Kick of Meeting – NASH study:

“Clinical and economic burden of NAFLD (NAFL and

NASH) in a Spanish population database, using
established clinical criteria and non-invasive
algorithms developed using supervised machine learning.”
MSD 2022

May 23, 2022

Proprietary

Agenda

1. Teams presentation (MSD) 4. Safety (MSD)

Organigram and contact details Pharmacovigilance training
AE and PQCs form

2. Study protocol (MSD) 5. Next steps (MSD + INCLIVA)

Background and rationale
Objectives
Methodology
Variables & Epidemiological measurement

3. Start-up
Timelines: Key dates and milestones (MSD)
Regulatory/ethics approvals (INCLIVA)
Proprietary

1. Teams presentation: MSD team – Dept. Medical Affairs

Gonzalo FERNÁNDEZ
(Dir. Medical Affaires – Vaccines/General medicine)
Gonzalo.fernandez@merck.com
MAIN CONTACT POINT
Marta CEDENILLA
(Medical Advisor – Study owner)
Marta.cedenilla@merck.com

Medical Scientific Liasion Clinical Operations Team

Clara SANTAMARÍA RODRIGO

(Clinical PM)
Carlos HURTADO María VILLAREJO Clara.santamaria@merck.com
(MSL) (MSL)
Carlos_hurtado@merck.com Maria.villarejo@merck.com

Karine FERREIRA Paula SANSIGRE GARCÍA Pilar MORALES ALHAMBRA

(Clinical Lead CRA) (Clinical Trial Coordinator)
(MSL)
Paula.sansigre.garca-a@merck.com Pilar.morales.alhambra@merck.com
Karine.ferreira@merck.com

3
Proprietary

4
2. Study Protocol
Background and rationale

Objetives

Methodology

Variables & Epidemiological meausurement

5
 LDG NASH
Proprietary
Proprietary

LDG NASH
Table of Contents

1 Background and rationale

2 Objectives

3 Methodology

4 Variables and epidemiological measurements

Proprietary

LDG NASH
Table of Contents

1 Background and rationale

2 Objectives

3 Methodology

4 Variables and epidemiological measurements

 NAFLD/NASH: the hidden liver disease

26%1
Main challenge:
3%2 • Do published studies identify
the majority of patients?

• Does published data represent

the real burden?

NAFLD NASH
1. Caballería L,, et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol. 2010;22(1):24–32. 2. Estes C, Anstee QM, Arias-Loste MT,
Bantel H, Bellentani S, Caballeria J, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol [Internet]. 2018;69(4):896–904.
Available from: https://doi.org/10.1016/j.jhep.2018.05.036 Bertot LC, Adams LA. Int J Mol Sci. 2016;17:774-785; Estes C, et al. Hepatology. 2018;67:123-133 Confidential
Proprietary

Rationale
Current situation & Data GAPs

• Lack of knowledge of the disease natural history and patient journey

• Low HCP disease awareness
• Suboptimal screening and diagnosis
• Lack of accurate, easy-to-use biomarkers and innovative tools to identify patients with a high probability of
NASH
• The links of NAFLD/NASH with comorbidities (T2DM, obesity) and clinical outcomes is not well understood
• Few epidemiological studies that evaluate incidence, prevalence, and disease natural history in Spain.
• Urgent need of generating Real-world data that represent the disease spectrum of the general population.

Our Goal
Determine clinical and economic burdens of NAFLD (NAFL and NASH) in adult
general, T2DM and obese populations in Spain by using different diagnostic criteria
and innovative tools such as supervised machine learning
Proprietary

LDG NASH
Table of Contents

1 Background and rationale

2 Objectives

3 Methodology

4 Variables and epidemiological measurements

 2.1 Primary Objective
Proprietary

Overall Objective
To estimate the overall clinical and economic burden of NAFLD, NAFL and NASH in adult general,
T2DM and obese populations in the Valencian Community region during a retrospective 8-year
follow-up (2012 to 2019).
Primary Objective
2.1.1 To describe the prevalence of NAFLD, NAFL and NASH in adult general, T2DM, and obese populations using
each of the following diagnostic criteria:
• Diagnosed by liver biopsy
• Diagnosed and registered using ICD-9, ICD-10 codes
• Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes
• Meeting diagnostic criteria used in relevant registries:
• European NAFLD Registry
• TARGET-NASH Study
• Meeting diagnostic criteria determined by Supervised Machine Learning (Proxy Model) using a
combination of biomarkers, imaging and clinical criteria.
 2.2 Secondary Objectives
Proprietary

2.2.1 To describe the incidence of NAFLD, NAFL and NASH in adult general, T2DM and obese populations during a
retrospective 8-year follow-up (2012 to 2019), using each of the following diagnostic criteria:
• Diagnosed by liver biopsy
• Diagnosed and registered using ICD-9, ICD-10 codes
• Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes
• Meeting diagnostic criteria used in relevant registries:
• European NAFLD Registry
• TARGET-NASH Study
• Meeting diagnostic criteria determined by Supervised Machine Learning (Proxy Model) using a combination of biomarkers, imaging
and clinical criteria.

