacy, Pharmacokinetic, and Safety Variables
2.12.1 Efficacy Variables

The efficacy of Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated considering
Primary endpoint:
ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52 (binary).
Furthermore, the following variables will be considered for the evaluation of efficacy:
Three key secondary endpoints:

• Response to treatment based on ALP normalization at week 52 (binary).
• Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with baseline
PBC Worst Itch NRS score ≥4 (continuous).
• Change in pruritus from baseline through week 24 on PBC Worst Itch NRS in patients with baseline
PBC Worst Itch NRS score ≥4 (continuous).

o Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks (continuous)
o ALP response definedas 10%, 20% and 40% ALP reduction from baseline at week 52 (binary)
o Response to treatment at week 52 according to (all binary):
a) ALP < 1.5x ULN, ALP decrease from baseline ≥ 40% and TB ≤ ULN
b) ALP < 3x ULN, AST < 2x ULN and TB < 1mg/dL (Paris I)
c) ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II)
d) TB response rate of 15% change from baseline
e) Normalization of abnormal TB (TB ≤ ULN) and/or ALB (ALB ≥ LLN) (Rotterdam)
f) TB ≤ 0.6x ULN
g) ALP ≤ 1.67x ULN and TB ≤ 1mg/dL (Momah/Lindor criterion, 2011)
h) No worsening of TB defined as level of TB < ULN or no increase from baseline of more than 0.1x
ULN
i) Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin, and INR
o PBC risk scores at week 52: UK PBC score (Carbone_et_al_2016) and GLOBE score (a risk score to
predict transplantation-free survival at 5, 10 and 15 years. (Lammers_et_al_2015))
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o Response to treatment based on the normalization of bilirubin (TB ≤ ULN) at week 52 (binary)
o Response to treatment based on the normalization of albumin (ALB ≥ LLN) at week 52 (binary)
o Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST,
(continuous)
o Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP,
o Change from baseline to week 52 in immune response as measured by IgG and IgM (continuous)
o Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis as
measured by ELF test (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver
stiffness measured by Transient Elastography (continuous)
o Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated
VLDL-C and TG (continuous)
o Change from baseline to week 52 in Fasting Plasma Glucose (continuous)
o Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured
by bile acids, C4 and FGF-19 (continuous)
o Proportion of responders in PBC Worst Itch NRS according to clinically meaningful change; at least
30% reduction; and one point, two points or three points decrease in score from baseline through
week 52 and through week 24 in patients with a baseline NRS score ≥ 4 (binary)
o Proportion of participants achieving sustained improvement in PBC Worst Itch NRS as defined as
having responses for all the last three 4-week periods (periods 11, 12 and 13) according to clinically
meaningful change; at least 30% reduction; and one point, two points or three points decrease in
score from baseline in patients with a baseline NRS score ≥ 4 (binary)
o Proportion of patients with no worsening of pruritus from baseline through week 52 and through
week 24 as measured by the PBC Worst Itch NRS (binary)
o Change from baseline to week 52 in 5D-Itch (continuous)
o Change from baseline to week 52 in PROMIS Fatigue Short Form 7a(continuous)
o Change from baseline to week 52 in ESS (continuous)
o Change from baseline to week 52 in PBC-40 (continuous)
o Change from baseline to week 52 in health utility as measured by the EQ-5D-5L(continuous)
o Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density
(hip and lumbar) assessed by DEXA scanning (continuous)
o Onset of clinical outcomes, described as a composite endpoint (binary) composedof:
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a) MELD-Na > 14 for patients with baseline MELD-Na < 12

b) Liver transplant
i) Variceal bleed
ii) Hepatic encephalopathy defined as West-Haven/Conn score of 2 or more
iii) Spontaneous bacterial peritonitis
e) Death
2.12.2 Pharmacokinetic Variables
The statistical considerations applicable to the popPK modeling, including the definition of the PK
population and the description of the statistical analyses, will be fully described in a dedicated Analysis Plan
(popPK SAP).
2.12.3 Safety Variables
The safety and tolerability profiles of Elafibranor (80mg/day) will be assessed from the recordings of:
a) Serious adverse events (SAEs), adverse events (AEs), and adverse events of special interest
(AESIs),
b) Physical examination findings, vital signs (including weight), medical history, 12-lead
Electrocardiogram (ECG), ultrasound examination of liver and bladder/urinary tract,
c) Serum chemistry (Sodium, potassium, chloride, calcium, ALB, BUN, creatinine, fasting
plasma glucose, total proteins, lipase, amylase, TC, LDL-C, HDL-C, VLDL-C, TG, CPK, eGFR,
MELD-Na) and hematology (Hemoglobin, hematocrit, WBC with differential, platelet count,
PT),
d) Hepatobiliary injury and liver function markers AST, ALT, GGT, 5’ NT, total and conjugated
bilirubin, ALB, International normalized ratio (INR) and ALP fractionated (hepatic),
e) Renal biomarkers (including urinalysis: Specific gravity, pH, protein, glucose, ketones,
bilirubin, urobilinogen, blood, nitrite, leukocytes), and
f) Other biochemical safety markers (Cystatin C, urine ACR, urinary myoglobin) and biomarkers
of inflammation (HsCRP, fibrinogen, haptoglobin, TNF-α, IL-6, ELF test (HA, PIINP, TIMP-1),
PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3).
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The planned statistical analyses related to the open label LTE period are not within the scope of this SAP
and will be described in a separate SAP.
2.12.4 Exploratory Variables (related to histological assessment):

f) Other exploratory scores (Fibrosis according to Ishak scoring, Portal inflammation, Ductular reaction,
Cholestasis, Concentric periductal fibrosis)
2) Correlation between histological fibrosis scores (Nakanuma and Ishak scores) and non-invasive
markers of fibrosis (Liver stiffness, ELF test, ProC3)
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3. SUBJECT POPULATIONS
3.1 Population Definitions
The following patient populations will be used for the analysis and the presentation of the data:
Screened Analysis Set: All patients who sign informed consent. This population will be used to summarize
disposition.
Intent-to-treat (ITT) Analysis Set: All randomized patients. Patients will be analyzed according to
randomized treatment.
Pruritus ITT Analysis Set: All patients from the ITT analysis set with baseline PBC Worst Itch NRS score ≥4.
Per Protocol (PP) Analysis Set: All patients from the ITT population without any major protocol deviation
or event affecting the primary efficacy endpoint (see section 3.2).
Pruritus PP Analysis Set: All patients from the Pruritus ITT analysis set without any major protocol deviation
or event affecting the primary efficacy endpoint and/or the second and third key secondary endpoint.
Safety Analysis Set: All patients who were administered at least one dose of DB study drug irrespective of
the treatment received. Patients will be analyzed according to the treatment received. Patients who
received any amount of active treatment, even by mistake and for one intake, will be assigned to the active
treatment group.
Pharmacokinetics Analysis Set (PKS): All patients who were administered at least one dose of Elafibranor
and have at least one post-dose PK sample. Patients of the PKS must have data for time of dosing, time of
sampling and amount of product administered. Whereas all patients are sampled in order to maintain the
blind, the PKS will only include patients under Elafibranor.
Exploratory (Histological) Analysis Set: All patients from the ITT population who consent to have liver
biopsy samples collected at baseline and/or week 52. Patients will be analyzed according to randomized
treatment.
The primary and first key secondary efficacy analyses will be performed primarily on the ITT analysis set,
while only the main analyses of the primary and first key secondary endpoints will be replicated on the PP
analysis set.
The second and third key secondary analyses will be performed primarily on the pruritus ITT analysis set,
while only the main analyses of the second and third key secondary endpoints will be replicated on the
pruritus PP analysis set.
Each efficacy endpoint will be evaluated up to week 52. For patients who completed additional visits during
the DB period, descriptive statistics will be presented up to the end of the DB period.
The Safety Set will be typically the primary analysis set for the analysis of safety endpoints.
The Exploratory Analysis Set will be used to describe and perform the analyses on histological findings and
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correlation with non- invasive markers of fibrosis.

If both ITT and safety analysis sets are the same, meaning that all randomized patients have taken at least
one study treatment dose and none are reallocated to a different treatment group compared to
randomization, the replicated analysis planned on safety analysis set for demographics, screening and
baseline characteristics will not be done.
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3.2 Protocol Deviations

All protocol deviations will be entered in a Risk and Issue Management System (RIM) and managed
according to the Protocol Deviation Plan (PDP). They will be classified as non-important or important based
on their effect on the rights, safety, or well-being of the patients and/or the quality and integrity of the
data, and the final rating of all deviations will be confirmed on a case-by-case basis and prior to database
lock (DBL). Important deviations do not necessarily lead to the exclusion from the PP population. Some
examples of protocol deviations are given below:
• Protocol deviations related to Inclusion/Exclusion criteria (ineligible patient randomized to the study)
• Randomization/drug dispensation errors (incorrect kit dispensed to apatient)
• Treatment compliance less than 80% or greater than 120% from baseline to Week 52
• Any other protocol deviations that may affect patient safety, data integrity, or future conduct of the
study.
The sponsor, or designee, will be responsible for producing the final protocol deviations file (formatted as
a Microsoft Excel file), in collaboration with Cytel and the data monitoring group as applicable, and for
determining in a blinded way what kind of deviations will require the corresponding data to be excluded
from the PP population according to the Per Protocol Set Plan.
This file will include a description of the protocol deviation, and clearly identify whether this deviation
warrants exclusion from the PP/pruritus PP populations or not. This file will be finalized as well as the list
of events that exclude from PP/pruritus PP (according to the Per protocol set definition plan) prior to hard
database lock at the end of the DB period and completed prior to the DB hard database lock for the primary
endpoint analysis.
No update will be allowed after the DB database lock on the data collected up to the Last Patient Last Visit
performed during DB period (V6/V8/LVDB, Safety Follow-up 16-30 days after last dose of study drug).
All protocol deviations will be presented in data listings. All important deviations and deviations that lead
to the exclusion from the PP population will be summarized in a table.
Note: Major/Minor and Important/Non-important have been used interchangeably in the study capturing
the exact same notion.
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4. STATISTICAL METHODS
4.1 Sample Size Justification

study supporting the regulatory approval of OCA (Ocaliva) (10%) (Nevens, 2016),
• an expected response rate in the Elafibranor group at least similar to OCA (47%).
The response rates from the phase 3 pivotal study supporting the regulatory approval of OCA have been
estimated after imputation of missing data as non-response.
One hundred and fifty patients (100 Elafibranor vs 50 placebo) allow to achieve at least 90% power to
demonstrate a statistically significant between group difference of 35% (47% in Elafibranor group vs 12% in
Assuming 1/50 (2.0%) patients in the placebo arm with ALP normalization at week 52 (first key secondary
endpoint), 150 patients (100 Elafibranor vs 50 placebo) provide at least 80% power to detect a statistically
significant between group difference of 20.0% at a two-sided 0.05 alpha level.
Assuming a pooled standard deviation of 2.3 points, 60 patients (40 Elafibranor vs 20 placebo) with baseline
PBC Worst Itch NRS score ≥4 provide approximately 80% power to detect a statistically significant between
group difference of 1.8 points in mean change from baseline in PBC worst itch NRS score (second key
secondary endpoint) at a two-sided 0.05 alpha level. It is assumed that the same assumptions would apply
to the two key secondary endpoints for pruritus (through week 52 and through week 24).
4.2 General Statistical Methods and Data Handling
4.2.1 General Methods
All output will be incorporated into Rich Text Format (RTF) files, sorted and labeled according to the
International Conference on Harmonization (ICH) recommendations, and formatted to the appropriate
page size(s).
Statistical methods will focus on summarizing the data collected using appropriate graphical and tabular
presentations and on generation of inferential summaries.
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety parameters.
For measurements of continuous endpoints, summary statistics of absolute values and absolute/relative
changes from baseline, where appropriate, will be summarized and will include n, mean, standard
deviation, median, 25th percentile - 75th percentile (Q1-Q3), and minimum and maximum values. The
number of missing values will be displayed in parenthesis next to ‘n’. Mean, standard deviation, median,
Q1 and Q3 will be presented with one more decimal place compared to the raw data, and minimum and
maximum will be presented with the same number of decimal places as the raw data.
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For categorical variables, summary tabulations of the number and percentage within each category of the
parameter will be presented (as well as the number for missing data). The total number of non- missing
patients will be used as the denominator. Percentages will be rounded to one decimal place. Therefore,
there may be cases where for instance the total of the percentages does not exactly equal 100%. Where
applicable confidence intervals (95% CI for primary, key secondary endpoints and for all other secondary
endpoints, 2-sided) will be presented, and they will be shown with 1 decimal place for percentages, and
with 2 decimal places for continuous measures.
Formal statistical hypothesis testing will be performed on the primary and key secondary efficacy
endpoints, with all tests conducted at the 2-sided, 0.05 level of significance. The fixed-sequence testing
approach will be used to control the overall type I error rate at a two-sided 0.05 level. Summary statistics
will be presented, as well as CIs on selected parameters, as described in the sections below.
The fixed-sequence testing approach implies that if the primary endpoint is statistically significant at a two-
sided 0.05 level, the first key secondary endpoint (ALP normalization) will be tested at the same level. If the
first key secondary endpoint is statistically significant at a two-sided 0.05 level, the second key secondary
endpoint (change in pruritus through week 52) will be tested at the same level. If the second key secondary
endpoint is statistically significant at a two-sided 0.05 level, the third key secondary endpoint (change in
pruritus through week 24) will be tested at the same level. If the primary endpoint is NOT statistically
significant, none of the key secondary endpoints will be tested. If the primary endpoint is statistically
significant and the first key secondary endpoint is NOT statistically significant, the second and third key
secondary endpoints will not be tested. Finally, if the second key secondary endpoint is NOT statistically
significant, the third key secondary endpoint will not be tested.
Statistical testing for other secondary endpoints will be of exploratory nature and will be performed at the
two-sided 0.05 level of significance.
All summarized data will be listed in addition to the analyses and summaries described below.
Analyses described in this SAP will be dependent on the availability of the data collected. Additional
exploratory analyses may be performed as well as those described below, if suggested by inspection of the
final database.
4.2.2 Data Conventions
In the context of this SAP, we will consider 4 periods (max. 12 weeks screening, max. 104 weeks DB, max.
260 weeks LTE, 4 weeks follow-up; only the statistical analyses of the first two periods are detailed in this
SAP):
1) Screening period, defined as the period prior to Study Visit 1 (before first study drug dispensation),
which could last from 2 to 12 weeks.
2) Double-blind treatment period of the study, defined as the time between Study Visit 1 (first study drug
dispensation) and the last completed week 52 (V6) or a maximum of 104 weeks DB period, whichever
happens first.
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The double-blind period includes the screening period and the double-blind treatment period, and its start
date will be the first screening visit date.
The double-blind period end date will be derived according to the patient status at the time of database
lock:
– if the patient discontinued the study treatment or the study, it will be the last available date from all
domains or the death date.
– For other patients for whom rollover to long-term extension period is assumed:
o if patient doesn’t have first intake date of long-term extension period then it will be the last double-
blind visit date;
o if patient has first intake date of long-term extension period then it will be the maximum date of the
first intake date of long-term extension period -1 and the last double-blind visit date.
Note that the last double-blind visit date is the maximum of the last visit date including visit 6, visit 7, visit 8,
and last visit double-blind.
3) Long-term extension period of the study, defined as the time between the Week 52/LVDB/week 104
visit and the Week 312 visit (max. 260 weeks for the LTEperiod)
4) Follow-up period, defined as the period beyond the Week 312 visit or beyond the study treatment
discontinuation happening during LTE period (follow-up period allowing 4 weeks for safety follow-up).
The study period will end after approximately 6 years from SV1, but this SAP only provides the details for
the DB (12 weeks of screening and up to 104 weeks of DB period) analyses.
The week 0 Visit 1 (V1) is defined as the first treatment visit, where the patient is randomized and given the
study Treatment carton (kit) for the first time.
Treatment day 1 is defined as the date of first study drug intake of any of the following study drugs: Placebo
or Elafibranor 80mg.
The EOT DB visit (in case of study drug discontinuation during the DB period), is defined as the safety visit
date recorded during Double-blind period.
Either the V6, LVDB, V7 or V8 can be defined as the latest visit date recorded during Double-blind period.
The Week 312 visit (LT9/LT10/LT11) is defined as the latest date from any panel of Long-term extension
period.
The EOT LTE visit date is defined as the last recorded visit date from any panel of the Follow-up period.
The following conversion factors will be used to convert days to months or years, or Fahrenheit to Celsius,
where applicable:
• 1 month = 30.4375 days
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• 1 year = 365.25 days

• 1 week = 7 days
• °C = (°F - 32)/1.8.
Additional data handling rules are as follows:
• Age (years) = (date of informed consent – date of birth + 1) / 365.25, rounded to the lowest whole
number.
• Weight values recorded in pounds will be converted to kilograms using the following formula:
kilograms = pounds/2.2046.
• Height values recorded in inches will be converted to centimeters using the following formula:
centimeters = inches*2.54.
• Duration on study (weeks) = (Last visit date – randomization date + 1) / 7.
• Duration on treatment (weeks) = (Last study drug intake date – first study drug intake date + 1
– days of treatment interruption) / 7.
• Duration of exposure (weeks) = (Last study drug intake date – first study drug intake date + 1) /
7.
• (Absolute) Change from baseline = Value at the time point – Baselinevalue.
• Relative change from baseline = [(Value at the time point – Baseline value) / Baseline value] x 100.
As a general rule of thumb, each laboratory value below/above the limit of quantification will be imputed
numerically by the limit of quantification.
4.2.3 Computing Environment
All descriptive statistical analyses will be performed using SAS statistical software version 9.4. Medical
history, Adverse Events and Procedures will be coded using version 26.0 of the Medical Dictionary for
Regulatory Activities (MedDRA). Concomitant medications will be coded in the same way using World
Health Organization (WHO) Drug dictionary version B3 WHO Drug global March 2023.
4.2.4 Methods of Pooling Data
N/A.
4.2.5 Adjustments for Covariates
The randomization will be stratified across two factors: (ALP > 3x ULN or total bilirubin > ULN (Yes/No) and
PBC Worst Itch NRS score averaged - over the 14 days preceding baseline - value ≥ 4) (Yes/No) at baseline
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(V1) (see section 2.9).

All the categorical endpoints will be analyzed using the exact Cochran-Mantel-Haenszel (CMH) test
stratified by the randomization factors.
The sensitivity analysis to the statistical model (see section 4.6.2.2) performed on the primary endpoint and
the first key secondary endpoint will be analyzed using an exact logistic regression model stratified by
randomization strata with treatment group as factor, on both ITT and PP populations.
The continuous endpoints will be compared between treatment groups using the Mixed effect Model for
Repeated Measurement (MMRM), including the treatment indicator, visit and stratification factors as fixed
factors, interaction of treatment and visit and the respective baseline value as covariate.
4.2.6 Multiple Comparisons/Multiplicity
Multiplicity will be dealt with through the Fixed-sequence Testing Procedure that implies a pre- specified
sequence of hypotheses testing. In this study the first key secondary endpoint will only be tested if the
primary endpoint is statistically significant, the second key secondary endpoint (change in pruritus through
week 52) will only be tested if the first key secondary endpoint is statistically significant and the third key
secondary endpoint (change in pruritus through week 24) will only be tested if the second key secondary
endpoint is statistically significant (see section 4.2.1).
4.2.7 Subpopulations
Exploratory analyses of the primary endpoint (ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from
baseline ≥ 15% at week 52) and the three key secondary endpoints (Response to treatment based on ALP
normalization at week 52 and Change from baseline through week 52 and through week 24 in PBC Worst
Itch NRS) will be done for the following subgroups:
• Age at randomization (< 65 years, >= 65 years)
• Sex (Female, Male)
• Race (White, Others defined by American Indian or Alaska Native, Asian, Black or African American,
Native Hawaiian or Other Pacific Islander or Others))
• ALP level at baseline > 3x ULN (Yes/No)
• TB at baseline > ULN (Yes/No)
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• Geographic region: Europe, North America, Latin America, Other (including Turkey and South
Africa)
• ALP > 3x ULN or TB > ULN at baseline (Yes/No). In case of mis-stratification during the
randomization, the true screening value will be used.
• PBC Worst Itch NRS score ≥ 4 at baseline (averaged over the 14 days preceding randomization)
(Yes/No). In case of mis-stratification during the randomization, the true screening value will
be used.
• Cirrhotic defined by Liver stiffness at baseline ≥ 16.9 KPa at Fibroscan exam (Yes/No) and/or
bridging fibrosis or cirrhosis on histology
4.2.8 Withdrawals, Dropouts, Loss to Follow-up
Discontinued patients who received the study drug are not to be replaced.
Over the DB period, follow-up of the patients who discontinue early the study drug will continue until the
end of the DB period (V8 or until last V6 performed). The study procedures will be assessed as per Table 1
and Table 2.
To limit the occurrence of intercurrent events (ICEs) such as study treatment discontinuations and/or use
of rescue medication such as OCA, the treatment allocation as well as values of ALP, GGT and 5’NT will
remain blinded for the Investigator and for the patient up to the DB database lock.
Rescue therapy for PBC and Pruritus will be identified during the Blind Data Review Meetings (BDRM). Use
of PBC rescue therapies and pruritus rescue therapies will be handled as ICE for the primary endpoint, first
key secondary endpoint, and second and third key secondary endpoints respectively. The final list will be
provided and approved at the last BDRM (i.e. before unblinding).
4.2.9 Missing, Unused, and Spurious Data
The patient's outcomes will be considered censored at the time of an ICE (study treatment discontinuation
or use of rescue therapy) and any data observed one day or more after the occurrence of this event will be
considered according to the estimand strategy for the main, sensitivity and supplementary analyses.
However, these data will be included and flagged in any efficacy data listings. For any descriptive summary
of efficacy (including the primary, the key secondary endpoints and all other secondary endpoints), these
data will be described as collected.
In the summary tables of the safety data (laboratory, vital signs (including weight), physical examination,
and ECG), any data observed more than 30 days after the last dose of study treatment intake for patients
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who discontinued study treatment will be handled as missing data. However, this data will be included and
flagged in any safety data listings.
For all the binary/categorical efficacy endpoints (including the primary endpoint, the first key secondary
endpoint and all other binary secondary endpoints), the patient’s outcome after the occurrence of an ICE
(study treatment discontinuation or use of rescue therapy) will be considered as non-responders in a
composite strategy for the main analysis. For the primary and key secondary endpoints, missing data at
week 52 (i.e. visit 6) for patients without ICE will be replaced by the closest non-missing assessment from
the DB treatment period for the main analysis, or patients will be considered as non-responders for the first
supplementary analysis. In addition, for the primary and the first key secondary (ALP normalization)
endpoints, three supplementary analyses will be performed using relevant multiple imputation methods
(see section4.6.2.3.1 The first one will be Missing at Random (MAR) multiple imputation to impute values
as if patients would follow their initial treatment. A second one will impute values using the information
from the placebo group. The third one will be a tipping point analysis to explore several scenarios about
the missing outcomes. A fourth supplementary analysis will use outcome post ICE values through week 52
regardless of treatment discontinuation or use of rescue therapy. Finally supplementary analyses will be
performed to evaluate the impact of COVID-19 pandemic.
For continuous endpoints, the patient’s outcome after the occurrence of an ICE (study treatment
discontinuation or use of rescue therapy) will be considered as missing for the main analysis. Missing values
for continuous efficacy endpoints with repeated measurements will be handled within the analysis itself via
a MMRM with the assumption that the model specification will be correct, and that the data will be MAR.
In addition, for the second and third key secondary criteria, a tipping point analysis to explore several
scenarios about the missing outcomes, a supplementary analysis using post ICE outcome values regardless
of treatment discontinuation or use of rescue therapy, and a supplementary analysis to evaluate the impact
of COVID-19 pandemic will be performed in a similar way than described in sections 4.6.2.3.1, 4.6.2.3.3 and
4.6.2.3.4, respectively, with appropriate modifications.
Unless otherwise specified, there will be no substitutions made to accommodate missing data points.
All data recorded during the DB period in the electronic Case Report Form (eCRF) or provided by external data
transfer (ePRO and Central Laboratory data) will be included in data listings that will accompany the CSR.
Imputation of missing/partial AE dates will be done only to identify treatment-emergent AEs (TEAEs).
AE onset dates
• Partially missing onset dates will be imputed as follows:
o When only Day is missing:
 If Month & Year of the onset date are the same as Month & Year of the first
administration date, the imputed onset date will be imputed as the minimum of
the first administration date and the AE resolution date (imputed if needed).
 Otherwise, the missing day will be replaced by “1.”
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o When Day & Month are missing:

 If Year of the onset date is the same as Year of the first administration date, the
imputed onset date will be imputed as the minimum of the first administration
date and the AE end date (imputed if needed).
 Otherwise, the missing Day & Month will be replaced by “01 JAN.”
• Completely missing onset dates for AEs will be imputed by the first administration date and the AE
will be considered as treatment-emergent, unless the end date of the AE (imputed if needed) or the
end year of the AE (if day and month are missing) is entered and is before the first administration
date. If the end date is before the first administration date, the AE will not be considered as
treatment-emergent and onset date of AE will be imputed by the end date of AE.
AE end dates
• If Day only is missing, incomplete end dates will be replaced by the last day of the month if it is
not resulting in a date later than the date of the patient's death. In the latter case, the date of
death will be used to impute the incomplete end date.
• If Day & Month are missing, Day & Month will be replaced by 31DEC if it is not resulting in a date
later than the date of the patient's death. In the latter case, the date of death will be used to
impute the incomplete end date.
• In all other cases the incomplete end date will not be imputed.
• If after imputation, the imputed AE start date is after the AE end date, the imputed AE start date
will be replaced by the AE end date.
Treatment-emergent flag is defined according to the study treatment administered.
Treatment-emergent is defined as:
• All events which started after the first study treatment dose intake* (all episodes with start after
or on (≥) the first study treatment dose intake) up to 30 days after the last study treatment dose
intake (episodes with start before or on (≤) the last study treatment dose intake + 30 days) for
the patients that discontinue the study treatment during DB period, and up to the date of the
last DB data collection for the patients that complete DB period and switch in LTE, respectively.
• Or as all events which started before the first study treatment dose intake and worsened or
became serious after or on the first study treatment dose intake (in case of multiple episodes of
the same event before the first study treatment dose intake, the severity of the episode closest
to the first study treatment dose intake will be considered) up to 30 days after the last study
treatment dose intake for the patients that discontinue the study treatment during DB period,
and up to the date of the last DB data collection for the patients that complete DB period and
switch in LTE, respectively.
In case of missing severity, the emergence of AEs will be determined as shown in Table 4.
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Table 4: Missing Severity and Definition of Treatment-emergent
Severity
Closest episode before Episode(s) after* the Adverse event considered as
the first study treatment first study treatment
dose intake dose intake (included)
Missing Missing  Emergent
Missing Mild  Emergent
Missing Moderate  Emergent
Missing Severe  Emergent
Mild Missing  Emergent
Moderate Missing  Emergent
Severe Missing  Non emergent
Concomitant medication and procedure dates imputation:

The same rules as for start and end dates of adverse events will be applied for partially or completely
missing concomitant medications and procedures dates.
4.2.10 Visit Windows
For all analyses, the visit dates as collected in the eCRF will be used. However, the visits will be checked for
accuracy according to protocol-specified intervals (Table 5) and sensitivity analyses may be deemed
necessary considering this derivation, in particular for Week 52 comparative analyses.
For all efficacy and safety laboratory endpoints (from central laboratory), if the results are not available at
the scheduled visit, then results from the closest unscheduled visit will be used if within the visit window
and if still in DB treatment period.
Table 5: Evaluation Intervals for Efficacy and Safety Analysis
Evaluation Protocol-Specified Interval

Screening Day -84 to day -14
Baseline (V1) 1 Day 1
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LVDB Within 91 days after last V5 (of the last patient) performed
Safety Contact – DB period Day 456 and day 638 (±14 days)
Long term visit 1 (LT1) 91 days after V6/V8/LVDB (±14 days)
Long term visit 2 (LT2) 91 days after LT1 (±14 days)
Safety Contact – LTE period Every 182 days, starting 91 days after LT2 (±14 days)
LT3 to LT11 Every 182 days, starting 182 days after LT2 (±14 days)
EOT/end of study (EOS) – Safety 16 to 30 days after last study drug intake
follow- up
1 Baseline value: Last non-missing assessment prior to first study drug intake
4.2.11 Data Derivation
PBC Worst Itch NRS average at Baseline will be calculated based on available data within 14 days prior the
day of randomization (baseline period). The 4-week period post-baseline averages will be calculated based
on available data every 28 days after the day of first study drug intake. The following formula for the PBC
Worst Itch NRS average will be used:
[Sum (efficacy endpoint data during the period)/Number of Days with assessments recorded during
the period]
For the baseline value, patients must have at least 4 values of the PBC Worst Itch NRS score during each of
the two 7-day intervals prior to the day of randomization, otherwise the baseline value is considered as
missing.
The 4-week period post baseline average NRS score will be calculated as follows:
- For a full 4-week period, at least 3 weeks out of 4 weeks complying with the rule of 4 out of 7 daily NRS
score assessed and no less than 14 out of 28 daily (at least 50% of expected daily data) assessments of
the full period will induce computation of the average 4-week period NRS score, otherwise, the average
NRS score will be considered missing.
- For the last period (13th period) which is truncated by design, the rule will be flexible based on the
number of expected weeks (2 to 4 weeks):
o If two or three weeks are expected: each week has to be compliant with the rule of 4 out 7 daily
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NRS score,
o If four weeks are expected: same rule as for a full 4-week period,
- Note: Data collected after W52 (365 days) will not be used
With a treatment duration of 52 weeks and calculated averages done every four weeks (28 days), 13 4-
week periods average at most will be calculated.
PBC Worst Itch NRS average through week 52 and week 24 will be estimated based on the actual 4-week
periods available for each patient, using the period 1 to period 13 and the period 1 to period 6 respectively.
For any combined response efficacy endpoint, e.g. primary endpoint, if one evaluated parameter reaches
a non-responder condition (e.g. ALP >= 1.67 x ULN for the primary endpoint) while other parameters are
missing then the patient will be considered as non-responder, otherwise the response will be considered
as missing and handled as per analysis rule.
4.3 Interim Analyses

No interim analysis is planned for this study.
A full analysis will be performed after all patients have completed Week 52. Previous treatment allocation
will remain blinded for the Investigator and the patient up to the DB database lock (see section 2.4).
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4.4 Subject Disposition

All patients screened will be summarized overall and separately by geographical region and by country/site
ID. Patients who failed screening and the primary reason for screening failure will be summarized.
All patients screened, randomized, and treated will be accounted for in this study. A table summarizing the
number of patients per visit will be prepared.
Patient disposition will be tabulated and will include the number of patients treated, the number in each
analysis population, the number who discontinued from treatment and reason(s) for discontinuation from
treatment, and the number who discontinued from the study and reason(s) for discontinuation from study
(including discontinuation due to Covid-19) prior to week 52 and prior to the end of the double-blind period.
Summary data will be presented by treatment group and overall. The denominator for all percentages is
the total number of patients in each dose group. Treatment group is as randomized or as received according
to the respective analysis population definition.
The following by-patient data listings will be presented:
• Study completion information including the reason for premature study discontinuation, if
applicable.
• Inclusion/exclusion criteria.
• Patients inclusion in each of the analysis populations [ITT, pruritus ITT, PP, pruritus PP and Safety
analysis sets].
• Patients excluded from the analysis sets (i.e. from the Safety, pruritus ITT, PP analysis set and
pruritus PP set).
• Protocol Deviations.
• Patients that were unblinded before the DBL (who requested unblinding, date of unblinding, and
the reason for unblinding).
• Patients affected by the COVID-19 related to study disruption
4.5 Demographic, Screening and Baseline Characteristics

All collected demographic, screening, baseline characteristics, prior medications, prior procedures and
medical history data will be provided in data listings. The demographic, screening, baseline characteristics,
prior medications, prior procedures and medical history data will also be summarized by treatment group
and overall.
No formal statistical comparisons will be performed.
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4.5.1 Demographics
Demographic characteristics at baseline (sex, age at randomization (years), age categories (<65 years/>=65
years), race, height (cm), weight (kg), Body Mass Index (BMI) (kg/m2)), vital signs (i.e., systolic blood
pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats/minute) respiratory rate
(breaths/minute) and temperature (C)) will be summarized using descriptive statistics for the ITT, the Safety
and the PP, the exploratory, the pruritus ITT and the pruritus PP analysis sets.
4.5.2 Screening Characteristics
Screening characteristics data will be summarized for the ITT, for the Safety and for the PP analysis sets, as
follows:
• Screening PGIS at Screening Visit 1.
• Screening laboratory measures of ALP, AST, ALT, GGT, CPK, total and direct bilirubin, ALB,
creatinine, sodium, AFP, estimated glomerular filtration rate (eGFR),MELD-Na.
• Screening serum hematology measures of hemoglobin, hematocrit, WBC with differential,
platelet count, PT, INR.
• Screening serology measures of HIV Ab I/II, Anti- HAV IgM, HBsAg, HCV Ab, HCV RNA.
• Screening urinalysis (dipstick) measures of specific gravity, pH, protein, glucose, ketones, bilirubin,
urobilinogen, blood, nitrite, leukocytes.
• Screening urine-based β-hCG pregnancy test for all women of childbearingpotential.
• Screening serum pregnancy test (from central laboratory).
Note: for the screening laboratory parameters, the summaries will be provided by visit (i.e.: screening visit
1, screening visit 2, screening visit 3) where applicable.
Among the concomitant medications (see section 4.8.8), those which started during 30 days before and at
first screening visit 1 including but not limited to UDCA, Colchicine, cholestyramine, rifampin, naltrexone,
sertraline, statins, ezetimibe will be displayed by treatment group using Therapeutic Subgroup [ATC2] and
Therapeutic Subgroup [ATC4] for the ITT and the Safety analysis sets.
Data collected at screening will be also included in the corresponding listings.
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4.5.3 Baseline Disease Characteristics
Baseline disease characteristics will be summarized for the ITT, the Safety, the PP and the exploratory
analysis sets, as follows:
• Duration since diagnosis of PBC in years defined as (year of randomization – year of diagnosis).
• Frequency and percentage of the randomization factor: ALP > 3x ULN or TB > ULN-(Yes/No)
• Baseline PBC Worst Itch NRS average over the 14 days preceding the randomization (V1).
• Baseline PBC Worst Itch NRS average score categorization ≥ 4 (Yes/No).
• Baseline laboratory measures of ALP, AST, ALT, GGT, CPK, total bilirubin, ALB, creatinine, creatine
kinase, platelets, INR,MELD-Na.
• Frequency and percentage of baseline laboratory binary parameters (Yes/No): ALP level > 1.67x
ULN, > 3x ULN, TB > ULN, ALB < LLN, TB > ULN or ALB < LLN, TB > 0.6x ULN.
• UDCA treatment at baseline
o Yes/No
o Duration (months): (randomization date – UDCA Initiation date + 1) / 30.4375
o Duration (months) under stable dose: (randomization date – UDCA current date + 1) /
30.4375
o Total daily dose (mg)
• Prior Bezafibrate treatment (Yes/No)
• Baseline Liver biopsy (Yes/No) (will be only displayed for the Exploratory analysis set)
• Baseline Transient Elastography (Fibroscan) (Yes/No)
• Baseline Liver stiffness (KPa)
• Baseline Liver stiffness (KPa) categorization ≥ 16.9 and/or cirrhosis on histology (Yes/No)
bridging fibrosis or cirrhosis on histology (Yes/No)
General medical history coded using MedDRA will be summarized per System Organ Class (SOC) and Preferred
Term (PT) for the ITT and PP analysis sets. Medical history includes past and/or ongoing diseases or surgeries
recorded in the Medical History eCRF. Reported terms will be coded using the latest MedDRA at the time of
database lock.
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4.5.4 Prior Medications
Any medication which was started before the first study drug intake will be counted as a prior medication.
Prior medications will be coded, summarized and listed for the ITT and Safety analysis sets in a similar way
as described in section 4.8.8.
4.5.5 Prior Procedures
Any procedure that was started before the first study drug intake will be counted as a prior procedure.
Prior procedures will be coded, summarized and listed for the ITT and Safety analysis sets in a similar way
as described in section 4.8.9.
4.6 Efficacy Evaluation
4.6.1 Estimand Framework for Primary and Key Secondary Endpoints

The primary objective of the study is to evaluate the effect of Elafibranor (80 mg/day) on cholestasis over
52 weeks of treatment compared to placebo.
The key secondary objectives of the study are to evaluate the effect of Elafibranor (80 mg/day) over 52
weeks of treatment compared to placebo based on ALP normalization, and through 52 weeks and through
24 weeks on pruritus.
As detailed below, in line with ICH E9 (R1) addendum five attributes (treatment condition, population,
endpoint, ICEs and population level summary) have been specified to translate the primary objective and
key secondary objectives into treatment effect that is to be estimated (estimands):
• Primary estimand:
The composite strategy imputing non-response for patients who experienced ICEs prior to week 52 will
be applied.
A. Treatment Administration of Elafibranor or Placebo on top of UDCA or in patients intolerant

condition: to UDCA.
B. Population: Randomized patients with PBC and inadequate response or intolerance to UDCA.
C. Endpoint: Response to treatment (binary variable) indicating a successful response at week

52 for a patient with ALP < 1.67x ULN, TB ≤ ULN and ALP decrease from baseline
≥15%, and who does not stop prematurely the study treatment nor uses any
rescue therapy.
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D. Intercurrent To be considered as non-response irrespective of data after the study treatment

events: discontinuation (ICE-1) or use of rescue therapy for PBC (ICE-2) being missing or
not.
E. Population- Odds ratio between treatment groups.
level summary
The primary estimand can be defined as the odds ratio between treatment groups, from all randomized
patients, achieving response at week 52 (defined as: ALP < 1.67x ULN, TB ≤ ULN and ALP decrease ≥ 15%),
and not stopping prematurely the study treatment nor using rescue therapy for PBC.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE, the closest non-missing assessment
from the DB treatment period before or after the theoretical visit 6 date (i.e. visit 1 date + 52 * 7 days) will
be taken into account. It may correspond to an unscheduled visit or a visit prior (i.e. visit 5) or after (i.e. visit
7) the visit 6.
In addition, the following strategies will be explored as supplementary analyses:
- The exact same composite strategy as for the main analysis will be used, except that patients
without ICE but missing data at week 52 will be considered as non-responders.
- the hypothetical strategy (section 4.6.2.3.1) will be investigated comparing the potential
outcomes that would have been observed at week 52 between the treatment arms as if:
o The patients who experienced an ICE (ICE-1 treatment discontinuation or ICE-2 use of rescue
therapy for PBC) would follow their initial randomized treatment,
o The patients who experienced an ICE (ICE-1 or ICE-2) from both arms would continue on
placebo,
- In addition, a tipping point analysis will explore various scenarios among the hypothetical
strategy where missing outcomes experienced after an ICE (ICE-1 or ICE-2) vary independently
from Elafibranor and placebo groups
- the treatment policy strategy will be investigated where patients are classified as responders
based on their outcome value at week 52 regardless of treatment discontinuation (ICE-1) or use
of rescue therapy (ICE-2). In case of missing values at week 52, missing data are imputed as
described in section 4.6.2.3.3
Finally, a supplementary analysis will be performed to evaluate the impact of COVID-19 pandemic (section
4.6.2.3.4) only if more than 10% of treatment discontinuation are due to COVID-19 pandemic. Two types of
intercurrent events will affect the analysis strategy:
• Treatment discontinuation due to COVID-19 pandemic (ICE-1a). The hypothetical strategy will be
applied to the ICE-1a, as if the patients who experienced an ICE-1a would follow their initial
randomized treatment (“as treated” hypothetical strategy).
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• Treatment discontinuation for any other reason (ICE-1b) or use of rescue therapy (ICE-2) being
missing or not. The composite strategy will be applied to the ICE-1b and ICE-2, as for the primary
estimand, imputing non-response for patients who experienced ICE-1b and ICE-2 prior to week
52.
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• First Key secondary estimand (ALP normalization)

The composite strategy imputing non-response for patients who experienced ICEs prior to week 52 will be
applied.
A. Treatment condition: Administration of Elafibranor or Placebo on top of UDCA or in patients

intolerant to UDCA.
B. Population: Randomized patients with PBC and inadequate response or intolerance to
UDCA.
C. Endpoint: Response to treatment (binary variable) indicating a successful normalization
of ALP at week 52 without stopping prematurely the study treatment nor
using any rescue therapy.
D. Intercurrent events: To be considered as non-response irrespective of data after the study
treatment discontinuation (ICE-1) or use of rescue therapy for PBC (ICE-2)
being missing or not.
E. Population- level Odds ratio between treatment groups.
summary:
The first key secondary estimand can be defined as the odds ratio between treatment groups from all
randomized patients who successfully normalize their ALP at week 52 and who do not prematurely stop
the study treatment nor use any rescue therapy.
In addition, the supplementary analyses used for the primary estimand will be applied to the first key
secondary estimand (see section 4.6.2.3).
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• Second and third key secondary estimands (Change in pruritus through week 52 and week 24
respectively)
A. Treatment Administration of Elafibranor or Placebo on top of UDCA or in patients intolerant

condition: to UDCA.
B. Population: Randomized PBC patients with baseline PBC Worst Itch NRS score ≥4 and
inadequate response or intolerance to UDCA.
C. Endpoint: Change from baseline through week 52 (and week 24) in 4-week period averaged
PBC Worst Itch NRS respectively, (continuous).
D. Intercurrent Any outcome value after a treatment discontinuation (ICE-1) or use of rescue
events: therapy for pruritus (anti-pruritic medications, see section 4.2.8) (ICE-3) will be
considered as missing.
E. Population- Between treatment group difference in means of 4-week period averaged change
level summary: in PBC Worst itch NRS through week 52 (and week 24) respectively.
The second and third key secondary estimands can be defined as the between treatment group difference
in 4-week period means change from baseline from patients with baseline PBC Worst Itch NRS score ≥4
through week 52 and week 24 respectively, assuming they continued the assigned treatment after they
experienced an ICE.
As for the key binary endpoints, tipping point analysis will be performed to explore several scenarios where
missing outcomes experienced after an ICE vary independently from Elafibranor and placebo groups, and a
supplementary analysis evaluating the impact of COVID-19 pandemic will be performed (see section
4.6.2.3.1 and section 4.6.2.3.4).
In addition, the treatment policy strategy where all outcome values until week 52 and week 24
(respectively) will be used regardless of treatment discontinuation (ICE-1) or use of rescue therapy (ICE-3)
(see section 4.6.2.3.3).
Finally, a supplementary analysis will be performed to assess whether the concomitant medications used
by patients in this study induce bias to the interpretability of treatment effects based on the PBC WI NRS
score. Use of concomitant medication affecting pruritus will be considered as ICE. The ICE use of
concomitant therapy affecting pruritus will be split into two separate ICEs and the hypothetical strategy will
be applied to the new ICEs (ICE-4 and ICE-5). Then, three types of intercurrent events will affect the analysis
strategy:
• ICE-4: use of concomitant medication that create or increase pruritus. Post ICE-4 data of patients
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who experienced an ICE-4 from both arms would be imputed as if would follow their initial
randomized treatment (“as treated” hypothetical strategy)
• ICE-5: use of concomitant medication (including rescue therapy for PBC and pruritus) that reduce
pruritus (anti-pruritus). Post ICE-5 data of patients who experienced an ICE-5 from both arms would
be imputed as if would continue on placebo (“placebo-based” hypothetical strategy)
• ICE-1: Treatment discontinuation. The hypothetical strategy will be applied to the post ICE-1 data,
and any patient’s outcome will be considered as missing for patients who experienced ICE-1 prior
to week 52.
All efficacy analyses for primary and first key secondary endpoints will be based on the ITT analysis set and
all efficacy analyses for second and third key secondary endpoints will be based on pruritus ITT analysis set.
Descriptive statistics at each planned visit over the whole DB period (including V7 and V8 if applicable) will
be summarized by treatment group (Elafibranor and Placebo) on efficacy endpoints (primary and
secondary). To assess robustness of the results, the main analyses of the primary endpoint, the first key
secondary endpoint will be repeated on the PP set and the main analyses of the second and third key
secondary endpoints will be repeated on the pruritus PP set. That is, sensitivity analyses and supplementary
analyses will not be repeated on the PP set or pruritus PP set.
All the intercurrent events and their associated first date of occurrence will be included in by-patient data
listing. Here the list of all the intercurrent events identified for the study:
- ICE-1: treatment discontinuation
o ICE-1a: treatment discontinuation due to COVID-19 pandemic
o ICE-1b: treatment discontinuation for any other reason
- ICE-2: use of rescue therapy for PBC
- ICE-3: use of rescue therapy for pruritus
- ICE-4: use of concomitant medication that creates or increases pruritus
- ICE-5: use of concomitant medication (including rescue therapy for PBC and pruritus) that reduces
pruritus (anti-pruritus)
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4.6.2 Primary Efficacy endpoint analysis
4.6.2.1 Main Analysis
The efficacy of Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated considering
ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52 (binary: YES/NO)
The null hypothesis for response to treatment based on the primary endpoint is that there is no difference
in response rates between the Elafibranor and the placebo group. The alternative hypothesis is that there
is a difference in response rates between both groups. The null hypothesis will be tested at a two-sided
alpha of 0.05.
Patients who stopped prematurely the study treatment (ICE-1) or used rescue therapy for PBC (ICE-2) prior
to week 52 assessment will be considered as non-responders.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE (ICE-1 or ICE-2), the closest non-
missing assessment from the DB treatment period before or after the theoretical visit 6 date (i.e. visit 1
date + 52 * 7 days) will be taken into account. It may correspond to an unscheduled visit or a visit prior (i.e.
visit 5) or after (i.e. visit 7) the visit 6.
The number and percentage of patients with favorable response to treatment at the end of the 52 weeks
of the DB period will be summarized by treatment group. The number and percentage of non-responder
patients without ICE-1 nor ICE-2 as well as the number and percentage of non-responder patients due to
ICE-1 or ICE-2 will be summarized. Response to treatment at Week 52 in patients with ICE (overall and by
ICE-1 or ICE-2) will be described as well.
Finally, a descriptive summary by visit of cholestasis response using data of ALP and TB as collected will also
be summarized in a separate table by treatment group.
The response proportions at week 52 will be compared between the treatment groups using the exact CMH
test stratified by the randomization strata. The estimate of the odds ratio and the corresponding 95% exact
CI and exact p-value will be provided. In addition, the risk difference between the treatment groups and
95% CI will be calculated using the Newcombe method stratified by randomization strata. For consistency,
the Wilson score 95% CI for single proportion will be provided for within group description.
Sample SAS code snippets:

Exact Cochran-Mantel-Haenszel (CMH):
PROC FREQ DATA=dataset NOPRINT;
EXACT COMOR;
TABLES randstrata*treatment*response / ALPHA= 0.05;
RUN;
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Risk difference and 95% CI (Newcombe):

PROC FREQ DATA=dataset NOPRINT;
TABLES randstrata*treatment*response / commonriskdiff(CL=Newcombe) ALPHA= 0.05;
RUN;
The treatment and response should be labelled so that the labels are alphabetically sorted in a given order
(treatment: active treatment, placebo; response: event, no event).The main analysis will be conducted
using the ITT analysis set and will be repeated on the PP analysis set.
Figures of mean (+/- SE), mean change from baseline (+/- SE) and mean percentage change from baseline
(+/- SE) over time up to week 52 and up to week 104 separately for ALP and TB will be produced using data
as collected.
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4.6.2.2 Sensitivity analysis to the statistical model
A sensitivity analysis, in addition to the exact CMH, will be performed on ITT analysis set, using an exact
logistic regression model stratified by the randomization strata with treatment group as a factor.
Sample SAS code snippets:

Exact PROC LOGISTIC (SAS Institute) will be used for the statistical analysis
PROC LOGISTIC DATA = dataset;
CLASS treatment(param=ref ref="Placebo");
MODEL response (EVENT = ”Yes”) = treatment;
STRATA randstrata;
EXACT treatment / ESTIMATE = odds ALPHA=0.05;
RUN;
4.6.2.3 Supplementary analyses