2.2.2 To describe the temporal trends of prevalence and incidence of NAFLD, NAFL and NASH in adult general,
T2DM and obese populations during a retrospective 8-year follow-up (2012 to 2019), using each of the
following diagnostic criteria:
• Diagnosed by liver biopsy
• Diagnosed and registered using ICD-9, ICD-10 codes
• Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes
• Meeting diagnostic criteria used in relevant registries:
• European NAFLD Registry
• TARGET-NASH Study
• Meeting diagnostic criteria determined by Supervised Machine Learning (Proxy Model) using a combination of biomarkers, imaging
and clinical criteria.
 2.2 Secondary Objectives
Proprietary

2.2.3 To describe the main demographic and clinical characteristics of patients with NAFLD, NAFL and NASH in
adult general, T2DM and obese populations.
To focus on NASH for the following objectives:
• To analyze possible differences between the subpopulations of patients with NASH: patients with and
without obesity, patients with and without T2DM and patients with and without obesity and T2DM.

2.2.4 To describe the proportion of NAFLD, NAFL and NASH patients with high probability of advanced fibrosis
using:

• Clinically available biomarkers (FIB4, NAFLD Fibrosis Score)

• Imaging techniques: TE (LSM FibroScan®)

2.2.5 To describe bariatric surgery interventions, including their effect on weight loss, when available
 2.2 Secondary Objectives
Proprietary

2.2.6 To estimate the disease progression and associated risk of the following clinical complications
among patients with NAFLD, NAFL and NASH, in both the general population, in T2DM and obese
patients:
• Hospitalizations: in general and due to CV, renal and liver-related complications
• Liver complications:
o Cirrhosis and its associated complications: ascites, variceal bleedings, encephalopathy, worsening MELD score (especially ≥ 15).
o Hepatocellular carcinoma.
o Liver transplantation.
• CV events.
• Renal events.
• Mortality: All-cause mortality Intrahospital mortality due to CV, renal, and liver causes.

2.2.7 To estimate the healthcare resource utilization in patients with NAFLD, NAFL and NASH in the adult
overall, T2DM and/or obese populations, specifically those associated to pre-specified clinical
complications, and trends during the retrospective 8-year follow-up (2012 to 2019).

2.2.8 To estimate the costs associated to resource utilization in patients with NAFLD, NAFL and NASH in the
adult overall and T2DM and/or obese populations, specifically those associated to pre-specified clinical
complications during the retrospective 8-year follow-up (2012 to 2019).
Proprietary

LDG NASH
Table of Contents

1 Background and rationale

2 Objectives

3 Methodology

4 Variables and epidemiological measurements

 3. Methodology: Database, study population and study period
Proprietary

Real-world, longitudinal retrospective study on a populational database, using only

structured secondary data fully anonymized.
Databases Study population
Valencian Community DB Inclusion Criteria
3.72 million people >24 years old • Adult patient 24 years or older at the initiation of the index
period, January 1, 2012.
Malva-Rosa Clinic DB • Patients must have a diagnosis of NAFLD, NAFL, NASH, T2DM
Building the proxy and/or obesity as defined in the study protocol.
290,349 people>18 years model
Exclusion Criteria
Individualized data (EHR) from all patients • Patients with lack of appropriate information in the database
registered, reflecting the routine clinical practice. • Patients with Viral hepatitis, Alcoholic hepatitis, Toxic
hepatitis
• Autoimmune hepatitis, Patients with a registered diagnosis
Performing the real-world, longitudinal retrospective study of gestational DM or any secondary DM

Index Period
January 1st, 2012 December 31st, 2019
Index Date: Follow-Up Period:

The date of the patient’s first diagnosis Post-index date follow-up time for resource
of NAFLD, NAFL or NASH during the utilization within the Index Period
index period
 3. Methodology: Available study population data
Proprietary

ALUMBRA PLATFORM
Available study population data from databases
The databases integrate hospital, sociodemographic and primary care
information

Valencian Community DB
3.72 million people >24 years old ORION ABUCASIS

Malva-Rosa Clinic DB
290,349 people>18 years

Individualized data (EHR) from all patients December 31st, 2019

registered, reflecting the routine clinical practice.

CMBD: Conjunto Mínimo Básico de Datos (Minimum Basic Dataset)

GAIA: Gestión de la prestación farmacéutica (Pharmaceutical Service Management)
SIA: Sistema de Información Ambulatoria (Ambulatory Information System)
SIP: Sistema de Información Poblacional (Population Information System)
 3. Methodology: Proxy Model development
Proprietary

Malva-Rosa Clinic DB Proxy Models

NASH Algorithm 1

290,349 people NASH Algorithm 2

NASH Algorithm 3
NASH
Data Data NAFL Algorithm 1
input output
NASH NAFL
NAFL Algorithm 2

NAFL
NAFLD Algorithm 1

NAFLD NAFLD Algorithm 2

NAFLD Algorithm 3
NAFLD

Patient selection according to their Dx of NASH, Development of several models based on