4.6.2.3.1 Composite strategy with missing data as non-responders
The exact same composite strategy as for the main analysis (see section 4.6.2.1 Main Analysis) will be
performed, except that patients without ICE but missing data at week 52 will be considered as non-responders.
4.6.2.3.2 Hypothetical strategy
The first supplementary analysis strategy using three relevant multiple imputation methods of the primary
endpoint [ALP < 1.67x ULN and TB ≤ ULN and ALP decrease from baseline ≥ 15% at week 52] will be
performed imputing outcomes experienced after an ICE at Week 52 (see section 4.2.9) and using the ITT
analysis set.
The imputations of post ICE-1 or ICE-2 ALP and TB will be based on patients completing the week 52 DB
period and relevant baseline covariates.
Three relevant multiple imputation scenarios/assumptions will be modeled:
1) Based on assigned treatments (MAR)
Outcomes imputed assuming that patients would follow their initial treatment (rather than switching to
placebo after discontinuation). This scenario assumes MAR where missingness is independent of
unobserved outcomes given observed data. The multiple imputation method will impute values as if
patients would follow their initial treatment, conditional on baseline and pre- withdrawal data included in
the analysis. Therefore, the treatment arm will be included in the imputation model as a covariate.
Note that missing response at week 52 for patients without an ICE (ICE-1 or ICE-2) will also be imputed
assuming that patients would follow their initial treatment (multiple imputation MAR).
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Post ICE-1 or ICE-2 ALP and TB values will be set to missing up to week 52 and will be imputed multiple
times to account for the uncertainty about the true values to impute. In case of non-monotone missingness,
firstly the Markov Chain Monte Carlo (MCMC) method will be used for completing data to a monotone
pattern. Then, in case of missing response at week 52 for patients without an ICE (ICE-1 or ICE-2) prior week
52, a monotone regression will be applied with m imputed datasets (data of patients without ICE-1 or ICE-
2) imputing missing ALP and TB up to week 52 assuming that patients would follow their initial treatment
(MAR). Finally, a monotone regression will be applied with m imputed datasets (all patients) imputing
remaining missing ALP and TB up to week 52, assuming that patients would follow their initial treatment
(MAR).
To consider the correlation between ALP and TB, both parameters will be jointly imputed using the repeated
measurements of ALP and TB as covariates.
For this multiple imputation analysis, a separate random seed between 1 and 10000 will be generated. 1000
imputed datasets will be generated.
/* Step 1: imputation to complete missing to monotone pattern */

PROC MI DATA=datain OUT=datain_mono NIMPUTE=1000 SEED=1234;
VAR treatment basALP basTB w4ALP w4TB w13ALP w13TB w26ALP w26TB w39ALP w39TB
w52ALP w52TB;
MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE;
RUN;
PROC SORT DATA=datain_mono; BY _IMPUTATION_ treatment; RUN;
/* Step 2: Multiple Imputation of missing data not due to ICE (MAR); */

data data_mi1;
set datain_mono;
if ICETYP not in ("Rescue Therapy for PBC" "Treatment Discontinuation") then output;
run;
proc sort data=data_mi1 out =data_mi1_st; by _IMPUTATION_ TRT01PN;run;
PROC MI DATA=data_mi1_st OUT=data_mi1_ipte SEED=465 NIMPUTE=1 noprint;

by _IMPUTATION_;
VAR TRT01PN ALP_BASE BILI_BASE w4ALP w4BILI w13ALP w13BILI w26ALP w26BILI w39ALP
w39BILI w52ALP w52BILI;
MONOTONE REGRESSION;
RUN;
/* Step 3: Multiple Imputation of post ICE data (MAR); */

data data_mi2;
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set datain_mono;
if ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation") or (w52ALP ne . and w52TB ne
.) then output;
run;
PROC MI DATA=data_mi2 OUT=datain_reg SEED=465 NIMPUTE=1; BY

_IMPUTATION_;
VAR treatment basALP basTB w4ALP w4TB w13ALP w13TB w26ALP w26TB w39ALP w39TB
w52ALP w52TB;
CLASS treatment;
RUN;
/* Step 4: Pool the data; */

data data_impute;
set datain_reg (where=(ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation")))
data_mi1_ipte;
run;
DATA datain_reg1;
SET data_impute ;
BY _IMPUTATION_;
IF [ALP < 1.67x ULN (at V6) and TB ≤ ULN (at V6) and ([ALP (at V6)- ALP (at V1)]/ALP *100 (at V1
≤-15))] THEN response= 1;
ELSE response =0;
RUN;
PROC SORT DATA=datain_reg1; BY _IMPUTATION_;RUN;
After calculation of the response to treatment (primary endpoint) based on imputed ALP and TB, the m
imputed datasets will be used separately in the statistical analysis model (exact CMH stratified on the
stratification factors of the randomization). The resulting log (odds ratios) will be combined via Rubin’s rules
to provide a global estimate of the odds ratio after back transformation. Furthermore, the p-values from
exact CMH tests based on the m imputed sets will be transformed into a Z statistic by applying the inverse
normal cumulative distribution function. Since the resulting Z statistics are normally distributed and have
unit variances, they can be combined using standard Rubin's combination rules across the multiply imputed
sets. Lower and Upper bounds of the 95% CI around the odds ratio will be given in addition and estimated
as the median of the lower bounds and the median of the upper bounds of the imputations.
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/* Step 5: Exact Cochran-Mantel-Haenszel (CMH) ***/

ODS OUTPUT CommonOddsRatioCL= lgsparms;
ODS OUTPUT CommonPdiff = riskDiff;
PROC FREQ DATA=datain_reg1;
BY _IMPUTATION_;
EXACT COMOR;
TABLES randstrata*treatment*response / COMMONRISKDIFF(CL=Newcombe) ALPHA= 0.05;
RUN;
* Step 6.1: Obtain Mantel-Haenszel estimate of the common odds ratio, CI and p-value ;
DATA lgsparms;
SET lgsparms;
log_or_lr_value=LOG(value);
RUN;
Use a proc mean on log_or_lr_value to combine transformed estimates odds ratio and back
transform.
Use a proc mean or univariate to provide the medians of the exact lower bounds and upper bounds
of the 1000 odds ratios to provide a combine CI.
Transform into a Z statistic the 1000 p-values using the function quantile('NORMAL', p-value),
calculate the mean and provide the combined p-value as CDF('NORMAL',mean-p-value)
* Step 6.2: Obtain Mantel-Haenszel estimate of the common risk difference and CI ;
The Mantel-Haenszel estimate of the common risk difference will be combined using the Rubin’s
rules.
The Newcombe CI comes in a form of:
- Lower bound: MH estimate – Zalpha/2 * SE1
- Upper bound: MH estimate + Zalpha/2 * SE2
SE1 and SE2 will be combined separately using the Rubin’s rules.
ODS OUTPUT COMMONPDIFF = Risk0 ;

PROC FREQ DATA=datain ;
TABLES STRATUM_ID * TRT01P * RESP / riskdiff(common CL=Newcombe) ALPHA=0.05 ;
BY _IMPUTATION_;
RUN;
DATA Risk;
SET Risk0;
IF METHOD=”Newcombe” ;
Stderr1=(value-LOWERCL)/1.96; **use: quantile('NORMAL', .975) instead of 1.96**;
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Stderr2=(UPPERCL – value)/1.96;
RUN;
ODS OUTPUT PARAMETERESTIMATES=Risk_fin_Lower;

PROC MIANALYZE DATA= Risk;
MODELERRECTS value;
STDERR stderr1;
RUN.
ODS OUTPUT PARAMETERESTIMATES=Risk_fin_Upper;
PROC MIANALYZE DATA= Risk;
MODELERRECTS value;
STDERR stderr2;
RUN.
The combined CI will be provided using stderr1 and stderr2 for the lower and upper bound
respectively.
2) Based on placebo
Outcomes imputed for both placebo and treatment post ICE-1 or ICE-2 data as if they would continue on
placebo (using placebo-based multiple imputation (PBI)): The PBI method assumes the statistical behavior
of placebo- and drug-treated patients after ICE-1 or ICE-2 is the statistical behavior of placebo- treated
patients.
Note that patients without an ICE but with missing data at week 52 for any reason will also be imputed
assuming that patients would follow their initial treatment (multiple imputation MAR).
Thus, post ICE-1 or ICE-2 ALP and TB values will be set to missing and will be imputed using a pattern mixture
model. This analysis will use the placebo group as the basis for imputation of any missing values. To
implement this approach, the MNAR statement of PROC MI will be used along with the monotone
regression (similarly to the imputation strategy described above).
The proposed pattern-mixture analysis imputes missing values for ALP and TB using the repeated
measurements of ALP and TB as covariates.
/* Steps 1 and 2 from MAR strategy will be done */
/* Step 3: Multiple Imputation of post ICE data (MNAR); */

data data_mi2;
set datain_mono;
if ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation") or (w52ALP ne . and w52TB ne
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.) then output;
run;
proc sort data=data_mi2 out =data_mi2_st;
by _IMPUTATION_ TRT01PN;
run;
PROC MI DATA=data_mi2_st OUT=datain_mnar NIMPUTE=1 SEED=465;
BY _IMPUTATION_;
CLASS treatment;
VAR basALP basTB w4ALP w4TB w13ALP w13TB w26ALP w26TB w39ALP w39TB w52ALP w52TB;
MNAR MODEL (w4ALP / MODELOBS=(treatment=’Placebo’));
…
MNAR MODEL (w52ALP / MODELOBS=(treatment=’Placebo’));
MNAR MODEL (w4TB / MODELOBS=(treatment=’Placebo’));
…
MNAR MODEL (w52TB / MODELOBS=(treatment=’Placebo’));
RUN;
/* Steps 4 to 6 from MAR strategy will be done */
3) Tipping point analysis

Outcomes imputed for both placebo and treatment post ICE-1 or ICE-2 data under a number of scenarios
about the missing outcomes (delta-adjusted imputation or tipping point analysis).
Multiple imputation will be conducted to impute the post ICE (ICE-1 or ICE-2) data of ALP and TB values at
week 4, week 13, Week 26 and Week 39 via sequential Bayesian regression with the stratification factor as
well as baseline and earlier post-baseline values of ALP and TB included as covariates. Non- monotone
missingness will be imputed via MCMC for multivariate normal data using the same variables to complete
the data to a monotone pattern. Then, in case of missing response at week 52 for patients without an ICE
(ICE-1 or ICE-2) prior week 52, a monotone regression will be applied with m imputed datasets (data of
patients without ICE-1 or ICE-2) imputing missing ALP and TB up to week 52 assuming that patients would
follow their initial treatment (MAR). For remaining missing response, the final binary response at week 52
will be imputed using a Bayesian logistic regression model for the clinical response with the stratification
factor as well as baseline and earlier post-baseline values of ALP and TB included as covariates.
Imputations will be conducted within each treatment arm and represent values expected under a
hypothetical estimand that patients who experienced an ICE would have continued their assigned
treatment despite the ICE under the assumption of MAR.
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The sensitivity analysis will stress-test the MAR assumption by assuming two sensitivity parameters, δ1 and
δ2, for the Elafibranor and placebo arms, respectively, representing an adjustment to the probability of
clinical response at week 52 compared to that expected under MAR on the log-odds scale. MAR-based
method will be used and then only apply 𝛿𝛿 at each imputed time-point. For details refer to section 7.
The sensitivity analysis will be implemented via PROC MI with the MNAR option and ADJUST statement.
The analysis of 1000 multiply imputed data sets will be conducted by using the same CMH statistic as in the
main analysis, which will be subsequently transformed into Z scores by an appropriate transformation. The
final analysis will be conducted via Rubin’s combination rules (PROC MIANALYZE) with these Z scores from
the multiply imputed sets (assuming unit standard errors). The overall response rate for each treatment
group using the imputed data sets will be presented. The resulting p- values will be shown on a two-
dimensional plane as functions of the sensitivity parameters δ1 and δ2, or their exponentiated values (odds
ratios). The regions on the plane when the significance of the primary analysis will be overturned will be
highlighted, and their clinical plausibility will be interpreted.
The proposed delta-adjusted imputation will be implemented using PROC MI. Code snippets are presented
below (here Z is the binary response at week 52 and basALP, basTB, w4ALP, w4TB, w13ALP, w13TB, w26ALP,
w26TB, w39ALP and w39TB denote the appropriate values of ALP and TB, for example, w4ALP is ALP at
week 4).
/* Step 0: Define the response variable */

DATA dataset;
SET dataset;
if .<w52ALP < 1.67* ALP_ULN and .<w52BILI <= BILI_ULN and ((w52ALP- ALP_BASE)/ALP_BASE*100)
<=-15 then Z="Y";ELSE Z ="N";
if ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation") or w52ALP=. or w52BILI=. then
Z ="";
RUN;
/* Steps 1 and 2 from MAR strategy will be done */
/* Step 3: MNAR imputation using delta adjustment, separately by treatment arm*/

data data_mi2;
set dataset;
if ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation") or (w52ALP ne . and w52TB ne .)
then output;
run;
PROC MI DATA=data_mi2(where=(treatment=’Elafibranor 80mg’)) SEED=1214 OUT=outmi_1
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NIMPUTE=1;
CLASS treatment Z;
BY _Imputation_;
VAR basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB Z;
MONOTONE REG /* imputing all variables except Z using sequential Bayesian regression */
LOGISTIC (Z = basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB
/LIKELIHOOD=AUGMENT);
MNAR ADJUST(Z (event= 'Y')/ delta=&delta1 adjustobs=(treatment=’Elafibranor 80mg’));
RUN;
PROC MI DATA= data_mi2 (where=(treatment=’Placebo’)) SEED=1214 OUT=outmi_2 NIMPUTE=1;

CLASS treatment Z;
BY _Imputation_;
VAR basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB Z;
MONOTONE REG /* imputing all variables except Z using sequential Bayesian regression */
LOGISTIC (Z = basALP basTB w4ALP w4TB w13ALP, w13TB w26ALP w26TB w39ALP w39TB
/LIKELIHOOD=AUGMENT);
MNAR ADJUST (Z (event= 'Y')/ delta=&delta2 adjustobs=(treatment=’Placebo’));
RUN;
/* Steps 4 to 6 from MAR strategy will be done */
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4.6.2.3.3 Treatment policy strategy
The second supplementary analysis strategy will be investigated on ITT analysis set using outcome values
at week 52 regardless of treatment discontinuation or use of rescue therapy to classify patients as
responders or non-responders. The same model as the one described in section 4.6.2.1 will be applied. In
this strategy, missing data after ICE-1 or ICE-2 will be imputed. In addition, patients without an ICE-1 or ICE-
2 but with missing data at week 52 for any reason will also be imputed assuming that patients would follow
their initial treatment (multiple imputation MAR).
Imputation of missing data resulting from intercurrent events
Although the treatment policy strategy aims to use post ICE data in the analysis, post ICE missing data may
exist; assuming that missing data for other reasons than ICE is already addressed (multiple imputation
MAR).
The post ICE missing data will be imputed assuming that patients would follow their initial treatment and
using only observed data of patients with ICE-1 and ICE-2 for post ICE-1 and post ICE-2 missing data
respectively, within the treatment policy strategy. Therefore, the treatment arm will be included in the
imputation model as a covariate.
If convergence issues are encountered due to the lack of observed post ICE data, then a dynamic approach
removing ALP and TB data in proc MI of step 2 will be done. In that case, the multiple imputation of post
ICE missing data will be done first removing ALP and TB data at week 13. If the model still doesn’t converge,
ALP and TB data at week 26 will also be removed. And again, if the model still doesn’t converge, ALP and
TB data at week 39 will also be removed. If there is still convergence issue after removing ALP and TB data
at weeks 13, 26 and 39, the results will not be presented.
/* Step 1: imputation to complete missing to monotone pattern; */
PROC MI DATA=datain OUT=datain_mono NIMPUTE=1000 SEED=1234 noprint;
MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE;
RUN;
/* Step 2: imputation of missing data post ICE using only observed data of patients with ICE-1
and/or ICE-2*/
data data_ice;
set datain_mono;
if ICETYP in ("Rescue Therapy for PBC" "Treatment Discontinuation") then output;
run;
proc sort data=data_ice out =data_ice_st; by _IMPUTATION TRT01PN ICEPROFIL ;run;
PROC MI DATA=data_ice_st OUT=data_ice_ipte SEED=465 NIMPUTE=1 noprint;

by _IMPUTATION_;
CLASS ICEPROFIL;
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VAR TRT01PN ICETYP ALP_BASE BILI_BASE w4ALP w4BILI w13ALP w13BILI w26ALP w26BILI w39ALP
RUN;
/* Step 3: Multiple Imputation of missing data (MAR) not due to ICE; */

data data_mi1;
set datain_mono;
if ICETYP ="" then output;
run;
PROC MI DATA=data_mi1_st OUT=data_mi1_ipte SEED=465 NIMPUTE=1 noprint;

by _IMPUTATION_;
RUN;

data data_impute;
set data_ice_ipte data_mi1_ipte;
run;
/* Step 5: Define the response; */

data datain_reg ;
set data_impute;
* Cholestasis Response;
if W52ALP < 1.67* ALP_ULN and W52BILI <= BILI_ULN and ((W52ALP- ALP_BASE)/ALP_BASE*100)
<=-15 then AVALC="Y";
else AVALC ="N";
run;
The results of these supplementary analyses, based on ITT analysis set, will allow assessing the robustness
of the findings and conclusions based on the primary analysis by changing the level of quality of the
measure.
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4.6.2.3.4 COVID-19
This supplementary analysis will be performed using the ITT analysis set to evaluate the impact of COVID-
19 pandemic on the primary endpoint and the same model as the one described in section 4.6.2.1 will be
applied. This supplementary analysis will only be performed if more than 10% of treatment discontinuation
are due to COVID-19 pandemic.
Two types of intercurrent events will affect the analysis strategy:
• Treatment discontinuation prior to week 52 due to COVID-19 pandemic (ICE-1a). The hypothetical
strategy will be applied to the ICE-1a, as if the patients who experienced an ICE-1a would follow
their initial randomized treatment (“as treated” hypothetical strategy) (see section 4.6.2.3.1).
• Treatment discontinuation for any other reason (ICE-1b) or use of rescue therapy (ICE-2) being
missing or not prior to week 52. The composite strategy will be applied to the ICE-1b and ICE-2, as
for the primary estimand, imputing non-response for patients who experienced ICE-1b and ICE-2
prior to week 52.
4.6.3 First Key Secondary Efficacy Endpoint
The response to Elafibranor (80 mg/day) compared to placebo on cholestasis will be evaluated considering
A successful normalization of ALP at week 52 (ALP ≤ ULN) - (binary: YES/NO).
The null hypothesis for response to treatment based on the first key secondary endpoint is that there is no
difference in response rates between the Elafibranor and the placebo group. The alternative hypothesis is
that there is a difference in response rates between both groups. The null hypothesis will be tested at a
two-sided alpha of 0.05, only if the primary endpoint is statistically significant (see section 4.2.1).
Patients who stopped prematurely the study treatment (ICE-1) or took a rescue therapy for PBC (ICE-2)
prior to week 52 assessment will be considered as non-responders.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE (ICE-1 or ICE-2), the closest non-
missing assessment from the DB treatment period before or after the theoretical visit 6 date (i.e. visit 1
date + 52 * 7 days) will be taken into account. It may correspond to an unscheduled visit or a visit prior (i.e.
The number and percentage of patients with response to treatment at the end of the 52 weeks of the DB
period will be summarized by treatment group, similar to the primary endpoint analysis.
The analysis of the first key secondary efficacy endpoint will be conducted similarly to the primary endpoint
(see section 4.6.2). A sensitivity analysis to the statistical model, a supplementary analysis considering
missing data at Week 52 in patients without ICE as non-response, a hypothetical strategy and a treatment
policy strategy will be implemented the same way as for the primary efficacy endpoint. For the
supplementary analyses with multiple imputation of the first key secondary endpoint, only the ALP will be
imputed and not the TB (see section 4.6.2.3.1), re-running the imputation process with the same random
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seed including just the ALP variables.

A supplementary analysis to evaluate the impact of COVID-19 pandemic will be implemented the same way
as for the primary efficacy endpoint.
4.6.4 Second Key Secondary Efficacy Endpoint
4.6.4.1 Main Analysis
For this endpoint “4-week period” is used as a synonym for the 28-day interval.
The response to Elafibranor (80 mg/day) compared to placebo on pruritus will be evaluated using the
pruritus ITT analysis set and considering the response to treatment in terms of:
Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with
baseline PBC Worst Itch NRS score ≥4 (continuous)
The null hypothesis for response to treatment based on the second key secondary endpoint is that there is
no difference in mean change from baseline through week 52 of PBC Worst Itch NRS score in patients with
baseline PBC Worst Itch NRS score ≥4 between the Elafibranor and the Placebo group. The alternative
hypothesis is that there is a difference in mean change from baseline through week 52 of PBC Worst Itch
NRS score in patients with baseline PBC Worst Itch NRS score ≥4 between both groups. The null hypothesis
will be tested at a two-sided alpha of 0.05, only if the primary endpoint and the first key secondary endpoint
are statistically significant (see section 4.2.1).
PBC Worst Itch NRS scores for patients who stopped prematurely the study treatment (ICE-1) or took a
rescue therapy for pruritus (ICE-3) prior to week 52 assessment will be considered as missing.
Mean PBC Worst Itch NRS values (13 4-week periods plus baseline) and change from baseline for each 4-
week period (see section 4.2.11) will be summarized by treatment group (Elafibranor 80mg and Placebo).
The number of compliant patients as well as the number of non-missing scoring days (see section 4.2.11)
for baseline and for the 13 4-week periods will be provided by treatment group. Change from baseline at
each 4-week period over time will also be plotted as well as the mean PBC Worst Itch NRS score over time
using the least squares means (LSM) + 95% CI. Additionally, PBC Worst Itch NRS past week values at V7 and
V8 as well as the change from baseline will be summarized only.
The analysis of the second key secondary efficacy endpoint will be conducted modeling the change from
baseline values over the entire duration between baseline and week 52 via a MMRM adjusting for baseline
PBC Worst Itch NRS score and the stratification factor [ALP > 3x ULN or TB > ULN-(Yes/No)] as possible
covariates (see section 4.2.7). Please refer to the methods specified in section 4.6.7.1 for the verification of
the dependency structure modelled if needed.
The estimated LSMeans, treatment differences, together with the 95% CIs and p value will be presented
separately for the overall period (i.e. through week 52) and for each 4-week period until Week 52.
All 4-week periods [1,2, …, 13] until week 52 will be included as fixed effects along with treatment,
treatment by 4-week period interaction and baseline PBC Worst Itch NRS average value. As a first intention,
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the unstructured variance- covariance structure will be applied to model the within-patient variability. If
there is no convergence, the following structures will be tested until the model succeeds to converge:
heterogeneous Toeplitz structure (TOEPH), heterogeneous autoregressive(1) (ARH(1)), heterogeneous
compound symmetry (CSH), Toeplitz structure (TOEP), autoregressive(1) (AR(1)), and compound
symmetry.. The comparison between Elafibranor and Placebo will be based on the average (i.e. equal
weights) of the 13 4-week period contrast.
Missing values will be handled within the analysis itself with the assumption that the model specification
will be correct and that the data will be MAR (see section 4.2.9).
The 4-week periods will be considered as a repeated variable within a patient. The treatment by 4-week
period interaction will be included in the model.
Sample SAS code Snippet:
PROC MIXED DATA=dataset;
CLASS usubjid 4-w-period treatment randstrata;
MODEL change = baseline randstrata treatment 4-w-period treatment*4-w-period /
DDFM=KENWARDROGER;
REPEATED 4-w-period / SUBJECT=usubjid TYPE=UN;
LSMEANS treatment 4-w-period treatment*4-w-period / PDIFF
CL;
ODS OUTPUT LSMeans = lsm; * contains the adjusted means;
ODS OUTPUT Diffs = dif; * contains treatment differences;
RUN;
This main analysis will be repeated using the pruritus PP and ITT analysis sets.
4.6.4.2 Supplementary analysis
All supplementary analysis will be provided using the pruritus ITT analysis set.
4.6.4.2.1 Tipping point analysis
A supplementary tipping point analysis for the second key secondary endpoint based on the PBC WI NRS
score will be performed in a similar way than described in section 4.6.2.3.1 with appropriate modifications.
In particular, imputation will be applied to impute the missing 4-week period PBC WI NRS scores, after
applying derivation rules described in section 4.2.11, following an ICE, in the corresponding treatment arm.
Non-monotone missingness will be imputed via MCMC for multivariate normal data using the same
variables to complete data to monotone. The sensitivity parameters δ1 and δ2 specified within clinically
plausible ranges, including both positive and negative values, will be added using 0.5 increments to the
imputed 4-week period PBC WI NRS scores within week 52 in the Elafibranor and Placebo arms,
respectively, in each completed data set. The imputed PBC WI NRS scores +/- δ will be capped at 0 for the
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minimum value and at 10 for maximal value. Then, analysis will be conducted via the same method as for
the main analysis of the second key secondary efficacy endpoint. The resulting treatment effect p- values
based on Rubin’s combination rules will be plotted as functions of δ1 and δ2.
implemented using PROC MI. Code snippets are presented below (here 4W1NRS through 4W13NRS denote
the 4-week periods NRS scores).
/* Complete the data to a monotone pattern under MAR, separately by treatment arm using MCMC
*/
PROC MI DATA=ex SEED=1214 OUT=outmi NIMPUTE=1000;
BY treatment;
VAR basNRS 4W1NRS – 4W13NRS;
MCMC IMPUTE=MONOTONE;
RUN;
/* MNAR imputation using delta adjustment, separately by treatment arm*/

PROC MI DATA=outmi(where=(treatment=’Elafibranor 80mg’)) SEED=2023 OUT=outmi_1
NIMPUTE=1;
CLASS treatment;
BY _Imputation_;
MONOTONE REG(4W1NRS – 4W13NRS );
MNAR ADJUST(4W1NRS /delta=&delta1 adjustobs=(treatment=’Elafibranor 80mg’));
..
MNAR ADJUST(4W13NRS /delta=&delta1 adjustobs=(treatment=’Elafibranor 80mg’));
RUN;
PROC MI DATA= outmi (where=(treatment=’Placebo’)) SEED=1214 OUT=outmi_2 NIMPUTE=1;

CLASS treatment;
BY _Imputation_;
MONOTONE REG( 4W1NRS – 4W13NRS);
MNAR ADJUST(4W1NRS /delta=&delta2 adjustobs=(treatment=Placebo’));
..
MNAR ADJUST(4W13NRS /delta=&delta2 adjustobs=(treatment=’Placebo’));
RUN;
/* add delta1 and delta2 to the imputed 4-week periods scores up to week 52 in the Elafibranor and
Placebo arms */
For each of the 1000 completed data sets, run PROC MIXED and compute the overall treatment contrast
for the mean of the 13 4-week periods using the MMRM method, as shown for the main analysis of the
second key secondary efficacy endpoint.
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Process the completed_stats data set using PROC MIANALYZE as follows:

PROC MIANALYZE DATA=completed_stats;
MODELEFFECTS contrast;
STDERR StdErr;
RUN;
4.6.4.2.2 Other supplementary analysis
1) A supplementary analysis based on treatment policy will be investigated using the same SAS code
as above but considering outcome values through week 52 regardless of treatment discontinuation
(ICE-1) or use of rescue therapy for pruritus (ICE-3) in a similar way than described in section
4.6.2.3.3.
2) A supplementary analysis to evaluate the impact of COVID-19 pandemic will be performed using
the same SAS code as above but considering outcome values through week 52 with the ICE strategy
described in section 4.6.2.3.4.
3) Finally, a supplementary analysis will be performed to assess whether the concomitant medications
used by patients in this study induce bias to the interpretability of treatment effects based on the
PBC WI NRS score. This analysis will be performed using the same SAS code as above but considering
outcome values through week 52 with the following ICE strategy. The ICE use of concomitant
therapy will be split into two separate ICEs and the hypothetical strategy will be applied to the new
ICEs (ICE-4 and ICE-5). Then, three types of intercurrent events will affect the analysis strategy:
• ICE-4: use of concomitant medication that create or increase pruritus.
• ICE-5: use of concomitant medication (including rescue therapy for PBC and pruritus) that
reduce pruritus (anti-pruritus).
• ICE-1: Treatment discontinuation.
The post intercurrent event data will be imputed with respect to the type of intercurrent event using a
hybrid strategy. Post ICE-1 and ICE-4 data will be considered as missing, and these missing data as well as
missing data not due to ICE will be handled within the analysis itself with the assumption that the model
specification will be correct, and that the data will be MAR.
Finally, post ICE-5 data will be multiply imputed under MNAR assumption for both placebo and treatment
patients as if they would continue on placebo (using placebo-based multiple imputation (PBI)).
If convergence issues are encountered due to the lack of observed post ICE-5 data, then a dynamic approach
removing PBC WI NRS scores at specific 4-week periods in proc MI of step 2 will be done. In that case, the
multiple imputation of post ICE-5 missing data will be done first removing PBC WI NRS score at 4-week
period 4. If the model still doesn’t converge, PBC WI NRS score at 4-week period 5 will also be removed.
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This could be repeated until 4-week period 12. If there is still convergence issue after removing PBC WI NRS
scores from 4-week period 4 to 4-week period 12, the results will not be presented.
/* Step 1: Complete data to monotone pattern using MI ;*/

PROC MI DATA=datain SEED=1214 OUT=datain_mono NIMPUTE=1000 noprint ;
VAR trt01pn w4per0 w4per1 w4per2 w4per3 w4per4 w4per5 w4per6 w4per7 w4per8 w4per9
w4per10 w4per11 w4per12 w4per13;
MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE ;
RUN;
proc sort data = datain_mono ;by _imputation_ usubjid trt01p trt01pn RANDFFL base;run;
/* Step 2: imputation of post ICE-5 data using all placebo patients */

data data_mono_ice4_pla;
set datain_mono;
where ICETYP = "Use of concomitant medication that decrease pruritus" OR TRT01P = "Placebo";
run;
PROC SORT DATA=data_mono_ice4_pla; BY _IMPUTATION_ TRT01P; RUN;
PROC MI DATA=data_mono_ice4_pla OUT=datain_ipte_ice4 SEED=465 NIMPUTE=1 noprint;

by _IMPUTATION_;
class TRT01P;
VAR w4per0 w4per1 w4per2 w4per3 w4per4 w4per5 w4per6 w4per7 w4per8 w4per9 w4per10
w4per11 w4per12 w4per13;
MNAR MODEL(w4per1 / MODELOBS=(TRT01P='Placebo'));
RUN;

data data_combine;
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set datain_mono(where=(ICETYP ne "Use of concomitant mediciation that decrease pruritus " AND
TRT01P ne "Placebo"))
datain_ipte_ice4;
run;
4.6.5 Third Key Secondary Efficacy Endpoint
As for the second key secondary endpoint, “4-week period” is used as a synonym for the 28-day interval.
The response to Elafibranor (80 mg/day) compared to placebo on pruritus will be evaluated using the
pruritus ITT analysis set, repeated on ITT analysis set and considering the response to treatment in terms
of:
Change in pruritus from baseline through week 24 on PBC Worst Itch NRS score in patients with
baseline PBC Worst Itch NRS score ≥4 (continuous)
The null hypothesis for response to treatment based on the third key secondary endpoint is that there is
no difference in mean change of PBC Worst Itch NRS score in patients with baseline PBC Worst Itch NRS
score ≥4 between the Elafibranor and the Placebo group through 24 weeks of treatment. The alternative
hypothesis is that there is a difference in mean change of PBC Worst Itch NRS score in patients with baseline
PBC Worst Itch NRS score ≥4 between both groups through 24 week of treatment. The null hypothesis will
be tested at a two-sided alpha of 0.05, only if the primary endpoint, the first and the second key secondary
endpoints are statistically significant (see section 4.2.1).
PBC Worst Itch NRS values for patients who stopped prematurely the study treatment (ICE-1) or took a
rescue therapy for pruritus (ICE-3) prior to week 52 assessment will be considered as missing.
The analysis of the third key secondary efficacy endpoint will be conducted modeling the change from
baseline values over the entire duration between baseline and week 52 via a MMRM adjusting for baseline
PBC Worst Itch NRS score and the stratification factor [ALP > 3x ULN or TB > ULN-(Yes/No)] as possible
covariates (see section 4.2.7). Please refer to the methods specified in section 4.6.7.1 for the verification of
the dependency structure modelled if needed. All 4-week periods [1,2, …, 13] until week 52 will be included
as fixed effects along with treatment, treatment by 4-week period interaction and baseline PBC Worst Itch
NRS average value.
The estimated LSMeans, treatment differences, together with the 95% Cis and p value will be presented for
the period through week 24 using contrast.
The same analyses, main and supplementary, as described above for the second key secondary endpoint will
be repeated for the change from baseline in PBC Worst Itch NRS score through week 24 in patients with
Note that all supplementary analysis will be provided using the pruritus ITT analysis set.
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4.6.6 Subgroup Analysis
This analysis will be performed in each subgroup separately.

The primary endpoint and first key-secondary endpoint will also be analyzed within subgroups using the
exact CMH with the composite strategy using the ITT analysis set. This model will be stratified by the
randomization strata in the analyses for all subgroups defined in section 4.2.7 excluding the analyses for
the randomization strata subgroups themselves. The subgroup analyses of second and third key secondary
endpoints will be conducted on the pruritus ITT analysis set and with the model for the change from
baseline values over the entire duration between baseline and week 52 and analyzed using the MMRM
while any outcome value after ICE-1 or ICE-3 will be considered as missing and will not be imputed as any
other missing observation (e.g. missing value not related to intercurrent event). Corresponding forest plots
for odds ratios/overall contrast by subgroup will be presented.
Within each subgroup, the treatment effect will be analyzed comparing Elafibranor to Placebo by
presenting the estimate of the risk difference, odds ratio/overall contrast and their corresponding 95% CIs.
For subgroup analysis, if the subgroup at baseline includes less than 20 patients across treatment groups
or less than 5 patients for a treatment group, the analysis will be omitted. In this case only descriptive
analysis by group will be provided. In addition, in the instance where there are no observations for a
treatment group for a unique randomization stratum then the stratification factors will be removed from
the analysis (exact CMH).
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4.6.7 Other secondary endpoints

For each other secondary endpoint, descriptive summary by visit, for each post-baseline visit (i.e. Visit 2 –
Week 4, Visit 3 – Week 13, Visit 4 – Week 26, Visit 5 – Week 39, Visit 6 – Week 52, Visit 7 – Week 78, Visit
8 – Week 104 if applicable) will be provided by treatment group on the ITT analysis set or pruritus ITT
analysis set according to the endpoint and based on available data as collected (see section 4.2.9).
Analyses of all other secondary endpoints will be performed using the ITT analysis set or pruritus ITT analysis
set according to the endpoint and using the composite strategy for binary endpoints (similar to the main
analysis for the primary efficacy endpoint, except that missing data for patients without ICE will be kept
missing), and hypothetical strategy for continuous endpoints (MAR assumption).
If the other secondary endpoint analyses lead to a subgroup analysis (e.g. defined on baseline) and the
subgroup includes less than 20 patients across treatment groups or less than 5 patients for a treatment
group, the analysis will be omitted. In this case only descriptive analysis by group will be provided. In
addition, in the instance where there are no observations for a treatment group for a unique randomization
stratum then the stratification factors will be removed from the analysis (exact CMH).
4.6.7.1 Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks (continuous)
Mean ALP values and change from baseline at each visit (baseline, V2, V3, V4, V5, V6, V7 and V8) will be
summarized by treatment group (Elafibranor 80mg and Placebo) using the ITT analysis set. Change from
baseline over time will also be plotted as well as the mean ALP over time using the LSM + 95% CI.
To assess the treatment effect on data collected up to week 52, change from baseline in ALP will be
compared between treatment and placebo using the MMRM with stratification groups as fixed factors. Visit
will be included as a fixed effect along with baseline ALP value. Visit will be considered as a repeated variable
within a patient. The treatment by visit interaction will be included in the model.
Missing values for any reason will be handled within the analysis itself with the assumption that the model
specification will be correct and that the data will be MAR (see section 4.2.9).
The treatment will be compared to placebo through week 52 for each scheduled visit from visit2-week 4 to
visit 6-week 52. As a first intention, the unstructured variance- covariance structure will be applied to model
the within-patient errors. If there is no convergence, the following structures will be tested until the model
succeeds to converge: heterogeneous Toeplitz structure (TOEPH), heterogeneous autoregressive(1)
(ARH(1)), heterogeneous compound symmetry (CSH), Toeplitz structure (TOEP), autoregressive(1) (AR(1)),
and compound symmetry.
The model will be fitted using the Restricted Maximum Likelihood method (REML). Denominator degrees
of freedom will be estimated using Kenward roger approximation. The statistical model will be used to
estimate the mean treatment difference and its 95% CI.
The estimated LSM, treatment difference, together with the 95% CIs and p-value will be presented. Sample
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SAS code (SAS code will be fully validated at the analysis stage):
Mixed Model Repeated Measures
PROC MIXED DATA=dataset;
CLASS usubjid visit treatment randstrata;
MODEL value = baseline randstrata treatment visit treatment*visit /
DDFM=KENWARDROGER; REPEATED visit / SUBJECT=usubjid TYPE=UN;
LSMEANS treatment treatment*visit / PDIFF CL;
ODS OUTPUT LSMeans = lsm; * contains the adjusted means;
ODS OUTPUT Diffs = dif; * contains treatment differences;
RUN;
4.6.7.2 ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
(binary)
ALP response rates at 52 weeks will be classified as:

3) ≥ 40% decrease from baseline (Yes/No).
The analysis for each ALP response rates described above will be conducted similar to the main analysis for
the primary efficacy endpoint (see section 4.6.2.1).
4.6.7.3 Response to treatment according to ALP < 1.5x ULN, ALP decrease from baseline ≥ 40%
and TB ≤ ULN at week 52 (binary)
The analysis on this endpoint will be conducted the same way as the analysis described in section 4.6.2.1.
4.6.7.4 Response to treatment according to ALP < 3x ULN, AST <2x ULN and TB ≤ 1 mg/dL (Paris I)
at week 52 (binary)
Note: the standard unit of Total bilirubin values is umol/L, then the conversion factor 1 mg/dL = 17.1 umol/L
will be applied to derive the criterion.
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4.6.7.5 Response to treatment according to ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ 1mg/dL (Paris
II) at week 52 (binary)
The analysis on this endpoint will be conducted the same way as the analysis described in section 4.6.2.1
Note: the standard unit of Total bilirubin values is umol/L, then the conversion factor 1 mg/dL = 17.1 umol/L
will be applied to derive the criterion.
4.6.7.6 Response to treatment according to TB decrease of 15% change from baseline at week 52
(binary)
4.6.7.7 Response to treatment according to normalization of abnormal TB (TB ≤ ULN) and/or ALB
(ALB ≥ LLN) (Rotterdam) at week 52 (binary)
The endpoint will only be derived and analyzed in patients with abnormal total bilirubin or albumin at
baseline.
Then patient will be considered as responder at week 52 only if total bilirubin and albumin are normal.
4.6.7.8 Response to treatment according to TB ≤ 0.6x ULN at week 52 (binary)
4.6.7.9 Response to treatment according to ALP ≤ 1.67x ULN and TB ≤ 1mg/dL (Momah/Lindor
criterion, 2011) at week 52 (binary)
4.6.7.10No worsening of TB defined as TB ≤ ULN at week 52 or no increase from baseline of more

than 0.1x ULN at week 52 (binary)
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4.6.7.11Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin, and INR at
week 52 (binary)
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4.6.7.12 UK-PBC score at week 52 (continuous)
The continuous UK-PBC score will be calculated at baseline and from week 4 to week 52 (V1 to V6) in
patients under UDCA through week 52 as follows:
UK-PBC score = 0.0287854*(alpEPxuln-1.722136304) - 0.0422873*(((altastEPxuln/10)^-1) - 8.675729006)
+ 1.4199 * (LN(bilEPxuln /10)+2.709607778) - 1.960303*(albxlln -1.17673001)-0.4161954*(pltxlln -
1.873564875)
Where
alpEPxuln=ALP /Upper Level Normal ALP at the timepoint
altastEPxuln=(ALT, AST or TA) /upper level normal of the value at the timepoint
bilEPxuln=bilirubin /upper level normal bilirubin at the timepoint
albxlln=alb /alb lower level normal at baseline
pltxlln=plt / plt lower level normal at baseline
The baseline survival function at the mean UK-PBC score S0(t) was: 0. 982, 0. 941, 0.893 at 5-, 10- and 15-
year follow-up, respectively. The survival S(t) for any given patients was then calculated by S(t) = S0(t)
exp(UK-PBC score).
Descriptive statistics, value and change from baseline, at baseline and from week 4 to week 52 (V1 to V6)
will be provided on the continuous UK-PBC PBC score.
Descriptive statistics at baseline and from week 4 to week 52 (V1 to V6) will be provided on the continuous
UK-PBC score predicted transplant-free survival at 5, 10 and 15 years.
The interpretation of this analysis should be made with caution. This analysis relies on strong assumptions
that the score computed for patients under UDCA after one year of treatment is also applicable to patients
with Elafibranor on top of UDCA, and the coefficients used to compute the score are applicable beyond 1
year of treatment.
4.6.7.13 GLOBE PBC score at week 52 (continuous)
The continuous GLOBE score will be calculated at the timepoints baseline and from week 4 to week 52 (V1
to V6) in patients under UDCA through week 52 as follows:
GLOBE score = 0.044378 * age at start of UDCA therapy + 0.93982 * LN(TBxuln) + 0.335648 * LN(ALPxuln)
– 2.266708 * ALBxlln – 0.002581 * platelet count per 10^9/L) + 1.216865.
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Where
TBxuln = bilirubin/ULN at the timepoint
ALPxuln = ALP/ULN at the timepoint
ALBxlln = ALB/LLN at the timepoint
platelet count per 10^9/L = platelet count per 10^9/L at the timepoint
The baseline survival curve at the mean GLOBE score S0(t) was: 0.9385, 0.8429, 0.7361 at 5-, 10- and 15-
year follow-up, respectively. The survival S(t) for any given patients was then calculated by S(t) = S0(t)
exp(GLOBE score).
Descriptive statistics, value and change from baseline, at baseline and from week 4 to week 52 (V1 to V6)
will be provided on the continuous GLOBE PBC score.
Descriptive statistics at baseline and from week 4 to week 52 (V1 to V6) will be provided on the continuous
Globe PBC score predicted transplant-free survival at 5, 10 and 15 years.
The interpretation of this analysis should be made with caution. This analysis relies on strong assumptions
that the score computed for patients under UDCA after one year of treatment is also applicable to patients
with Elafibranor on top of UDCA, and the coefficients used to compute the score are applicable beyond 1
year of treatment.
4.6.7.14 Response to treatment based on the proportion of patients who normalized bilirubin (TB
≤ ULN) at week 52 (binary)
The endpoint will only be derived and analyzed in patients with abnormal total bilirubin at baseline.
4.6.7.15Response to treatment based on the proportion of patients who normalized albumin

(ALB ≥ LLN) at week 52 (binary)
The endpoint will only be derived and analyzed in patients with abnormal albumin at baseline.
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4.6.7.16Change from baseline to week 52 in hepatobiliary injury and liver function as measured
by AST, ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated
(hepatic) (continuous)
Since the ALP fractionated (hepatic) is performed at baseline and Visit 6 - week 52 only, the MMRM reduces
to an ANCOVA.
Mean ALP, GGT, AST and ALT values and relative change from baseline at each visit (baseline , V2, V3, V4,
V5,V6, V7 and V8) will be summarized by treatment group (Elafibranor 80mg/day and Placebo).
The relative change ALP, GGT, AST, ALT from baseline to week 52 will be compared between Elafibranor
and placebo using a nonparametric randomization-based Analysis of Covariance method (LaVange et al,
2005). This methodology uses weighted least squares on the treatment differences of outcome and
covariate means. The resulting model estimates give the treatment effects for the outcomes, adjusting for
the covariates added into the model.
The method will be applied using the SAS NParCov4 macro (©Zinc and Koch, 2001), adjusting for baseline
ALP (or GGT, AST and ALT) level as a covariate.
Macro example for ALP relative change from baseline:
The macro will be applied to compare the relative change from baseline in ALP (PCTCHG) between the
active treatment and placebo, adjusting for baseline ALP (BASE).
Assumptions for this model are minimal:
• Randomization to treatment
• Patients in the study are a simple random sample
The macro will be applied in the following steps:

1. Create a dataset DATAIN. The dataset should include one observation per patient and include the
variables TRTPN (1 denotes placebo, 2 denotes Elafibranor 80mg), BASE (baseline ALP) and PCTCHG (relative
change at endpoint in ALP from baseline) calculated as described above. Restrict DATAIN to patients with
TRTPN=1 and TRTPN=2.
2. Apply the macro as shown: %NPARCOV4(OUTCOMES=PCTCHG, COVARS=BASE, C=0, HYPOTH=NULL,
STRATA=NONE, TRTGRPS=TRTP, TRANSFORM=NONE, COMBINE=NONE, DSNIN=DATAIN,
DSNOUT=DATAOUT)
3. Dataset _OUTDAT_COVTEST contains the evaluation of the covariate imbalance. P-value > 0.05
indicates random imbalance for the distribution of covariates between the 2treatments.
4. Extract the relevant data from the output datasets. Dataset _OUTDAT_DEPTEST gives the estimate
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(beta), standard error (sebeta) and p-value (pvalue) for the treatment difference and dataset
_OUTDAT_CI gives a 95% CI for this treatment estimate. The model compares TRTPN 2 vs 1.
Note: The variance under the null (HYPOTH=NULL) will be the structure for producing p-values, while the
variance under the alternative (HYPOTH=ALT) will be used for computing CIs.
4.6.7.17Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP,

For the hsCRP, before computing the model, the hsCRP value will be log-transformed. After back
transformation, the estimate of the between group geometric mean ratio and the corresponding 95% CI
and p-value will be displayed.
4.6.7.18Change from baseline to week 52 in immune response as measured by IgG and IgM
(continuous)
4.6.7.19Change from baseline to week 52 in biomarkers, non-invasive measures of hepatic

fibrosis as measured by ELF test (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30),
Pro-C3 and liver stiffness measured by Transient Elastography (continuous)
The Enhanced Liver Fibrosis score (ELF) will be calculated based on the following parameters: Hyaluronic
acid (HA) (ng/mL), PIIINP (ng/mL) and TIMP-1 (ng/mL) at baseline and each scheduled post-baseline visit.
The analysis on these measures will be conducted the same way as the analysis described in section 4.6.7.1.
4.6.7.20Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C,
4.6.7.21 Change from baseline to week 52 in Fasting Plasma Glucose (continuous)
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4.6.7.22Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as
4.6.7.23No worsening of pruritus based on PBC Worst Itch NRS through week 52 and through
week 24 (binary)
A worsening is defined by a positive change in PBC Worst Itch NRS from baseline greater than 2. The criteria
will be derived at week 52, i.e. at 4-week period 13 and at week 24, i.e. at 4-week period 6 respectively. It may
also be repeated at other time points.
The analysis on this measure will be conducted in patients who can experience “worsening” (i.e. with PBC
Worst Itch NRS score <8) at baseline and in the same way as the analysis described in section 4.6.2.1
4.6.7.24Proportion of responders in PBC Worst Itch NRS score according to clinically meaningful
change; at least 30% reduction; and one point, two points or three points decrease in score
from baseline through week 52 and through week 24 in patients with baseline PBC Worst
Itch NRS score ≥ 4
The proportion of responders in PBC Worst Itch NRS score at week 52, i.e. at 4-week period 13, and at week
24, i.e. at 4-week period 6, in patients with baseline PBC Worst Itch NRS score ≥ 4 (pruritus ITT analysis set)
will be investigated in different ways as follows:
- According to clinically meaningful (clinical important response): a meaningful change analysis in
PBC Worst Itch NRS score within the Psychometric Analysis, using scores on the PGIC and PGIS as
anchors, will be performed when approximately 100 patients will attend week 52 (V6) visit. The
meaningful change is defined by the amount of individual level change over a predefined period
that could be interpreted as a meaningful benefit. This analysis will be performed before the
database lock and in a blinded manner. The clinical important response (CIR), which represents
the threshold for clinical relevance for a within-patient change, will be derived according to the
determined threshold in the 4-week period PBC worst Itch NRS change from baseline.
- With at least a 30% of reduction in the 4-week period PBC Worst Itch NRS score change from
baseline
- With at least a one-point decrease in the 4-week period PBC Worst Itch NRS score change from
baseline
- With at least a two-point decrease in the 4-week period PBC Worst Itch NRS score change from
baseline
- With at least a three-point decrease in the 4-week period PBC Worst Itch NRS score change from
baseline
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The analysis on these outcomes will be conducted the same way as the analysis described in section 4.6.2.1
and may also be repeated at other time points.
4.6.7.25Proportion of participants achieving sustained improvement in PBC Worst Itch NRS

(binary)
The proportion of participants achieving sustained improvement in PBC Worst Itch NRS score in patients
with baseline PBC Worst Itch NRS score ≥ 4 (pruritus ITT analysis set) will be investigated in different ways
as follows:
- With a clinically meaningful change (improvement) at all the last three 4-week periods (periods
11, 12 and 13)
- With at least a 30% reduction in the 4-week period PBC Worst Itch NRS score from baseline in all
the last three 4-week periods (periods 11, 12 and 13)
- With at least a one-point decrease in the 4-week period PBC Worst Itch NRS score from baseline
in all the last three 4-week periods (periods 11, 12 and 13)
- With at least a two-point decrease in the 4-week period PBC Worst Itch NRS score from baseline
- With at least a three-point decrease in the 4-week period PBC Worst Itch NRS score from baseline
The analysis on these outcomes will be conducted the same way as the analysis described in section 4.6.2.1.
Note that if only one period among periods 11, 12 and 13 is missing then the remaining 2 available periods
will be used to derive the criteria and if more than 1 period among of the 3 periods, 11, 12 and 13 are
missing the criteria will be defined as missing.
4.6.7.26 PGIC and PGIS
The PGIC and PGIS are both single item 5-point scales. Whereas the PGIC assesses the change in overall itch
intensity since the baseline visit, the PGIS assesses the patient’s impression of itch severity.
PGIC and PGIS are collected as anchors to facilitate the derivation of a clinically meaningful threshold. Both
scales will be analyzed descriptively by visit and treatment groups. Shift from baseline for PGIS will also be
presented. In particular, shift tables for patients who achieved one-category and two-category PGIS
improvement respectively at visit 6 – week 52 will be presented.
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4.6.7.27 Change from baseline to week 52 in 5-D Itch (continuous)
The items of the 5-D Itch Scale are grouped into five domains: duration, degree, direction, disability and
distribution. The duration, degree and direction domains each include one item, while the disability domain
has four items. All items of the first four domains are measured on a five-point Likert scale. The distribution
domain includes 16 potential locations of itch, including 15 body part items and one point of contact with
clothing or bandages.
Single-item domain scores (duration, degree and direction) are equal to the value indicated below the
response choice (range 1–5).
The disability domain includes four items that assess the impact of itching on daily activities: sleep,
leisure/social activities, housework/errands and work/school. The score for the disability domain is
achieved by taking the highest score on any of the four items.
For the distribution domain, the number of affected body parts is tallied (potential sum 0–16) and the sum
is sorted into five scoring bins: sum of 0–2 = score of 1, sum of 3–5 = score of 2, sum of 6–10 = score of 3,
sum of 11–13 = score of 4, and sum of 14–16 = score of 5.
The scores of each of the five domains are achieved separately and then summed together to obtain a total
5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus).
Descriptive statistics will be provided by domain (considered as categorical) and for the Total 5-D score
(considered as continuous) at each visit and by treatment group for the ITT and pruritus ITT analysis sets.
A comparative analysis between treatment groups on the Total 5-D score will be conducted the same way
as the analysis described in section 4.6.7.1 using a MMRM with stratification groups as fixed factors. Visit
will be included as a fixed effect along with baseline Total 5-D score. Missing values will be handled within
the analysis itself with the assumption that the model specification will be correct and that the data will be
MAR (see section 4.2.9). This analysis will be provided for the ITT and pruritus ITT analysis sets.
4.6.7.28 Change from baseline to week 52 in PROMIS Fatigue Short Form 7a (continuous)
In PROMIS Fatigue short form 7a, each of the 7 questions has five response options ranging in value from
one (never) to five (always). First, the total raw score is computed by summing the values of the response
to each question. All questions must be answered in order to produce a valid score using the scoring tables,
otherwise the total raw score will be handled as missing. Finally, the score conversion table in APPENDIX C
will be used to translate the total raw score into a T-score for each participant. The T-score rescales the raw
score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Descriptive statistics will be provided by question (considered as categorical), for the total raw score
(considered as continuous) and the T-score (considered as continuous) at each visit by treatment group for
the ITT and pruritus ITT analysis sets.
A comparative analysis between treatment groups on the T-score will be conducted the same way as the
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analysis described in section 4.6.7.1 using a MMRM with stratification groups as fixed factors. Visit will be
included as a fixed effect along with baseline T-score. Missing values will be handled within the analysis
itself with the assumption that the model specification will be correct and that the data will be MAR (see
section 4.2.9). This analysis will be provided for the ITT and pruritus ITT analysis sets.
4.6.7.29 Change from baseline to week 52 in Epworth Sleepiness Scale (continuous)
The Epworth Sleepiness Scale (ESS) is composed of 8 items investigating the same domain. Each item is
scored using the 4-point Likert scale ranging from 0: would never doze to 3: high chance of dozing. The total
score is the sum of all item scores and ranges from 0 to 24. If one or more item-scores are missing, the
questionnaire is invalid, and the total score will be handled as missing.
The Total ESS score can be interpreted as follows: 0-5 Lower Normal Daytime Sleepiness; 6-10 Higher
Normal Daytime Sleepiness; 11-12 Mild Excessive Daytime Sleepiness; 13-15 Moderate Excessive Daytime
Sleepiness; 16-24 Severe Excessive Daytime Sleepiness.
Descriptive statistics will be provided by item (considered as categorical) and for the total score (considered
as continuous) at each visit by treatment group for the ITT and pruritus ITT analysis sets.
A comparative analysis between treatment groups on the total score will be conducted the same way as
the analysis described in section 4.6.7.1 using a MMRM with stratification groups as fixed factors. Visit will
be included as a fixed effect along with baseline total score. Missing values will be handled within the
analysis itself with the assumption that the model specification will be correct and that the data will be
MAR (see section 4.2.9). This analysis will be provided for the ITT and pruritus ITT analysis sets.
4.6.7.30 Change from baseline to week 52 in PBC-40 (continuous)
In PBC-40 measures, each item is scored from 1 to 5 and the individual item scores are summed to give a
total domain score (Symptoms, Itch, Fatigue, Cognition, Social, Emotional). Data should be considered by
domain rather than in terms of a cumulative PBC-40 score. If data are missing from a domain (typically
missed or duplicated answers) the whole domain should be discarded if <50% of items are completed. If
>50% of responses are present, then the median value for the completed items in the domain should be
ascribed to the missing item. The direction of scoring of some items is reversed for calculation of domain
scores so that in all cases, high scores represent high impact and low scores low impact of PBC on quality
of life.
Descriptive statistics will be provided by domain (Symptoms, Itch, Fatigue, Cognition, Social, Emotional) at
each visit by treatment group for the ITT and pruritus ITT analysis sets.
A comparative analysis between treatment groups by domain (Symptoms, Itch, Fatigue, Cognition, Social,
Emotional) will be conducted the same way as the analysis described in section 4.6.7.1 using a MMRM with
stratification groups as fixed factors. Visit will be included as a fixed effect along with baseline domain score.
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Missing values will be handled within the analysis itself with the assumption that the model specification
will be correct and that the data will be MAR (see section 4.2.9). This analysis will be provided for the ITT
and pruritus ITT analysis sets.
4.6.7.31Change from Baseline to week 52 in health utility as measured by the EQ-5D-5L

(continuous)
The EQ-5D-5L questionnaire is composed of 5 dimensions (mobility, self-care, usual activities,

pain/discomfort and anxiety/depression), each one is scored from 1 (best) to 5 (worst), plus a visual analog
scale numbered from 0 (worst) to 100 (best).
Descriptive statistics will be provided by dimension (considered as categorical) and for the VAS (considered
as continuous) at each visit by treatment group for the ITT and pruritus ITT analysis sets.
A comparative analysis between treatment groups on the VAS will be conducted the same way as the
analysis described in section 4.6.7.1 using a MMRM with stratification groups as fixed factors. Visit will be
included as a fixed effect along with baseline VAS. Missing values will be handled within the analysis itself
with the assumption that the model specification will be correct and that the data will be MAR (see section
4.2.9). This analysis will be provided for the ITT and pruritus ITT analysis sets.
4.6.7.32Onset of clinical outcomes described as a composite endpoint of MELD-Na; Liver

transplant; Uncontrolled ascites requiring treatment; Hospitalization for Variceal bleed,
for Hepatic encephalopathy and for spontaneous bacterial peritonitis; death until week
52 (Binary)
Onset of clinical outcomes through week 52 will be described as a composite endpoint (binary) and will be
composed of at least one of the following events:
• MELD-Na > 14 for patients with baseline MELD-Na≤12
• Liver transplant
• Uncontrolled ascites requiring treatment
• Hospitalization for new onset or recurrence of any of the following:
a. Variceal bleed
b. Hepatic encephalopathy defined as West-Haven/Conn of 2 or more
c. Spontaneous bacterial peritonitis
• Death
Descriptive analyses of the composite endpoint and for each event will be conducted where number and
percentage of patients will be summarized by treatment group.
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4.6.7.33Change from baseline to week 52 in serum markers of bone turnover and in bone mineral
density (hip and lumbar) assessed by DEXA scanning (continuous)
The analysis on the serum markers of bone turnover (CTX, P1INP), and the analysis on the bone mineral
densities (in g/cm2) of the total hip, femoral neck and the lumbar will be conducted the same way as the
Since the DEXA scanning is performed at baseline and week 52 only, the MMRM reduces to an ANCOVA.
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4.7 Pharmacokinetic Evaluations
The statistical considerations applicable to the popPK modeling, will be fully described in a dedicated
Analysis Plan (popPK SAP).
All plasma concentration data will be summarized and listed. For participants from the Pharmacokinetics
Analysis Set, individual plasma concentrations for elafibranor and GFT1007 will be summarized by
timepoint and by visit, using descriptive statistics for continuous variables (number of available
observations, number of below the limit of quantification, mean, SD, % coefficient of variation (CV),
geometric mean and %CV geomean, median, minimum, maximum).
4.8 Safety Analyses
The analysis of the extent of exposure and compliance to treatment will be conducted using theSafety
analysis sets. Safety analyses of AEs, laboratory parameters, and vital signs will be conducted using the
Safety analysis set. Analyses of concomitant medications and concomitant procedures will be conducted
using the ITT analysis set and will be repeated on the Safety analysis set only if safety analysis set is different
from ITT.
4.8.1 Extent of Exposure and Compliance
4.8.1.1 Extent of Exposure
Duration of treatment and duration of exposure (in weeks) from Study Visit 1 to Week 52 visit and until the
end of double-blind period (EODB) will be summarized by treatment group (see section 4.2.2). The number
and percentage of patients in categories defined by duration of exposure in weeks will also be provided.
The definition is as follows:
• Total duration of exposure (in weeks):
o Up to week 52: (minimum of (date of last dose, date of death, date of data cutoff, date
of week 52 visit) – first dose date + 1)/7
o Up to EODB period: (minimum of (date of last dose, date of death, date of data cutoff,
date of last visit during the double-blind period) – first dose date + 1)/7
• Total duration of exposure (in weeks) up to week 52 and up to the EODB period in categories: ≥0
to <12, ≥12 to <24, ≥24 to <36, ≥36 to <48, ≥48 to <60, ≥60 to <72, ≥72 to <96, ≥96 to <104, >=
104
Exposure data will be listed in patient data listing.
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4.8.1.2 Compliance
The patient should take one tablet of Elafibranor (80 mg/day) or placebo every day:
While the patient is being treated with the study drug, the patient will be directed to bring back all used
and unused cartons and blisters at each visit. Compliance will be checked by the Investigator during those
visits and recorded on the eCRF. Percentage compliance will be calculated as:
100 * tablets taken/expected tablets taken,
Where the tablets taken is defined as the total number of tablets dispensed – the total number of tablets
returned. It is assumed that tablets not returned have been taken by the patient. If not the case, it may lead
to overestimation of the compliance.
The expected tablets taken is defined as the total duration of exposure in days.
The number and percentage of compliant patients will be presented for the Safety analysis set, where
compliant is defined as percentage compliance between 80.0% and 120.0% inclusive. The following
percentage compliance categories will be presented :<80.0%; ≥80.0% to ≤120.0%; >120.0%.
Compliance data will be summarized until Week 52 visit and until the EODB period. Cumulative dose (mg)
and total expected dose (mg) until Week 52 visit and until the EODB period will also be summarized for
Elafibranor arm.
Compliance data will also be listed.
4.8.2 Adverse Events
AEs will be coded using MedDRA and displayed in tables and listings using System organ class (SOC) and
grouped Preferred term (PT). Some groupings of Preferred Terms of AEs will be done. The intent of grouping
PTs for safety analyses is to avoid splitting of PTs to ensure that adverse events are adequately captured.
Two different approaches will be used to group PT: the first will be to use a three-level coding, system organ
class (SOC), high level term (HLT) and preferred term (PT), the second will be to use specific SMQ provided
by the medical team before DBL.
Analyses of AEs will be performed for those events that are considered treatment-emergent AE (TEAE),
where treatment-emergent is defined as any AE with onset on or after the date of first administration of
study treatment and up to the date of the last DB data collection for the patients that complete DB period
and will switch in LTE and up to 30 days after the date of the last study treatment for the patients that
discontinue the study treatment during DB period, respectively or any event with start date prior to first
dose of treatment whose severity worsened in intensity on or after the date of first dose of study treatment
and up to the date of the last DB data collection for the patients that complete DB period and switch in LTE
and up to 30 days after the date of the last study treatment for the patients that discontinue the study
treatment during DB period, respectively.
An overview of AEs will be provided displaying the number of events along with the number and percentage
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of patients with at least one:

• AE
• AESI
• Serious AE
• Severe AE
• TEAE
• TEAE by maximum severity
• TEAE related to study medication
• Serious TEAE
• Serious TEAE related to study medication
• TEAE leading to treatment discontinuation
• TEAE leading to study discontinuation
• TEAE related to study medication leading to treatment discontinuation
• TEAE related to study medication leading to study discontinuation
• Serious TEAE leading to treatment discontinuation
• Serious TEAE related to study medication leading to treatmentdiscontinuation
• Serious TEAE leading to study discontinuation
• Serious TEAE related to study medication leading to study discontinuation
• Serious TEAE leading to death
• Serious TEAE related to study medication leading to death.
• TEAE related to study procedure
AEs are summarized giving the total number of events as well as by patient incidence rates, therefore, in
any tabulation, a patient contributes only once to the count for a given AE (SOC or PT). For summaries by
maximum severity, patients with multiple AEs within a particular SOC or PT will be counted under the
category of their most severe AE within that SOC or PT. Tables will be sorted by descending frequency of
SOC/PT or SOC/HLT/PT (if applicable) in Elafibranor group.
The number of events along with the number and percentage of patients with any AE will be summarized
by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any TEAE will be summarized
by treatment group. Three distinct tables will be provided by SOC/PT, by SOC/HLT/PT, and by SMQ provided
by the medical.
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TEAEs with frequency of patients > 1%, >5% and >10% in any treatment group will also be summarized by
SOC/PT and by SOC/HLT/PT.
The number of events along with the number and percentage of patients with any severe TEAE will be
summarized by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any TEAE by maximum
severity (mild, moderate, severe) and TEAE related to study medication (i.e. related, possibly related, and
not assessable) will be summarized by treatment group and by SOC/PT. Relationship to study medication is
not expected to be missing after data cleaning; however, if relationship is confirmed as missing, the AE will
be considered as treatment related.
The number of events along with the number and percentage of patients with any serious TEAE and with
any serious TEAE related to study medication will be summarized by treatment group and separately by
SOC/PT and SOC/HLT/PT.
The number of events along with the number and percentage of patients with any TEAE leading to
treatment discontinuation will be summarized by treatment group and separately by SOC/PT and
SOC/HLT/PT.
The number of events along with the number and percentage of patients with any TEAE related to study
medication leading to treatment discontinuation will be summarized by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any TEAE leading to study
discontinuation and with any TEAE related to study medication leading to study discontinuation will be
summarized by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any serious TEAE leading to
treatment discontinuation and with any serious TEAE related to study medication leading to treatment
discontinuation will be summarized by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any serious TEAE leading to
study discontinuation and with any serious TEAE related to study medication leading to study
discontinuation will be summarized by treatment group and by SOC/PT.
The number of events along with the number of events along with the number and percentage of patients
with any serious TEAE leading to death and with any serious TEAE related to study medication leading to
death will be summarized by treatment group and by SOC/PT.
The number of events along with the number and percentage of patients with any TEAE related to the study
procedure will be summarized by treatment group and by SOC/PT. In these tabulations, each patient will
contribute only once (i.e., the most related occurrence or the most intense occurrence) to each of the
incidence rates in the descriptive analysis, regardless of the number of episodes.
No formal hypothesis-testing analysis of AEs incidence rates will be performed.
All AEs (more especially, death, serious TEAEs, non-treatment-emergent SAEs, TEAEs leading to withdrawal
or temporary withdrawal of study drug) occurring on study will be listed in patient data listings.
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AESI are TEAEs which are defined according to categories and sub-categories as follows:
• Muscle injury symptoms of severe intensity correspondingto:
o Muscle weakness
discontinuation
o Hepatic injury
o Hepatic failure
• Gastrointestinal symptoms of severe intensity correspondingto:
o Abdominal pain
o Constipation
o Diarrhea
o Nausea
o Vomiting
o Acute cholecystitis
• Serum creatinine elevations of severe intensity or leading to permanent study drug
discontinuation
• Renal injury events of moderate or severe intensity correspondingto:
o Renal injury
o Renal failure
o Renal impairment
o Renal colic
o Tremor
o Ataxia
o Fasciculations
o Non-fatal stroke
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o Unstable Angina
o Coronary Revascularization (bypass or percutaneous coronary intervention)
• Treatment-emergent Pregnancy and outcomes of Pregnancy
All of the above categories, with the exception of the pregnancy AESIs, will be identified via a list of MedDRA
queries of PT codes. Pregnancy AESIs will be identified using positive pregnancy assessment and reported
in the pregnancy report form.
For each of the AESI categories and subcategories defined above, besides treatment-emergent pregnancy,
the number and percentage of patients with at least one event and the corresponding number of events
will be summarized for any:
• AESIs
• Treatment related AESIs
• Serious AESIs
• AESIs leading to death
• AESIs leading to treatment discontinuation
In addition, the total number and percentage of patients with at least one AESI (with the exception of
treatment-emergent pregnancy), and the corresponding number of events will be summarized for the five
categories above.
A between-group comparison will be performed using the exposure-adjusted incidence rates (EAIR) of
treatment-emergent AEs (TEAE), serious TEAE, TEAE leading to treatment discontinuation, TEAE leading to
study discontinuation and AESIs.
The exposure-adjusted incidence rate (patients per patient-year) is defined as:
Number of patients with at least one event / Total exposure time for all patients at risk
and will be calculated by treatment arm.

The exposure time will be differentiated according to the occurrence or not of the event and will be
summarized. If the patient experiences an event: their exposure time will be the time until initial occurrence
of their events. If patient does not experience an event:
- For patients who discontinue the study treatment during the DB period, their exposure time will
be censored at the time of the last treatment intake date plus 30 days (minimum of ((last
treatment date + 30 days, date of death, database cut-off date) – first treatment date +
1)/365.25). The addition of 30 days matches the maximum time for scheduling the safety follow-
up visit and the SAE reporting period after treatment discontinuation.
- For patients who don’t discontinue the study treatment during the DB period, exposure time will
be censored on the patient DB period end date (minimum date of the last double-blind visit, first
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LTE treatment intake (if complete) – 1). The addition of 30 days after last dose of DB treatment
does not apply to those patients that will complete DB period and will enter in the LTE period to
receive open label elafibranor.
The comparison will be summarized using the EAIR difference, which will be accompanied by a 95% CI for
the overview of adverse event and AESI, TEAE, serious TEAE, TEAE leading to treatment discontinuation,
TEAE leading to study discontinuation. The 95% CI for the EAIR difference will be computed using the He
and al method (He et al, 2015).
For pregnancy, the number and percentage of patients with at least one event and the corresponding
number of events will be summarized by treatment group. The outcomes of pregnancy will also be
summarized by SOC and grouped PT.
The number and percentage of patients who developed lipid abnormality and/or dysglycemia through the DB
period will be summarized by SMQ code/PT and by treatment group using the following SMQ:
- Hypoglycaemia (SMQ Code 20000226)
- Hyperglycaemia/new onset diabetes mellitus (SMQ Code 20000041)
- Dyslipidaemia (SMQ Code 20000026)
The risk difference and its 95%CI (Newcombe) between Elafibranor and Placebo will also be provided.
The number and percentage of patients who developed hepatic injury and hepatic failure through the DB
period will be summarized by custom queries/PT and by treatment group using following custom queries
presented in Appendix F. These custom queries may be updated at the last BDRM before unblinding.
The risk difference and its 95%CI (Newcombe) between Elafibranor and Placebo will also be provided.
The incidence rate per patient exposure years, the EAIR difference and its 95% CI will be computed using
the He and al method (He et al, 2015) by treatment group and according to the custom queries will be
provided.
Time to the onset of first TEAEs, defined as (start date of the first TEAE – first study treatment date +1)/7,
and duration of first TEAEs, defined as (end date of first TEAE – start date of first TEAE +1)/7 and for ongoing
TEAE, the end date will be imputed as the datacut date, will be summarized by preferred term and by
treatment group. The table will be sorted by descending frequency of PT in Elafibranor group.
4.8.3 Adjudicated events

The number of events along with the number of events along with the number and percentage of patients
with any adjudicated adverse events including DILI will be summarized by treatment group. Only positively
adjudicated events will be displayed. The number and percentage of the adjudicated outcome of Clinical
Outcomes and DILI will be also summarized by treatment group. If the CEC identified any un-reported
events, they will be summarized by treatment group.
All adjudicated events for each patient will be provided in data listings.
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Note: for the adjudications of events, only collected data in the EDC will be used.
4.8.4 Laboratory Data
Clinical laboratory evaluations include hematology, chemistry and urinalysis. Clinical laboratory values will
be expressed using standard international (SI) and conventional (US) units with normal ranges and
respective units for each parameter provided. All analyses will be done on the central laboratory data
including baseline derivation. Local laboratory data will be provided on a patient data listing.
In the event of repeated post-baseline values, the first non-missing value per study day/time will be used.
In the following calculations, observed data more than 30 days after study treatment discontinuations for
patients who discontinued study treatment are handled as missing values (see section 4.2.9), but are
included and flagged in any data listings.
Potentially clinically significant laboratory abnormalities (PCSA) will be determined based on the CTCAE
criteria version 5.0 and defined as Grade 2 or higher for the laboratory tests of interest (see section 10).
Note that CTCAE scale could not cover all data cases and for such cases, clinically relevant PCSA thresholds
have been added in Appendix D (see section 10).
Serum hematology and serum chemistry (see Table 2) assessed from blood and urine samples taken at
baseline, V2, V3, V4, V5 and V6 will be summarized by treatment group. If applicable, values obtained at V7
and V8 will also be summarized by treatment group. Changes from baseline in serum hematology and
chemistry parameters will be summarized by treatment group and scheduled visit using shift tables to
present the frequencies and percentage of patients below, within and above the normal ranges at baseline
and at each post-baseline visit. In addition, change from baseline to worst value during the DB period in
serum hematology and chemistry parameters will be summarized by treatment group. Worst value and
change from baseline through the BD period, including scheduled and unscheduled visits, will be classified
by the medical team into the following categories: high worst, low worst or both (high and low worst)
according to the parameter (see Appendix E section 11).
Figures of chemistry mean creatinine and mean creatine phosphokinase will be produced using data as
collected for the change from baseline over time and separately up to week 52 and up to week 104.
A summary descriptive, shift table and a patient data listing of potentially clinically significant laboratory
abnormalities for the laboratory tests of interest (see section 10) identified using the CTCAE v5 will be
provided by treatment group, by scheduled visit and through DB period.
For serum creatinine, also the percentage change from Baseline by visit and the high worst value and
percentage change from baseline through DB period (including scheduled and unscheduled visits) will be
presented and all serum creatinine values of patients with a post-baseline percentage change increase by
25% or greater will be listed.
For urine ACR, the percentage change from Baseline by visit and the high worst value and percentage
change from baseline through DB period (including scheduled and unscheduled visits) will be presented.
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For patients with (at least one) increase by 25% change from baseline in serum creatinine, the percentage
change from baseline by visit and the high worst value and percentage change from baseline through DB
period (including scheduled and unscheduled visits) will be repeated for urine ACR.
For Cystatin C, the percentage change from Baseline will be presented for all patients by visit and the high
worst value and percentage change from baseline through DB period (including scheduled and unscheduled
visits), and in the subgroup of patients with (at least one) increase by 25% change from baseline in serum
creatinine. For patients with (at least one) increase by 25% change from baseline in serum creatinine,
summary statistics by visit and the high worst value and percentage change from baseline through DB
period (including scheduled and unscheduled visits) for Cystatin C will be repeated.
For eGFR, the CKD-EPI - Cystatin C parameter will be derived (Inker et al. 2012), the CKD-EPI creatinine
equation and the MDRD parameters will come from central laboratory. The percentage change from
baseline will be presented separately for those three eGFR parameters by visit in the subgroup of patients
with (at least one) increase by 25% change from baseline in serum creatinine and the high worst value and
percentage change from baseline through DB period (including scheduled and unscheduled visits) will also
be displayed.
Biobank samples (see Table 2) collected from additional blood samples from patients, who have given their
consent, at baseline, V2, V3, V4, V5 and V6 - and if applicable at V7 and V8- will be summarized by treatment
group.
Frequency and percentage of changes from Baseline classified as increase by 100%, 200% and 300% or
greater in biomarker results will be given (including other biochemical safety markers (Cystatin C, urine
ACR, urinary myoglobin) and biomarkers of inflammation (HsCRP, fibrinogen, haptoglobin, TNF-α, IL-6, ELF
(HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3).
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots will present the concomitant values of
aminotransferase (AT: ALT or AST) and TB at the visit corresponding to the peak of AT.
Distinct plots will be produced separately with regards to the peaks of ALT and AST. For each patient and
for both ALT and AST, the strategy is as follows:
• Among all the visits (includes only values as described in the beginning of section 4.2.9), identify
the maximum value of AT
• If the peak value occurs at just one visit, keep the value of TB at the visit corresponding to the
peak of AT
• If the peak value occurs at more than one visit, keep the highest value of TB at any of the visits
corresponding to the peak of AT
• If the peak value occurs at a visit/visits with no corresponding value/values of TB, keep the value
of bilirubin closest to the corresponding visit / any of the corresponding visits. In the event of
equidistant time from the peak value visit / visits, keep the highest value of TB at any of the visits
equidistant from the corresponding visit/visits of peak AT
• Classify patients into two subgroups: baseline value of ALT ≤ ULN or baseline value of ALT > ULN.
o If baseline value of ALT ≤ ULN, express TB in xULN on the y-axis and AT in xULN on the x-
axis. Add horizontal and vertical lines corresponding to TB = 2 ULN and AT = 3 ULN,
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respectively.
o If baseline value of ALT > ULN, present two plots:
 Express TB in xBaseline on the y-axis and AT in xBaseline on the x-axis. Add
horizontal and vertical lines corresponding to TB = 2xBaseline and AT =
3xBaseline, respectively. For TB values > 2xBaseline, values identified as > 2 ULN
will be plotted differently than values ≤ 2 ULN.
 Express TB in xULN on the y-axis and AT in xBaseline on the x-axis. Add horizontal
and vertical lines corresponding to TB = 2 ULN and AT = 3xBaseline, respectively.
Increases in serum creatinine through the end of the 52-week DB period and through the last post-baseline
visit during the double-blind period will be presented as:
• Occurrence of at least one post baseline value > ULN (only on the subset of patients with
baseline value ≤ ULN)
• Change from baseline in creatinine presented in classes according to KDIGO (Kidney Disease
Improving Global Outcomes) AKI (Acute Kidney Injury) stages. Among all visits, the worst case will
be retained:
o ≥ 1.5xBaseline and < 2.0xBaseline, or ≥ 0.3 mg/dL increase
o ≥ 2.0xBaseline and < 3.0xBaseline
o ≥ 3.0xBaseline or ≥ 4 mg/dL.
Hepatic laboratory test elevations (HLTE) will be based on fold changes above the upper limit of normal
(ULN).
Cumulative elevations
- ALT value > 1x, > 3x, > 5x, > 10x, > 20x ULN and ALT change from baseline >250 U/L
- AST value > 1x, > 3x, > 5x, > 10x, > 20x ULN and AST change from baseline >250 U/L
- ALP value > 2x, > 3x ULN and ALP change from baseline >150 U/L
- Total bilirubin value > 2x, > 5x, > 8x ULN and TB change from baseline > 2 mg/dL
- Direct bilirubin value > 2x, > 5x ULN and Direct bilirubin change from baseline > 1 mg/dL
- GGT value > 2x ULN
- INR value > 1.5x, 3x and 5x ULN
These are based on the highest ratio of value in the double-blind safety period, including scheduled and
unscheduled visits, to ULN for each laboratory test. Note that patients may be in > 1 category for each
laboratory test.
HLTE will be displayed in frequency tables presenting the number and percentage of patients in categories
and the associated risk difference and its 95% CI (Newcombe).
The incidence rate per patient exposure years, the EAIR difference and its 95% CI will be computed using
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the He and al method (He et al, 2015) by treatment group and according to the HLTE will be provided.
In order to identify patients who meet potential DILI triggers (parameters being assessed at the same visit),
the following biochemical triggers will be summarized:
- For patients with all normal AST, ALT, ALP, TB, direct bilirubin and GGT at baseline:
o (ALT >= 3x ULN or AST >= 3x ULN) and TB >= 2x ULN
o ALT >= 5x ULN or AST >= 5x ULN
o ALT >= 8x ULN or AST >= 8x ULN
o (ALT >= 3x ULN or AST >= 3x ULN) and INR > 1.5
o ALP >= 2x ULN and direct bilirubin >= 2x ULN
o GGT >= 2x ULN and direct bilirubin >= 2x ULN
- For patients with at least one abnormal laboratory parameter (AST, ALT, ALP, TB, direct bilirubin or
GGT) at baseline
o (ALT >= 3x baseline or AST >= 3x baseline) and TB >= 2x BL
o ALT >= 3x baseline or AST >= 3x baseline
o ALT >= 5x baseline or AST >= 5x baseline
o (ALT >= 2x baseline or AST >= 2x baseline) and INR > 1.5
o ALP >= 2x baseline and ALP > ULN and direct bilirubin >= 2x baseline and direct bilirubin >
ULN
o GGT >= 2x baseline and GGT > ULN and direct bilirubin >= 2x baseline and direct bilirubin >
ULN
Potential DILI triggers will be displayed in frequency tables presenting the number and percentage of
patients in categories and the associated risk difference and its 95%CI.
The incidence rate per patient exposure years (see section 4.8.1.1 for derivation rules), the EAIR difference
and its 95% CI will be computed using the He and al method (He et al, 2015) by treatment group and
according to the Potential DILI triggers will be provided.
Serum bile acids and biomarkers of bile acid synthesis, biomarkers of hepatic fibrosis and/or inflammation,
additional kidney safety markers and immunoglobulins (see Table 1 and Table 2) at baseline and each
scheduled post-baseline visit of the DB period will be summarized by treatment group.
All laboratory data will be provided in data listings.
4.8.5 Transient elastography
In the following calculations, observed data after the occurrence of the ICEs start of rescue therapy or more
than 30 days after other study treatment discontinuations for patients who discontinued study treatment
are handled as missing values (see section 4.2.9), but are included and flagged in any data listings.
The actual value and change from Baseline to each scheduled visit evaluation (baseline, V4, V6, and if
applicable V7 and V8) for transient elastography (continuous, including Stiffness / Liver Stiffness
Measurement in kPa, Interquartile range (IQR) in kPa and Interquartile range (IQR)/median in %) will be
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summarized by treatment group.

By-patient listings of transient elastography measurements will be presented in data listings.
4.8.6 Vital Signs and Physical Examinations
The actual value and change from Baseline to each study visit evaluation (baseline, V2, V3, V4, V5, V6, and
if applicable V7 and V8) for vital signs (continuous, including weight and derived BMI using height at
screening) will be summarized by treatment group. In addition, temperature, systolic and diastolic blood
pressure, respiratory and heart rates, will be summarized descriptively, including the number and percent
of patients with normal, abnormal, and clinically significant abnormal results at each applicable scheduled
visit and the worst value through DB period (including scheduled and unscheduled visits) by treatment
group; shifts from Baseline in those parameters to each scheduled visit and through DB period will also be
presented.
For gain weight, the number and percentage of patients who experienced weight gain by ≥+2 kg, ≥+5 kg, or
≥+10 kg over their baseline weight through the DB period, will be summarized by treatment group.
By-patient listings of vital sign measurements will be presented in data listings.
Physical examination results at baseline, V2, V3, V4, V5, V6 and if applicable V7 and V8 will be summarized
by treatment group; shifts from Baseline in physical examination findings to each scheduled visit and the
worst value through DB period (including scheduled and unscheduled visits) will also be presented.
All physical examination findings will be presented in a data listing.
Liver, and bladder and urinary tract ultrasound results will be summarized descriptively, including the
number and percent of patients with normal, abnormal, and clinically significant abnormal results at each
applicable study visit by treatment group; shifts from Baseline in Liver, and bladder and urinary tract
ultrasound results to each on study visit will also be presented. Data will be presented in a data listing.
4.8.7 Electrocardiogram
12-lead ECG results will be summarized descriptively, including the number and percent of patients with
normal, abnormal, and clinically significant abnormal results at Baseline, V4, V6 and if applicable V8; shifts
from Baseline in 12-lead ECG results to each scheduled visit and the worst value through DB period
(including scheduled and unscheduled visits) will also be presented.
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All ECG data for each patient will be provided in data listings.
4.8.8 Concomitant Medications
Any medications that did not stop before the first study treatment date and continued into the DB period
will be counted as concomitant medications as well as any medications that start on or after the first study
treatment date, whichever its end date.
Concomitant medications will be coded using the WHO Drug dictionary. Results will be summarized by
treatment group using Therapeutic Subgroup (ATC level 2) and Chemical Subgroup (ATC level 4).
Concomitant medications will be listed in descending order of total frequency within therapeutic and
chemical subgroup.
The use of concomitant medications will be included in by-patient data listing.
4.8.9 Concomitant Procedures
Any procedures that did not stop before the first study treatment date and continued into the DB period
will be counted as concomitant procedure as well as any procedures that start on or after the first study
treatment date, whichever its end date.
Concomitant procedures will be coded using MedDRA and displayed by treatment group in tables and
listings using system organ class (SOC) and preferred term (PT). Concomitant procedures will be listed in
tables by descending order of total frequency within SOC and PT.
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4.9 Exploratory analyses (related to histological assessments)
Exploratory analyses will be performed to evaluate the association between histological scores and non-
invasive markers of fibrosis on the Exploratory set.
The demographic and baseline disease characteristics (see section 4.5.1 and 4.5.3) will be summarized on
the Exploratory analysis set.
In case of limited number of patients who consent to have liver biopsy samples collected, only individual
patient’s data listings (including for demographics and baseline characteristics) will be provided.
The Histological endpoints and associated scorings are summarized in the following table:
Table 6: Histological Endpoints

Endpoint Scoring
Fibrosis (Nakanuma) score • 0
• 1
• 2
• 3
Bile duct loss score • 0
• 1
• 2
• 3
Cholangitis activity • Grade 0
• Grade 1
• Grade 2
• Grade 3
Interface hepatitis activity • Grade 0

• Grade 1
• Grade 2
• Grade 3
Stage of disease (according to sum of • Stage 1 if the sum is 0
Nakanuma and Bile duct loss scores) • Stage 2 if the sum is 1 or 2
• Stage 3 if the sum is 3 or 4
• Stage 4 if the sum is 5 or 6.
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Fibrosis (Ishak) score • Stage 0

• Stage 1
• Stage 2
• Stage 3
• Stage 4
• Stage 5
• Stage 6
Portal inflammation • None
• Mild
• Moderate
• Severe
Ductular reaction • Absent or very mild
• Mild
• Significant
Cholestasis • Yes
• No
Concentric periductal fibrosis • Yes
• No
The non-invasive markers considered in the analyses are:

• Liver stiffness,
• ELF test,
• ProC3
Descriptive statistics on the histological scores and the non-invasive markers will be provided by DB
treatment groups.
The histological scores will be described using shift tables to assess the change of each score between
baseline and week 52. If a sample reading is classified inadequate, the scores will be set at missing.
Non-invasive markers of fibrosis will be described as continuous endpoints, providing the descriptive
statistics at each visit as well as the change from baseline.
The correlation between the histological fibrosis scores (i.e., Nakanuma and Ishak scores) and non- invasive
markers of fibrosis will be assessed on the:
• values at baseline
• values at week 52
• change from baseline to week 52 values
The Spearman correlation coefficients and their 95%CIs will be estimated.
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5. CHANGES TO PLANNED ANALYSES
Another secondary endpoint was added (see section 2.12.1): Proportion of participants achieving sustained
improvement in PBC Worst Itch NRS as defined as having responses for all the last three 4-week periods
(periods 11, 12 and 13) according to clinically meaningful change; at least 30% reduction; and one-point,
two-point or three-point decrease in score from baseline in patients with a baseline PBC Worst Itch NRS
score ≥ 4 (binary), which is not mentioned in the protocol.
The other secondary endpoint “Proportion of patients with no worsening of pruritus from baseline through
week 52 and through week 24 as measured by the PBC Worst Itch NRS” has been re-defined at week 52,
i.e. at 4-week period 13 and at week 24, i.e. at 4-week period 6 and will be presented for patients with a
baseline PBC Worst Itch NRS score <8.
The other secondary endpoint “Proportion of responders in PBC Worst Itch NRS score according to clinically
meaningful change; at least 30% reduction; and one point, two points or three points decrease in score
from baseline at week 52 and at week 24 in patients with baseline PBC Worst Itch NRS score ≥ 4” has been
re-defined at week 52, i.e. at 4-week period 13 and at week 24, i.e. at 4-week period 6.
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6. REFERENCES
Lammers, W.J., K.V. Kowdley, and H.R. van Buuren, Predicting outcome in primary biliary cirrhosis. Ann
Hepatol, 2014. 13(4): p. 316-26.
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term
prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-7.
Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment
and prediction of long-term outcome. J Hepatol 2011;55:1361-7.
Dmitrienko, A, D’Agostino, RB, Huque, MF. (2013). Key multiplicity issues in clinical drug development.
Statistics in Medicine. 2013;32:1079-1111.
He X, Chen L, Lei L, Xia HA, Lee MLT (2015) A Simple Method for Estimating Confidence Intervals for
Exposure Adjusted Incidence Rate and Its Applications to Clinical Trials. J Biom Biostat 6: 238.
doi:10.4172/2155-6180.1000238
Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that
have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009;136:1281-7.
Carbone M et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term
prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016; VOL.63, NO.3.
ICH E9 (R1) addendum on estimands and Sensitivity Analysis in Clinical Trials to the guideline on statistical
principles for clinical trials EMA/CHMP/ICH/436221/2017.
Lammers WJ, Hirschfield GM, Corpechot C, et al. on behalf of the Global PBC Study Group. Development
and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving
ursodeoxycholic acid. Therapy, Gastroenterology (2015), doi: 10.1053/j.gastro.2015.07.061.
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are
surrogate end points of outcomes of patient with primary biliary cirrhosis: an international follow-up study.
Gastroenterology. 2014;147:1338-49.
Lipkovich I, O’Kelly M. Combining Analysis Results from Multiply Imputed Categorical Data. PharmaSUG
2013 - Paper SP03.
Ratitch B, O’Kelly M. Implementation of Pattern-Mixture Models Using Standard SAS/STAT Procedures.
PharmaSUG 2011 - Paper SP04.
S. Elman, L.S. Hynan, V. Gabriel, and M.J. Mayo, The 5-D itch scale: a new measure of pruritus, Br J Dermatol.
2010 March ; 162(3): 587–593. doi:10.1111/j.1365-2133.2009.09586.x.
PROMIS®, Scoring manual, A brief guide to scoring the PROMIS® Fatigue instruments. 2021 April.
Mapi Research Trust, Epworth Sleepiness Scale (ESS), Version 1.0, Scaling and Scoring, Version 2.0: August
2017.
A Jacoby, A Rannard, D Buck, N Bhala, J L Newton, O F W James, D E J Jones, Development, validation, and
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evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary
cirrhosis, 16 June 2005, Gut 2005;54:1622–1629. doi: 10.1136/gut.2005.065862.
Lesley A. Inker, M.D., Christopher H. Schmid, Ph.D., Hocine Tighiouart, M.S., John H. Eckfeldt, M.D., Ph.D.,
Harold I. Feldman, M.D., Tom Greene, Ph.D., John W. Kusek, Ph.D., Jane Manzi, Ph.D., Frederick Van Lente,
Ph.D., Yaping Lucy Zhang, M.S., Josef Coresh, M.D., Ph.D., and Andrew S. Levey, M.D. for the CKD-EPI
Investigators*, Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C, N Engl J Med.
2012 July 5.
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7. APPENDIX A
Tipping point analysis:
The sensitivity analysis will stress-test the MAR assumption by assuming two sensitivity parameters, and,
for the Elafibranor and placebo arms, respectively, representing an adjustment to the probability of clinical
response at week 52 compared to that expected under MAR on the log-odds scale.
Specifically, values of 𝛿𝛿 > 0 will represent a departure from MAR towards higher odds of response, and δ
< 0 will indicate a departure from MAR towards lower odds of response. A two-dimensional sensitivity
analysis will report outcomes for δ1and δ2 each varying independently within a plausible range. Typically,
δ1 ≤ 0 and δ2 ≥ 0 represent scenarios when dropouts from the Elafibranor arm have worse outcomes than
dropouts from the placebo arm. The assumed values of the sensitivity parameters will be applied to the
individual probabilities of response 𝑝𝑝𝑝𝑖𝑖 drawn from the posterior distributions at week 52 based on the
adj
p
̃ i
̃ i , where log
adj =
Bayesian logistic regression defined above, resulting in the adjusted probabilities p adj
1-p
̃ i
p̃ i
log + δ. Returning to a probability scale,
1-p̃ i
𝑝𝑝𝑝𝑖𝑖
exp(𝛿𝛿)
𝑝𝑝𝑝𝑖𝑖𝑎𝑎𝑎𝑎𝑎𝑎
1−𝑝𝑝𝑝𝑖𝑖
= 𝑝𝑝𝑝𝑖𝑖 .
1+ exp(𝛿𝛿)
1−𝑝𝑝𝑝𝑖𝑖
Then missing binary outcomes will be imputed separately by treatment arm via sampling from a Bernoulli
distribution with the adjusted probabilities, p̃ a di j , obtained as explained above using the arm-specific
sensitivity parameters, i.e., δ1 and 𝛿𝛿2
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8. APPENDIX B
The list of rescue therapies for primary biliary cholangitis (PBC) (ICE-2) and pruritus (ICE-3) will be approved
and finalized at last blinded data review meeting (BDRM) before unblinding, as well as the list of
concomitant medications that create/increase (ICE-4) or reduce pruritus (ICE-5).
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9. APPENDIX C
Table 7: PROMIS Fatigue short form 7a Conversion table

Fatigue 7a - Adult v1.0
Short Form Conversion Table
Raw Score T-score SE*
7 29.4 5.3
8 33.4 4.8
9 36.9 4.3
10 39.6 4.0
11 41.9 3.8
12 43.9 3.5
13 45.8 3.3
14 47.6 3.2
15 49.2 3.1
16 50.8 3.0
17 52.2 3.0
18 53.7 3.0
19 55.1 3.0
20 56.4 2.9
21 57.8 2.9
22 59.2 2.9
23 60.6 2.9
24 62.0 2.9
25 63.4 2.9
26 64.8 2.9
27 66.3 2.9
28 67.8 2.9
29 69.4 2.9
30 71.1 3.0
31 72.9 3.0
32 74.8 3.1
33 77.1 3.3
34 79.8 3.6
35 83.2 4.1
*SE = Standard Error on T-score metric
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Table 8: The six domains and 40 questions of the PBC-40
Domain Question Response options*

Symptoms In the last 4 weeks: Never, rarely, sometimes, most
I was able to eat what I liked the of the time, always
I ate or drank only a small amount, and still felt bloated
I felt unwell when I drank alcohol
I had discomfort in my right side
I had dry eyes
My mouth was very dry
I had aches in the long bones of my arms and legs
Itch In the last 4 weeks: Never, rarely, sometimes, most
Itching disturbed my sleep of the time, always
I scratched so much I made my skin raw
I felt embarrassed because of the itching
Fatigue In the last 4 weeks: Never, rarely, sometimes, most
I had to force myself to get out of bed of the time, always
I had to have a sleep during the day
Fatigue interfered with my daily routine
I felt worn out
I felt so tired, I had to force myself to do the things I
needed to do
I felt so tired, I had to go to bed earlier than usual
Fatigue just suddenly hit me
PBC drained every ounce of energy out of me
Some days it took me a long time to do anything
If I was busy one day I needed at least another day to
recover
I had to pace myself for day-to-day things
Cognition In the last 4 weeks: Never, rarely, sometimes, most
I had to make a lot of effort to remember things of the time, always
I had difficulty remembering things from one day to the
next
My concentration span was short because of PBC
I had difficulty keeping up with conversations
I found it difficult to concentrate on anything
I found it difficult to remember what I wanted to do
Social My sex life has been affected by having PBC Not at all, a little, somewhat,
I feel I neglect my family because of having PBC quite a bit, very much
I feel guilty that I can’t do what I used to do because of
having PBC
I sometimes feel frustrated that I can’t go out and enjoy
myself
I tend to keep the fact that I have PBC to myself
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I can’t plan holidays because of having PBC

My social life has almost stopped
Everything in my life is affected by PBC
PBC has reduced the quality of my life
I can still lead a normal life, despite having PBC
Emotional Because of PBC, I get more stressed about things than I Not at all, a little, somewhat,
used to quite
Having PBC gets me down a bit, very much
I worry about how my PBC will be in the future
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10. APPENDIX D
Laboratory test toxicity grades are assigned as specified in Table 10, using CTCAE V5.0 criteria or based on
clinically relevant PCSA thresholds for parameters for which no CTCAE grading is available and may have clinical
relevance. Grade 0 has been added for parameters for which no CTCAE grading is available and which have no
clinical relevance. Such additions are presented in bold in the table below.
Table 9: Laboratory Test Toxicity Grades

Test name Toxicity Unit Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
≥ LLN and ≤ULN and
Hemoglobin Anemia g/L baseline not ≥ 100 to < LLN ≥ 80 to < 100 < 80
missing
Hemoglobin
Hemoglobin g/L baseline not Increase in > 0 - 20 Increase in > 20 - 40 Increase > 40
increased
missing
Lymphocyte count
10^9/L baseline not > 4 to ≤ 20 > 20
increased
missing
Lymphocyte count
Lymphocytes 10^9/L >ULN to ≤4
increased [2]

Lymphocyte count
10^9/L baseline not ≥ 0.8 to < LLN ≥ 0.5 to < 0.8 ≥ 0.2 to < 0.5 < 0.2
decreased
missing
Neutrophil count
10^9/L baseline not ≥ 1.5 to < LLN ≥ 1 to < 1.5 ≥ 0.5 to < 1 < 0.5
decreased
Neutrophils missing
Neutrophil count
10^9/L >7.5 and >ULN ≥15
increased [2]

Platelet count
Platelet count 10^9/L baseline not ≥ 75 to < LLN ≥ 50 to < 75 ≥ 25 to < 50 < 25
decreased
missing
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Platelet count
10^9/L > ULN to ≤700 >700
increased [2]

Leukocytosis 10^9/L baseline not - > 100
missing
White blood cell

Leukocytosis [2] 10^9/L >ULN and < 15 ≥ 15
count

White blood cells
10^9/L baseline not ≥ 3 to < LLN ≥ 2 to < 3 ≥ 1 to < 2 <1
decreased
missing
≥ LLN and baseline
Albumin Hypoalbuminemia g/L ≥ 30 to < LLN ≥ 20 to < 30 < 20
not missing
> ULNto ≤ 2.5 x ULN
> 2.5 x ULN to ≤ 5 x ULN > 5 x ULN to ≤ 20 x ULN
≥ LLN and ≤ULN and and normal > 20 x ULN and normal
Alkaline and normal baseline OR and normal baseline OR
Alkaline normal baseline OR baseline OR > 2 x baseline OR > 20 x
phosphatase U/L > 2.5 x baseline to ≤ 5 x > 5 x baseline to ≤ 20 x
phosphatase abnormal baseline baseline to ≤ 2.5 x baseline and abnormal
increased baseline and abnormal baseline and abnormal
and ≤ 2 x baseline baseline and baseline
baseline baseline
abnormal baseline
> ULN to ≤ 3 x ULN
≥ LLN and ≤ULN and > 3 x ULN to ≤ 5 x ULN > 5 x ULN to ≤ 20 x ULN
and normal > 20 x ULN and normal
Alanine normal baseline OR and normal baseline OR and normal baseline OR
Alanine baseline OR >1.5 x baseline OR > 20 x
aminotransferase U/L abnormal baseline > 3 x baseline to ≤ 5 x > 5 x baseline to ≤ 20 x
aminotransferase baseline to ≤ 3 x baseline and baseline >
increased and ≤ 1.5 x baseline and baseline > baseline and baseline >
baseline and ULN
baseline ULN ULN
baseline > ULN
Serum amylase
U/L baseline not > ULN to ≤ 1.5 x ULN > 1.5 x ULN to ≤ 2 x ULN > 2 x ULN to ≤ 5 x ULN > 5 x ULN
increased
missing
Amylase
Serum amylase
U/L < LLN
decreased [1]
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> ULN to ≤ 3 x ULN
≥ LLN and ≤ULN and > 3 x ULN to ≤ 5 x ULN > 5 x ULN to ≤ 20 x ULN
and normal > 20 x ULN and normal
Aspartate normal baseline OR and normal baseline OR and normal baseline OR
Aspartate baseline OR > 1.5 x baseline OR > 20 x
aminotransferase U/L abnormal baseline > 3 x baseline to ≤ 5 x > 5 x baseline to ≤ 20 x
aminotransferase baseline to ≤ 3 x baseline and baseline >
increased and ≤ 1.5 x baseline and baseline > baseline and baseline >
baseline and ULN
baseline ULN ULN
baseline > ULN
> ULN to ≤ 1.5 x ULN
> 1.5 x ULN to ≤ 3 x ULN > 3x ULN to ≤ 10 x ULN
and normal baseline OR and normal baseline OR
Blood bilirubin normal baseline OR baseline OR > baseline OR > 10 x
Total bilirubin umol/L > 1.5 x baseline too ≤ 3 x > 3 x baseline to ≤ 10 x
increased abnormal baseline baseline to ≤ 1.5 x baseline and baseline >
baseline and baseline > baseline and baseline >
and ≤ baseline baseline and ULN
ULN ULN
baseline > ULN
Calcium Hypercalcemia mmol/L baseline not > ULN to ≤ 2.9 > 2.9 to ≤ 3.1 > 3.1 to ≤ 3.4 > 3.4
missing
Calcium Hypocalcemia mmol/L baseline not ≥ 2 to < LLN ≥ 1.75 to < 2 ≥ 1.5 to < 1.75 < 1.5
missing
> 1.5 x baseline to ≤ 3 x
> 3 x baseline OR < 3 x
Creatinine Creatinine increased umol/L ≥ LLN and ≤ULN > ULN to ≤ 1.5 x ULN baseline OR > 1.5 x ULN > 6 x ULN
ULN to ≤ 6 x ULN
to ≤ 3 x ULN
> ULN to ≤ 2.5 x ULN

> 2.5 x ULN to ≤ 5 x ULN > 5 x ULN to ≤ 20 x ULN
and normal baseline OR and normal baseline OR
Gamma glutamyl normal baseline OR baseline OR > 2 x baseline OR > 20 x
GGT increased U/L > 2.5 x baseline to ≤ 5 x > 5 x baseline to ≤ 20 x
transferase abnormal baseline baseline to ≤ 2.5 x baseline and baseline >
baseline and baseline > baseline and baseline >
and ≤ 2 x baseline baseline and ULN
ULN ULN
baseline > ULN

Glucose Hypoglycemia mmol/L baseline not ≥ 3 to < LLN ≥ 2.2 to < 3 ≥ 1.7 to < 2.2 < 1.7 g
missing
Glucose Hyperglycemia mmol/L baseline not > ULN to ≤ 8.9 > 8.9 to ≤ 13.9 > 13.9 to ≤ 27.8 > 27.8
missing
Potassium Hyperkalemia mmol/L baseline not > ULN to ≤ 5.5 > 5.5 to ≤ 6 > 6 to ≤ 7 >7
missing
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Potassium Hypokalemia mmol/L baseline not ≤ 3 to < LLN ≥ 2.5 to < 3 < 2.5
missing
Lipase increased U/L baseline not > ULN to ≤ 1.5 x ULN > 1.5 x ULN to ≤ 2 x ULN > 2 x ULN to ≤ 5 x ULN > 5 x ULN
Lipase missing
Lipase decreased [1] U/L < LLN

Sodium Hypernatremia mmol/L baseline not > ULN to ≤ 150 > 150 to ≤ 155 >155 to ≤ 160 > 160
missing
Sodium Hyponatremia mmol/L baseline not ≥ 130 to < LLN ≥ 125 to ≤ 129 ≥ 120 to ≤ 124 < 120
missing
Triglycerides Hypertriglyceridemia mmol/L baseline not ≥ 1.71 to ≤ 3.42 > 3.42 to ≤ 5.7 > 5.7 to ≤ 11.4 > 11.4
missing
Cholesterol Cholesterol High mmol/L baseline not > ULN to ≤ 7.75 > 7.75 to ≤ 10.34 > 10.34 to ≤ 12.92 > 12.92
missing
CPK increased U/L baseline not > ULN to ≤ 2.5 x ULN > 2.5 x ULN to ≤ 5 x ULN > 5 x ULN to ≤ 10 x ULN > 10 x ULN
Creatinine missing
Phosphokinase
CPK decreased [1] U/L < LLN
≥ LLN and ≤ULN and >1.2 to ≤ 1.5 and

Prothrombin Intl. > 1.5 to ≤ 2.5 and > 2.5 and baseline not
INR increased baseline not baseline not
Normalized Ratio baseline not missing missing
missing missing

Eosinophilia 10^9/L baseline not >ULN and >baseline
missing
Eosinophils
>ULN and
Eosinophilia [2] 10^9/L baseline>ULN and
not >baseline
[1] Addition of grade 0 for parameters with CTCAE grading is not available and have no clinical relevance.
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[2] Addition of grade(s) based clinically relevant PCSA thresholds for parameters with CTCAE grading is not
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11. APPENDIX E
Table 10: Classification of worst value for laboratory parameters of interest
Category Parameter name Worst value

Hematology Basophils (10^9/L) high
Basophils/Leukocytes (%) high
Eosinophils (10^9/L) high
Eosinophils/Leukocytes (%) high
Hematocrit (L/L) high/low
Hemoglobin (g/L) high/low
Lymphocytes (10^9/L) high/low
Lymphocytes/Leukocytes (%) high/low
Monocytes (10^9/L) high
Monocytes/Leukocytes (%) high
Neutrophils (10^9/L) high/low
Neutrophils/Leukocytes (%) high/low
Platelets (10^9/L) high/low
Erythrocytes (10^12/L) high/low
Reticulocytes (10^9/L) high
Reticulocytes/Erythrocytes (/RBC) high
Leukocytes (10^9/L) high/low
Coagulation Prothrombin Intl. Normalized Ratio High
Chemistry Alpha Fetoprotein (IU/mL) high
Albumin (g/L) low
Alkaline Phosphatase (U/L) high
Alanine Aminotransferase (U/L) high
Amylase (U/L) high
Aspartate Aminotransferase (U/L) high
Direct Bilirubin (umol/L) high
Bilirubin (umol/L) high
Calcium (mmol/L) high/low
Cholesterol (mmol/L) high
Cholesterol/HDL-Cholesterol (mmol/L) low
Creatine Kinase (U/L) high
Chloride (mmol/L) high/low
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Creatinine (umol/L) high

eGFR (CKD-EPI) (mL/min/1.73m2) low
eGFR (MDRD) (mL/min/1.73m2) low
Gamma Glutamyl Transferase (U/L) high
Glucose (mmol/L) high/low
Potassium (mmol/L) high/low
LDL Cholesterol (mmol/L) high
Lipase (U/L) high
5 Prime Nucleotidase (U/L) high
Protein (g/L) high/low
Sodium (mmol/L) high/low
Triglycerides (mmol/L) high
Urea Nitrogen (mmol urea/L) high
VLDL Cholesterol (mmol/L) high
Additional safety markers Cystatin C (mg/L) high
Albumin/Creatinine urine (mg/g cr) high
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12. APPENDIX F
The following tables list the PT used to define Hepatic failure and Hepatic injury. These lists may be updated at the last
BDRM and before unblinding.
Table 11: List of PT defining Hepatic Failure
PT
Acute hepatic failure
Acute on chronic liver failure
Acute yellow liver atrophy
Ammonia increased
Chronic hepatic failure
Coma hepatic
Hepatic encephalopathy
Hepatic failure
Hepatitis fulminant
Hepatopulmonary syndrome
Hepatorenal failure
Hepatorenal syndrome
Hyperammonaemic crisis
Liver dialysis
Minimal hepatic encephalopathy
Portal shunt procedure
Subacute hepatic failure
Ammonia abnormal
Anorectal varices
Anorectal varices haemorrhage
Ascites
Asterixis
Bacterascites
Biliary cirrhosis
Biliary cirrhosis primary
Biliary fibrosis
Bilirubin conjugated increased
Bilirubinuria
Blood bilirubin abnormal
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Blood bilirubin increased

Cardiohepatic syndrome
Child-Pugh-Turcotte score abnormal
Child-Pugh-Turcotte score increased
Cholestatic liver injury
Cirrhosis alcoholic
Cryptogenic cirrhosis
Duodenal varices
Gastric variceal injection
Gastric variceal ligation
Gastric varices
Gastric varices haemorrhage
Hepatic cirrhosis
Hepatic encephalopathy prophylaxis
Hepatic function abnormal
Hepatic hydrothorax
Hepatic necrosis
Hepatobiliary disease
Hepatocellular foamy cell syndrome
Hepatocellular injury
Hyperbilirubinaemia
Intestinal varices
Intestinal varices haemorrhage
Intrahepatic portal hepatic venous fistula
Jaundice
Jaundice cholestatic
Liver and small intestine transplant
Liver transplant
Non-alcoholic fatty liver
Non-alcoholic steatohepatitis
Non-cirrhotic portal hypertension
Oedema due to hepatic disease
Oesophageal varices haemorrhage
Peripancreatic varices
Peritoneovenous shunt
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Portal fibrosis
Portal hypertension
Portal hypertensive colopathy
Portal hypertensive enteropathy
Portal hypertensive gastropathy
Portal shunt
Portal vein cavernous transformation
Portal vein dilatation
Portopulmonary hypertension
Renal and liver transplant
Retrograde portal vein flow
Reynold's syndrome
Splenic varices
Splenic varices haemorrhage
Splenorenal shunt
Splenorenal shunt procedure
Spontaneous intrahepatic portosystemic venous
shunt
Stomal varices
Varices oesophageal
Varicose veins of abdominal wall
White nipple sign
Table 12: List of PT defining Hepatic Injury
PT
Acquired hepatocerebral degeneration
Acute fatty liver of pregnancy
Acute hepatic failure
Acute on chronic liver failure
Acute yellow liver atrophy
Adenoviral hepatitis
Alanine aminotransferase increased
Alcoholic liver disease
Allergic hepatitis
Alloimmune hepatitis
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Ammonia increased
Anorectal varices
Anorectal varices haemorrhage
Aspartate aminotransferase increased
Asymptomatic viral hepatitis
Autoimmune hepatitis
Biliary ascites
Biliary cirrhosis
Biliary cirrhosis primary
Biliary fibrosis
Bilirubin conjugated increased
Cardiohepatic syndrome
Child-Pugh-Turcotte score abnormal
Child-Pugh-Turcotte score increased
Cholestasis
Cholestasis of pregnancy
Cholestatic liver injury
Cholestatic pruritus
Chronic hepatic failure
Chronic hepatitis
Cirrhosis alcoholic
Coma hepatic
Cryptogenic cirrhosis
Cytolytic hepatitis
Cytomegalovirus hepatitis
Deficiency of bile secretion
Drug-induced liver injury
Fatty liver alcoholic
Foetor hepaticus
Gallbladder varices
Gastric variceal injection
Gastric variceal ligation
Gastric varices
Gastric varices haemorrhage
Granulomatous liver disease
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Hepatic cirrhosis
Hepatic encephalopathy
Hepatic encephalopathy prophylaxis
Hepatic failure
Hepatic fibrosis marker abnormal
Hepatic function abnormal
Hepatic hydrothorax
Hepatic hypertrophy
Hepatic infiltration eosinophilic
Hepatic lymphocytic infiltration
Hepatic necrosis
Hepatic steato-fibrosis
Hepatic vascular resistance increased
Hepatitis
Hepatitis A
Hepatitis acute
Hepatitis alcoholic
Hepatitis B
Hepatitis C
Hepatitis cholestatic
Hepatitis chronic active
Hepatitis chronic persistent
Hepatitis D
Hepatitis E
Hepatitis F
Hepatitis fulminant
Hepatitis G
Hepatitis H
Hepatitis infectious
Hepatitis infectious mononucleosis
Hepatitis mumps
Hepatitis non-A non-B
Hepatitis non-A non-B non-C
Hepatitis post transfusion
Hepatitis toxic
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Hepatitis viral
Hepatobiliary disease
Hepatobiliary scan abnormal
Hepatocellular damage
Hepatocellular damage neonatal
Hepatocellular foamy cell syndrome
Hepatocellular injury
Hepatomegaly
Hepatopulmonary syndrome
Hepatorenal failure
Hepatorenal syndrome
Hepatosplenomegaly
Hepatotoxicity
Herpes simplex hepatitis
Hyperammonaemia
Hyperammonaemic crisis
Intestinal varices
Intestinal varices haemorrhage
Intrahepatic portal hepatic venous fistula
Ischaemic hepatitis
Jaundice hepatocellular
Liver and small intestine transplant
Liver dialysis
Liver disorder
Liver injury
Liver transplant
Lupus hepatitis
Minimal hepatic encephalopathy
Mixed hepatocellular-cholestatic injury
Mixed liver injury
Model for end stage liver disease score abnormal
Model for end stage liver disease score increased
Non-alcoholic fatty liver
Nonalcoholic fatty liver disease
Non-alcoholic steatohepatitis
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Non-cirrhotic portal hypertension

Oedema due to hepatic disease
Oesophageal varices haemorrhage
Peliosis hepatis
Peripancreatic varices
Periportal oedema
Pneumobilia
Portal fibrosis
Portal hypertension
Portal hypertensive colopathy
Portal hypertensive enteropathy
Portal hypertensive gastropathy
Portal shunt
Portal shunt procedure
Portal tract inflammation
Portal triaditis
Portal vein cavernous transformation
Portal vein dilatation
Portal vein flow decreased
Portal vein pressure increased
Portopulmonary hypertension
Post cholecystectomy syndrome
Primary biliary cholangitis
Radiation hepatitis
Regenerative siderotic hepatic nodule
Renal and liver transplant
Retrograde portal vein flow
Reynold's syndrome
Splenic varices
Splenic varices haemorrhage
Splenorenal shunt
Splenorenal shunt procedure
Spontaneous intrahepatic portosystemic venous shunt
Steatohepatitis
Stomal varices
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Subacute hepatic failure

Total bile acids increased
Ultrasound liver abnormal
Varices oesophageal
Varicose veins of abdominal wall
White nipple sign
X-ray hepatobiliary abnormal
Zieve syndrome
Alanine aminotransferase abnormal
Ammonia abnormal
Ascites
Aspartate aminotransferase abnormal
Asterixis
Bacterascites
Bile output abnormal
Bile output decreased
Bilirubin conjugated abnormal
Bilirubin excretion disorder
Bilirubin urine present
Bilirubinuria
Blood alkaline phosphatase abnormal
Blood alkaline phosphatase increased
Blood bilirubin abnormal
Blood bilirubin increased
Blood bilirubin unconjugated increased
Blood cholinesterase abnormal
Blood cholinesterase decreased
Cholaemia
Computerised tomogram liver abnormal
Duodenal varices
Galactose elimination capacity test abnormal
Galactose elimination capacity test decreased
Gamma-glutamyltransferase abnormal
Gamma-glutamyltransferase increased
Glutamate dehydrogenase increased
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Guanase increased
Haemobilia
Haemorrhagic ascites
HELLP syndrome
Hepaplastin abnormal
Hepaplastin decreased
Hepatic artery flow decreased
Hepatic congestion
Hepatic enzyme abnormal
Hepatic enzyme increased
Hepatic sequestration
Hepatic steatosis
Hyperbilirubinaemia
Hyperbilirubinaemia neonatal
Hypercholia
Hypertransaminasaemia
Hypoalbuminaemia
Hypoproteinaemia
Icterus index increased
Increased liver stiffness
Jaundice
Jaundice acholuric
Jaundice cholestatic
Jaundice neonatal
Leucine aminopeptidase increased
Liver function test abnormal
Liver function test increased
Liver induration
Liver palpable
Liver scan abnormal
Liver tenderness
Mitochondrial aspartate aminotransferase increased
Molar ratio of total branched-chain amino acid to
tyrosine
Ocular icterus
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13. STATISTICAL OUTPUTS TO BE GENERATED
Sample tables, listings and figures will be provided in a separate document.
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Summary of main changes to ELATIVE study SAP between V1.0 to V4.0
Section Reason for change Previous text Elative SAP v4.0

1.2 Update the key secondary The key secondary objec�ves of the study are to evaluate the effect of
objec�ves of the study Elafibranor (80 mg/day) over 52 weeks of treatment compared to placebo
regarding the pruritus based on ALP normaliza�on, and through 52 weeks and through 24 weeks on
pruritus
2.12 Add a secondary Change from baseline to week 52 in serum markers of bone turnover and in
endpoint bone mineral density (hip and lumbar) assessed by DEXA scanning
(continuous)
2.12 Add an exploratory Correlation between histological fibrosis scores (Nakanuma and Ishak scores)
endpoint and non-invasive markers of fibrosis (Liver stiffness, ELF test, ProC3)
2.12 Definition of the Exploratory (Histological) Set: All patients from the Intent-to-Treat set who
exploratory Set due to consent and have liver biopsy samples collected at baseline and/or week 52.
the definition of Patients will be analyzed according to randomized treatment.
exploratory endpoints
2.12.1 Modifica�on according to Two key secondary Two Three key secondary endpoints:
protocol v4.0 endpoints: • Response to treatment based on ALP normaliza�on at week 52 (binary).
- Response to treatment • Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in
based on ALP normaliza�on pa�ents with baseline PBC Worst Itch NRS score ≥4 (con�nuous).
at week 52(binary). • Change in pruritus from baseline through week 24 on PBC Worst Itch NRS
- Change in pruritus from in pa�ents with baseline PBC Worst Itch NRS score ≥4 (con�nuous).
baseline through week 52
on PBC Worst Itch NR Other Secondary Endpoints:
i) Complete biochemical response defined as normal ALP, TB, AST, ALT,
albumin, and INR
Other secondary endpoints: 8) Rela�ve Change from baseline to week 52 in hepatobiliary injury and liver
8) Rela�ve Change from func�on as measured by ALP, GGT, AST, ALT (con�nuous) the endpoint (was
baseline to week 52 in deleted because the sponsor assumes it is already covered by change from
hepatobiliary injury and baseline endpoints)
liver func�on as measured
by ALP, GGT, AST, ALT Propor�on of responders in PBC Worst Itch NRS according to clinically
(con�nuous) meaningful change; at least 30% reduc�on; and one point, two points or
Page 516

three points decrease in score from baseline through week 52 and through
15) Response to treatment week 24 in pa�ents with a baseline NRS score ≥ 4 (binary) (These endpoints
defined as at least 30% have been added to replace the endpoint 15)
reduc�on from baseline in
PBC Worst Itch NRS at week Propor�on of par�cipants achieving sustained improvement in PBC Worst
52 in pa�ents with a Itch NRS as defined as having responses for all the last three 4-week periods
baseline NRS score ≥ 4 (periods 11, 12 and 13) according to clinically meaningful change; at least
(binary) 30% reduc�on; and one point, two points or three points decrease in score
from baseline in pa�ents with a baseline NRS score ≥ 4 (binary) (New
16) Propor�on of pa�ents endpoints added)
with no worsening of
pruritus based on PBC Propor�on of pa�ents with no worsening of pruritus from baseline through
Worst Itch NRS at week 52 week 52 and through week 24 as measured by the PBC Worst Itch NRS (This
(binary) endpoint in replacement of the endpoint 16)
3.1 Addi�on of specific Pruritus ITT Analysis Set: All pa�ents from the ITT analysis set with baseline
analysis sets for Pruritus PBC Worst Itch NRS score ≥4.
based on baseline PBC
Worst Itch NRS score ≥4 Pruritus PP Analysis Set: All pa�ents from the Pruritus ITT analysis set with
baseline PBC Worst Itch NRS score ≥4 without any major protocol devia�on
or event affec�ng the primary efficacy endpoint and/or the second and third
key secondary endpoint.
4.1 Modifica�on according to One hundred and fi�y pa�ents (100 Elafibranor and vs 50 placebo) allow to
protocol v4 0 Specifically : achieve at least 90% power to demonstrate a sta�s�cally significant between
- change the Type I error group difference of 35% (47% in Elafibranor group vs 12% in placebo group) in
from 0.01 to 0.05 - the response rate at week 52 of the primary efficacy endpoint with a two -
restrict the popula�on sided alpha of 0.0105 and using an exact Fisher test. Assuming 1/50 (2.0%)
analysis for pruritus (2nd pa�ents in the placebo arm with ALP normaliza�on at week 52 (first key
and 3rd key secondary secondary endpoint), 150 pa�ents (100 Elafibranor vs 50 placebo) provide at
endpoints) to pa�ents least 80% power to detect a sta�s�cally significant between group difference
with pruritus (PBC Worst of 20.0% at a two - sided 0.0105 alpha level. Assuming a pooled standard
Itch NRS score >=4) devia�on of 2.3 points, 150 60 pa�ents (100 40 Elafibranor vs 50 20 placebo)
Page 517

with baseline PBC Worst Itch NRS score ≥4 provide at least approximately
80% power to detect a sta�s�cally significant between group difference of 1.8
points in mean change from baseline in PBC worst itch NRS score (second key
secondary endpoint) at a two-sided 0.0105 alpha level. It is assumed that the
same assump�ons would apply to the two key secondary endpoints for
pruritus (through week 52 and through week 24).
4.2.1 Modifica�on according to Where applicable confidence intervals (99 95% CI for primary, and key
protocol v4.0 Specifically: secondary endpoints , 95% CI and for all other secondary endpoints, 2-sided)
- the 99% CI is replaced will be presented, and they will be shown with 1 decimal place for
by 95% CI - the 3rd key percentages, and with 2 decimal places for con�nuous measures.
secondary endpoint is
added to the fixed- Formal sta�s�cal hypothesis tes�ng will be performed on the primary and key
sequence tes�ng secondary efficacy endpoints, with all tests conducted at the 2-sided, 0.0105
approach level of significance. The fixed-sequence tes�ng approach will be used to
control the overall type I error rate at a two-sided 0.0105 level.
The fixed-sequence tes�ng approach implies that if the primary endpoint is

sta�s�cally significant at a two-sided 0.05 level, the first key secondary
endpoint (ALP normaliza�on) will be tested at the same level. If the first key
secondary endpoint is sta�s�cally significant at a two-sided 0.0105 level, the
second key secondary endpoint (change in pruritus through week 52) will be
tested at the same level. If the second key secondary endpoint is sta�s�cally
significant at a two-sided 0. 05 level, the third key secondary endpoint
(change in pruritus through week 24) will be tested at the same level.
If the primary endpoint is sta�s�cally significant and the first key secondary
endpoint is NOT sta�s�cally significant, the second and third key secondary
endpoints will not be tested. Finally, if the second key secondary endpoint is
NOT sta�s�cally significant, the third key secondary endpoint will not be
tested.
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4.2.7 Modifica�on according to Cirrho�c defined by Liver s�ffness at baseline ≥ 16.9 KPa at Fibroscan exam
protocol v4.0 – addi�onal (Yes/No) and/or cirrhosis on histology
subgroup
Advanced disease stage defined as liver s�ffness at baseline >10 kPa at
Fibroscan exam and/or bridging fibrosis or cirrhosis on histology
4.2.9 Clarification of rules post For all the binary/categorical efficacy endpoints (including the primary
ICE, imputation for endpoint, and the first key secondary endpoint and all other binary
missing data at week 52 secondary endpoints), the pa�ent’s outcome a�er the occurrence of an ICE
for patients without ICE, (study treatment discon�nua�on or use of rescue therapy) pa�ents who
supplementary analysis stopped prematurely the study treatment will be considered as non-
details and addition of responders in a composite strategy for the main analysis.
supplementary analysis
added to evaluate the For the primary and key secondary endpoints, missing data at week 52 (i.e.
impact of COVID -19 visit 6) for pa�ents without ICE will be replaced by the closest non-missing
pandemic assessment from the DB treatment period for the main analysis, or pa�ents
will be considered as non-responders for the first supplementary analysis.
In addi�on, for the primary and the first key secondary (ALP normaliza�on)
endpoints, three supplementary analyses will be performed using relevant
mul�ple imputa�on methods (see sec�on 4.6.2.3.1. The first one will be
Missing at Random (MAR) mul�ple imputa�on to impute values as if
pa�ents would follow their ini�al treatment. A second one will impute
values using the informa�on from the placebo group. The third one will be a
�pping point analysis to explore several scenarios about the missing
outcomes.
A fourth sensi�vity supplementary analysis will use outcome post ICE values
at through week 52 regardless of treatment discon�nua�on or use of rescue
therapy.
Finally supplementary analyses will be performed to evaluate the impact of

COVID-19 pandemic.
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For con�nuous endpoints, the pa�ent’s outcome a�er the occurrence of an

ICE (study treatment discon�nua�on or use of rescue therapy) will be
considered as missing for the main analysis.
4.2.9 Implementation of the Treatment-emergent is defined as:
split between DB and LTE
in the TEAE definition • All events which started a�er the first study treatment dose intake*
(all episodes with start a�er or on (≥) the first study treatment dose intake) up
to 30 days a�er the last study treatment dose intake (episodes with start
before or on (≤) the last study treatment dose intake + 30 days) for the
pa�ents that discon�nue the study treatment during DB period, and up to
the date of the last DB data collec�on for the pa�ents that complete DB
period and will switch in LTE, respec�vely.
• Or as all events which started before the first study treatment dose
intake and worsened or became serious a�er or on the first study treatment
dose intake (in case of mul�ple episodes of the same event before the first
study treatment dose intake, the severity of the episode closest to the first
study treatment dose intake will be considered) up to 30 days a�er the last
study treatment dose intake for the pa�ents that discon�nue the study
treatment during DB period, and up to the date of the last DB data
collec�on for the pa�ents that complete DB period and switch in LTE,
respec�vely.
4.2.10 Clarifica�on that data For all efficacy and safety laboratory endpoints (from central laboratory), if
collected at unscheduled the results are not available at the scheduled visit, then results from the
visits may be used in case closest unscheduled visit will be used if within the visit window and if still in
of missing data if within DB treatment period.
the window
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4.2.11 Update the postbaseline A�er V1, for pa�ents who The 4-week period post baseline average NRS score will be calculated as
PBC Worst Itch NRS have less than 10/28 values follows:
deriva�on accoun�ng for in an analysis window, the - For a full 4-week period, at least 3 weeks out of 4 weeks complying with
missing data monthly average PBC Worst the rule of 4 out of 7 daily NRS score assessed and no less than 14 out of
Itch NRS will be considered 28 daily (at least 50% of expected daily data) assessments of the full
as missing period will induce computation of the average 4-week period NRS score,
otherwise, the average NRS score will be considered missing.
- For the last period (13th period) which is truncated by design, the rule
will be flexible based on the number of expected weeks (2 to 4 weeks):
o If two or three weeks are expected: each week has to be
compliant with the rule of 4 out 7 daily NRS score,
o If four weeks are expected: same rule as for a full 4-week period,
- Note: Data collected after W52 (365 days) will not be used
4.2.11 Clarifica�on of the

PBC Worst Itch NRS average through week 52 and week 24 will be
calcula�on of the 4-week estimated based on the actual 4-week periods available for each patient,
period average through using the period 1 to period 13 and the period 1 to period 6 respectively.
W24 and W52 for the PBC
Worst Itch NRS For any combined response efficacy endpoint, e.g. primary endpoint, if one
evaluated parameter reaches a non-responder condition (e.g. ALP >= 1.67 x
Handling par�al missing ULN for the primary endpoint) while other parameters are missing then the
data in combined patient will be considered as non-responder, otherwise the response will be
responses to treatment considered as missing and handled as per analysis rule.
4.6.1 Handling of missing data The primary estimand can be defined as the odds ratio between treatment
in pa�ents without ICE groups, from all randomized patients, achieving response at week 52
clarified. (defined as: ALP < 1.67x ULN, TB ≤ ULN and ALP decrease ≥ 15%), and not
stopping prematurely the study treatment nor using rescue therapy for PBC.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE, the
closest non-missing assessment from the DB treatment period before or
after the theoretical visit 6 date (i.e. visit 1 date + 52 * 7 days) will be taken
Page 521

into account. It may correspond to an unscheduled visit or a visit prior (i.e.
In addition, the following strategies will be explored as supplementary and

sensitivity analyses:
- The exact same composite strategy as for the main analysis will be
used, except that patients without ICE but missing data at week 52
will be considered as non-responders.
4.6.1 Supplementary analyses

Finally, a supplementary analysis will be performed to assess whether the
are updated specifically
concomitant medications used by patients in this study induce bias to the
to account for FDA interpretability of treatment effects based on the PBC WI NRS score. Use
comment related to of concomitant medication affecting pruritus will be considered as ICE. The
possible bias due to ICE use of concomitant therapy affecting pruritus will be split into two
concomitant medica�ons separate ICEs and the hypothetical strategy will be applied to the new ICEs
use (ICE-4 and ICE-5). Then, three types of intercurrent events will affect the
analysis strategy:
• ICE-4: use of concomitant medication that create or increase
pruritus. Post ICE-4 data of patients who experienced an ICE-4 from
both arms would be imputed as if would follow their initial
randomized treatment (“as treated” hypothetical strategy)
• ICE-5: use of concomitant medication (including rescue therapy for
PBC and pruritus) that reduce pruritus (anti-pruritus). Post ICE-5
data of patients who experienced an ICE-5 from both arms would
be imputed as if would continue on placebo (“placebo-based”
hypothetical strategy)
• ICE-1: Treatment discontinuation. The hypothetical strategy will be
applied to the post ICE-1 data, and any patient’s outcome will be
considered as missing for patients who experienced ICE-1 prior to
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week 52.
4.6.2.1 Handling of missing data Patients without an ICE but with missing data at week 52 for any reason will
in pa�ents without ICE not be imputed unless these missing data represent more than 5% of the
clarified. total number of responder/non-responder. In this case, the missing
outcomes will be imputed assuming that patients would follow their initial
Risk difference and 95% treatment (multiple imputation MAR) as described in section 4.6.2.3.1.
CI have been added.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE (ICE-
1 or ICE-2), the closest non-missing assessment from the DB treatment
period before or after the theoretical visit 6 date (i.e. visit 1 date + 52 * 7
days) will be taken into account. It may correspond to an unscheduled visit
or a visit prior (i.e. visit 5) or after (i.e. visit 7) the visit 6.
The response proportions at week 52 will be compared between the

treatment groups using the exact CMH test stratified by the randomization
strata. The estimate of the odds ratio and the corresponding 95% exact CI
and exact p-value will be provided. In addition, the risk difference between
the treatment groups and 95% CI will be calculated using the Newcombe
method stratified by randomization strata. For consistency, the Wilson
score 95% CI for single proportion will be provided for within group
description.
4.6.2.2 Addi�on of a sensi�vity The exact same composite strategy as for the main analysis (see section
analysis related to 4.6.2.1 Main Analysis) will be performed, except that patients without ICE
missing data but missing data at week 52 will be considered as non-responders.
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4.6.2.3. Clarifica�on of the The following text has 1) Based on assigned treatments (MAR)
2 analysis for missing data been replaced
Outcomes imputed assuming that pa�ents would follow their ini�al
without ICE and the use After calculation of the
treatment (rather than switching to placebo a�er discon�nua�on). This
of the Rubin’s rules response to treatment
scenario assumes MAR where missingness is independent of unobserved
(primary endpoint) based
outcomes given observed data. The mul�ple imputa�on method will
on imputed ALP and TB,
impute values as if pa�ents would follow their ini�al treatment, condi�onal
the m imputed datasets
on baseline and pre- withdrawal data included in the analysis. Therefore,
will be used separately in
the treatment arm will be included in the imputa�on model as a covariate.
the statistical analysis
model (exact CMH Note that missing response at week 52 for pa�ents without an ICE (ICE-1
stratified on the or ICE-2) prior to week 52 will also be imputed assuming that pa�ents
stratification factors of would follow their ini�al treatment (mul�ple imputa�on MAR).
the randomization) and
the resulting log (odds Post ICE-1 or ICE-2, ALP and TB values will be set to missing up to week 52,
ratios) will be combined and will be imputed multiple times to account for the uncertainty about the
via Rubin’s rules (using true values to impute. In case of non-monotone missingness, firstly the
PROC MIANALYZE) to Markov Chain Monte Carlo (MCMC) method will be used for completing data
provide a global estimate to a monotone pattern. Then, in case of missing response at week 52 for
of the odds ratio. patients without an ICE (ICE-1 or ICE-2) prior week 52, a monotone
Furthermore, the p- regression will be applied with m imputed datasets (data of patients
values from exact CMH without ICE-1 or ICE-2) imputing missing ALP and TB up to week 52
tests based on the m assuming that patients would follow their initial treatment (MAR). Finally,
imputed sets will be a monotone regression will be applied with m imputed datasets (all patients)
transformed into a Z imputing remaining missing ALP and TB up to week 52, assuming that
statistic by applying the patients would follow their initial treatment (MAR).
inverse normal
cumulative distribution After calculation of the response to treatment (primary endpoint) based
function. Since the on imputed ALP and TB, the m imputed datasets will be used separately in
resulting Z statistics are the statistical analysis model (exact CMH stratified on the stratification
normally distributed and factors of the randomization). The resulting log (odds ratios) will be
have unit variances, they combined via Rubin’s rules to provide a global estimate of the odds ratio
can be combined using after back transformation. Furthermore, the p-values from exact CMH
standard Rubin's tests based on the m imputed sets will be transformed into a Z statistic by
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combination rules across applying the inverse normal cumulative distribution function. Since the
the multiply imputed resulting Z statistics are normally distributed and have unit variances, they
sets. can be combined using standard Rubin's combination rules across the
multiply imputed sets. Lower and Upper bounds of the 95% CI around the
odds ratio will be given in addition and estimated as the median of the
lower bounds and the median of the upper bounds of the imputations.
4.6.3 Clarifica�on of the Patients who stopped prematurely the study treatment (ICE-1) or took a
analysis for missing data rescue therapy for PBC (ICE-2) prior to week 52 assessment will be
without ICE considered as non-responders.
In case of missing data at week 52 (i.e. visit 6) for patients without ICE (ICE-
1 or ICE-2), the closest non-missing assessment from the DB treatment
period before or after the theoretical visit 6 date (i.e. visit 1 date + 52 * 7
days) will be taken into account. It may correspond to an unscheduled visit
or a visit prior (i.e. visit 5) or after (i.e. visit 7) the visit 6.
A sensitivity analysis to the statistical model, a supplementary analysis

considering missing data at Week 52 in patients without ICE as non-
response, a hypothetical strategy and a treatment policy strategy will be
implemented the same way as for the primary efficacy endpoint.
4.6.6 Addi�on of risk difference Within each subgroup, the treatment effect will be analyzed comparing
and condi�ons for Elafibranor to Placebo by presenting the estimate of the risk difference,
comparing treatment odds ratio/overall contrast and their corresponding 95% exact CIs as well as
groups and update on the exact p- value.
condi�ons for performing
subgroup analyses. For subgroup analysis, if the subgroup at baseline includes less than 20
patients across treatment groups or less than 5 patients for a treatment
group≥ 95% or ≤ 5% of the overall population, the analysis will be omitted.
In this case only descriptive analysis by group will be provided. In addition,
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Removal of subgroup in the instance where there are no observations for a treatment group for
analyses rela�ng to a unique randomization stratum then the stratification factors will be
secondary endpoints removed from the analysis (exact CMH).
Additionally, all secondary endpoints corresponding to response to treatment

according to TB and/or ALP (see section 2.12.1) will also be analyzed using
the ITT analysis set in the subgroups of patients with moderately severe
disease or at risk of progression defined as follows (see section 4.2.7):

• Baseline Liver stiffness (KPa) categorization ≥ 16.9 and/or
cirrhosis on histology (Yes/No)
• Liver stiffness at baseline >10 kPa at Fibroscan exam and/or

bridging fibrosis or cirrhosis on histology (Yes/No)
4.6.7 Clarifica�on of missing Analyses of all other secondary endpoints will be performed using the ITT
data management and analysis set or pruritus ITT analysis set according to the endpoint, and
condi�ons for comparing according to using the composite strategy for binary endpoints (similar to
treatment groups the main analysis for the primary efficacy endpoint except that missing
data for patients without ICE will be kept missing), and hypothetical
strategy for continuous endpoints (MAR assumption).
If the other secondary endpoint analyses lead to a subgroup analysis (e.g.

defined on baseline) and the subgroup includes less than 20 patients across
treatment groups or less than 5 patients for a treatment group, the
analysis will be omitted. In this case only descriptive analysis by group will
be provided. In addition, in the instance where there are no observations
for a treatment group for a unique randomization stratum then the
stratification factors will be removed from the analysis (exact CMH).
Page 526

4.6.7.23 Clarifica�on of the A worsening is defined by a positive change from baseline greater than 2. The
defini�on of worsening criteria will be derived at week 52, i.e.at 4-week period 13 and at week 24,
i.e. at 4-week period 6 respectively. It may also be repeated at other time
points.
The analysis on this measure will be conducted in patients with PBC Worst Itch
NRS score <8 at baseline. and in the same way as the analysis described in
section 4.6.2.1.
4.8.2 Clarifica�on of the split Analyses of AEs will be performed for those events that are considered
between DB and LTE treatment-emergent AE (TEAE), where treatment-emergent is defined as any
AE with onset on or after the date of first administration of study treatment
and up to the date of the last DB data collection for the patients that complete
DB period and will switch in LTE and up to 30 days after the date of the last
study treatment for the patients who discontinue the study treatment during
DB period, respectively or any event with start date prior to first dose of
treatment whose severity worsened in intensity on or after the date of first
dose of study treatment and up to the date of the last DB data collection for
the patients that complete DB period and switch in LTE and up to 30 days
after the date of the last study treatment for the patients that discontinue
the study treatment during DB period, respectively.
4.8.2 Addi�on of analyses on The number and percentage of patients who developed lipid abnormality
special AEs as per FDA and/or dysglycemia through the DB period will be summarized by SMQ
request code/PT and by treatment group using the following SMQ:
- Hypoglycaemia (SMQ Code 20000226)

- Hyperglycaemia/new onset diabetes mellitus (SMQ Code 20000041)
- Dyslipidaemia (SMQ Code 20000026)
The risk difference and its 95%CI (Newcombe) between Elafibranor and
Placebo will also be provided.
Page 527

The number and percentage of patients who developed hepatic injury and
hepatic failure through the DB period will be summarized by custom
queries/PT and by treatment group using following custom queries presented
in Appendix F. These custom queries may be updated at the last BDRM before
unblinding.
The risk difference and its 95%CI (Newcombe) between Elafibranor and
Placebo will also be provided.
The incidence rate per patient exposure years, the EAIR difference and its
95% CI will be computed using the He and al method (He et al, 2015) by
treatment group and according to the custom queries will be provided.
Time to the onset of first TEAEs, defined as (start date of the first TEAE – first
study treatment date +1)/7, and duration of first TEAEs, defined as (end date
of first TEAE – start date of first TEAE +1)/7 and for ongoing TEAE, the end
date will be imputed as the datacut date, will be summarized by preferred
term and by treatment group. The table will be sorted by descending
frequency of PT in Elafibranor group.
4.8.2. Clarifica�on to the A between-group comparison will be performed using the exposure-
exposure-adjusted adjusted incidence rates (EAIR) of treatment-emergent AEs (TEAE), serious
incidence rate: formula is TEAE, TEAE leading to treatment discontinuation, TEAE leading to study
added. discontinuation and AESIs.
The exposure-adjusted incidence rate (pa�ents per pa�ent-year) is
defined as:
Number of pa�ents with at least one event / Total exposure �me for all
pa�ents at risk
and will be calculated by treatment arm.

Page 528

The exposure time will be differentiated according to the occurrence or not
of the event and will be summarized. If the patient experiences an event:
their exposure time will be the time until initial occurrence of their events.
If patient does not experience an event:
- For patients who discontinue the study treatment during the DB
period, their exposure time will be censored at the time of the last
treatment intake date plus 30 days (minimum of ((last treatment date
+ 30 days, date of death, database cut-off date) – first treatment date
+ 1)/365.25). The addition of 30 days matches the maximum time for
scheduling the safety follow-up visit and the SAE reporting period after
treatment discontinuation.
- For patients who don’t discontinue the study treatment during the DB
period, exposure time will be censored on the patient DB period end
date (minimum date of the last double-blind visit, first LTE treatment
intake (if complete) – 1). The addition of 30 days after last dose of DB
treatment does not apply to those patients that will complete DB
period and will enter in the LTE period to receive open label
elafibranor.
4.8.4 Change in the hepa�c Occurrence of Hepatic laboratory test elevations (HLTE) will be based on fold changes
laboratory test analysis as aminotransferases (ALT and above the upper limit of normal (ULN).
per FDA request AST) increase will be
presented separately Cumulative elevations
according to the baseline
level (normal or abnormal). • ALT value > 1x, > 3x, > 5x, > 10x, > 20x ULN and ALT change from
The classes of baseline >250 U/L
aminotransferase increase • AST value > 1x, > 3x, > 5x, > 10x, > 20x ULN and AST change from
considered are: baseline >250 U/L
• > 3x ULN and ≤ 5x ULN, > • ALP value > 2x, > 3x ULN and ALP change from baseline >150 U/L
5x ULN and ≤ 10x ULN, >
10x ULN if the baseline
Page 529

level of aminotransferase is • Total bilirubin value > 2x, > 5x, > 8x ULN and TB change from baseline
normal (i.e. < ULN). The > 2 mg/dL
worst on treatment
classifica�on will be • Direct bilirubin value > 2x, > 5x ULN and Direct bilirubin change from
retained. baseline > 1 mg/dL
• > 3x Baseline and ≤ 5x • GGT value > 2x ULN
Baseline, > 5x Baseline if • INR value > 1.5x, 3x and 5x ULN
the baseline level of
aminotransferase is
These are based on the highest ratio of value in the double-blind safety
abnormal (i.e. ≥ ULN). The
period, including scheduled and unscheduled visits, to ULN for each
worst on treatment laboratory test. Note that patients may be in > 1 category for each
classifica�on will be laboratory test.
retained.
HLTE will be displayed in frequency tables presenting the number and
percentage of patients in categories and the associated risk difference and
its 95% CI (Newcombe).
The incidence rate per patient exposure years, the EAIR difference and its
95% CI will be computed using the He and al method (He et al, 2015) by
treatment group and according to the HLTE will be provided.
In order to identify patients who meet potential DILI triggers (parameters

being assessed at the same visit), the following biochemical triggers will be
summarized:
- For patients with all normal AST, ALT, ALP, TB, direct bilirubin and
GGT at baseline:
• (ALT >= 3x ULN or AST >= 3x ULN) and TB >= 2x ULN

• ALT >= 5x ULN or AST >= 5x ULN
• ALT >= 8x ULN or AST >= 8x ULN
Page 530

• (ALT >= 3x ULN or AST >= 3x ULN) and INR > 1.5
• ALP >= 2x ULN and direct bilirubin >= 2x ULN
• GGT >= 2x ULN and direct bilirubin >= 2x ULN
- For patients with at least one abnormal laboratory parameter (AST,

ALT, ALP, TB, direct bilirubin or GGT) at baseline:
• (ALT >= 3x baseline or AST >= 3x baseline) and TB >= 2x BL

• ALT >= 3x baseline or AST >= 3x baseline
• ALT >= 5x baseline or AST >= 5x baseline
• (ALT >= 2x baseline or AST >= 2x baseline) and INR > 1.5
• ALP >= 2x baseline and ALP > ULN and direct bilirubin >= 2x
baseline and direct bilirubin > ULN
• GGT >= 2x baseline and GGT > ULN and direct bilirubin >= 2x
baseline and direct bilirubin > ULN
Potential DILI triggers will be displayed in frequency tables presenting the

number and percentage of patients in categories and the associated risk
difference and its 95%CI.
The incidence rate per 100 patient exposure years (see section 4.8.1.1 for
derivation rules), the EAIR difference and its 95% CI will be computed using
the He and al method (He et al, 2015) risk ratio and its 95%CI by treatment
group and according to the Potential DILI triggers will be provided.

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CLINICAL PROTOCOL – PHASE 3

Elson S. Floyd College of Medicine

GENFIT CONFIDENTIAL Page 1 of 114

CLINICAL STUDY PROTOCOL SIGNATURE PAGE

Protocol N°: GFT505B-319-1

In signing below, I give agreement to the protocol.

On behalf of (the Sponsor):

GENFIT CONFIDENTIAL Page 2 of 114

CLINICAL STUDY PROTOCOL SIGNATURE PAGE

Protocol No: GFT505B-319-1

Release date: 22July 2O2O

In signing below, I give agreement to the protocol.

On behalf of (the Sponsor):

GENFIT CONFIDENTIAL Page 3 of 114

CLINICAL STUDY PROTOCOL SIGNATURE PAGE

Protocol N°: GFT505B-319-1

In signing below, I give agreement to the protocol.

On behalf of (the Sponsor):

CONFIDENTIAL Page 4 of 114

CLINICAL STUDY PROTOCOL SIGNATURE PAGE

Protocol N°: GFT505B-319-1

In signing below, I give agreement to the protocol.

On behalf of (the Sponsor):

GENFIT CONFIDENTIAL Page 5 of 114

CLINICAL STUDY PROTOCOL - INVESTIGATOR SIGNATURE PAGE

INVESTIGATOR NAME: _______________________________________

GENFIT CONFIDENTIAL Page 6 of 114

Protocol N°: GFT505B-319-1 / EudraCT N° 2019-004941-34 / IND n° 132202

PPD MD Elson S. Floyd College of Medicine

GENFIT CONFIDENTIAL Page 7 of 114

BARC USA Inc

GENFIT CONFIDENTIAL Page 8 of 114

GENFIT CONFIDENTIAL Page 9 of 114

eGFR estimated glomerular filtration rate

GENFIT CONFIDENTIAL Page 10 of 114

MDRD modification of diet in renal disease

GENFIT CONFIDENTIAL Page 11 of 114

TNFα tumor necrosis factor-alpha

GENFIT CONFIDENTIAL Page 12 of 114

CLINICAL STUDY SYNOPSIS

Title of the study:

GENFIT CONFIDENTIAL Page 13 of 114

Route of Administration: Oral

Key Secondary Objectives:

GENFIT CONFIDENTIAL Page 14 of 114

GENFIT CONFIDENTIAL Page 15 of 114

GENFIT CONFIDENTIAL Page 16 of 114

Criteria for Evaluation:

GENFIT CONFIDENTIAL Page 17 of 114

Response to treatment based on ALP normalization at week 52.

Other Secondary Endpoints:

GENFIT CONFIDENTIAL Page 18 of 114

Data Safety Monitoring Board (DSMB):

GENFIT CONFIDENTIAL Page 19 of 114

GENFIT CONFIDENTIAL Page 20 of 114

• Key secondary endpoints

GENFIT CONFIDENTIAL Page 21 of 114

GENFIT CONFIDENTIAL Page 22 of 114

Table 1: Study General Assessment Schedule

Obtain Informed Consent X

PBC Worst Itch NRS-Past Week X X X X X

GENFIT CONFIDENTIAL Page 23 of 114