Small dataset
NAFL and NAFLD Random Forest and XGBoost Algorithms
 3. Methodology: Proxy Model development
Proprietary

Malva-Rosa Clinic DB Proxy Models

NASH Algorithm 1

290,349 people

NASH
Data Data
input output
NASH NAFL
NAFL Algorithm 2

NAFL

NAFLD

NAFLD Algorithm 3
NAFLD

Patient selection according to their Dx of NASH, Development of several models based on

Small dataset
NAFL and NAFLD Random Forest and XGBoost Algorithms
 3. Methodology: Calculation of prevalences
Proprietary

Valencian Community DB

3.72 million people

%NASH %NAFL %NAFL %NASH %NAFL

%NAFLD %NASH %NAFLD %NAFLD
Prevalences in overall Prevalences in T2D Prevalences in obese
population population population

• Diagnosed by liver biopsy

• Diagnosed by liver biopsy • Diagnosed by liver biopsy
• Diagnosed and registered using ICD-9, ICD-10 codes
• Diagnosed and registered using ICD-9, ICD-10 codes • Diagnosed and registered using ICD-9, ICD-10 codes
• Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes
• Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes • Diagnosed by liver biopsy and/or ICD-9, ICD-10 codes
• Meeting diagnostic criteria used in relevant
• Meeting diagnostic criteria used in relevant registries: • Meeting diagnostic criteria used in relevant registries:
registries:
• European NAFLD Registry • European NAFLD Registry
• European NAFLD Registry
• TARGET-NASH Study • TARGET-NASH Study
• TARGET-NASH Study
• Meeting diagnostic criteria determined by Supervised • Meeting diagnostic criteria determined by Supervised
• Meeting diagnostic criteria determined by Supervised
Machine Learning (Proxy Model) NASH Algorithm 1 Machine Learning (Proxy Model) NAFL Algorithm 2 Machine Learning (Proxy Model) NAFLD Algorithm 3

January 1st, 2012 December 31st, 2019

Proprietary

LDG NASH
Table of Contents

1 Background and rationale

2 Objectives

3 Methodology

4 Variables and epidemiological measurements

Proprietary

4. Variables and epidemiological measurements

The comorbidities will be identified from the database using ICD-9 and ICD-10 codes available in the
database above mentioned and other clinical criteria

1 2
The following variables will be adjudicated taking into account the
Patients with the following ICD-9 classification/diagnostic criteria and definitions described below:
or ICD-10 codes will be excluded:
NASH Classification NAFL Classification NAFLD Classification Other comorbidites
1. Alcoholic liver disease: and Diagnostic Criteria and Diagnostic Criteria and Diagnostic Criteria
• ICD-9: 571.0, 571.1,
571.2, 571.3.
• ICD-10: K70.x.
2. Toxic hepatitis:
• ICD-9: 573.3.
• ICD-10: K71.x
3. Viral hepatitis: Other Variables
• ICD-9: 070.x Classification criteria for high probability of fibrosis
• ICD-10: B15.x, B16.x,
B17.x, B18.x, B19.x.
Proprietary
4. NASH Classification and Diagnostic Criteria
 4. NAFL Classification and Diagnostic Criteria
Proprietary
 4. NAFLD Classification and Diagnostic Criteria
Proprietary
Proprietary

4. Diagnostic criteria for other comorbidities

Proprietary

4. Diagnostic criteria for other comorbidities

Diagnosis criteria for liver-related complications
Mortality-related variables
and other liver disease
 4. Variables: Resource utilization and costs
Proprietary

Healthcare resources utilization and costs in patients with NAFLD, NAFL and NASH in the adult overall, T2DM and/or
obese populations, related to pre-specified clinical complications and events, will be adjudicated to each patient

Primary Care Hospital

• Outpatient Visits by specialty (number)

• Outpatient Visits (number and type)
• Outpatient procedures (number and type)
• Pharmacy electronic prescription system (number)
• Imaging diagnosis and laboratory tests (number)
In general, and due to CV, renal and liver-related
complications.
• Outpatient imaging diagnosis and laboratory tests (number)
• Pharmacy electronic prescription system (number)
• Hospitalizations according to the rates established for the Diagnosis related group
(DRG) (number and length)
• Complications (1. Liver complications: Cirrhosis and its associated complications:
ascites, variceal bleedings, encephalopathy, worsening MELD score (especially ≥
15),Hepatocellular carcinoma, Liver transplantation. 2. CV events. 3. Renal events)
• Emergency Room (ER) Visits (number and length)
In general, and due to CV, renal and liver-related complications.

Estimation of Costs

Based on the collection of information of natural units of health care resources used in clinical practice, and their cost estimated using unit
(unitary standard) costs extracted either from the health care provider (SIE , GAIA) , and from a unit costs database (eSalud) that compiles
information collected from public sources.
Proprietary

38
3. Start-up
Timelines

Regulatory/ethics approvals

39
Proprietary

3. Start-up: Key dates/Milestones

CORE Approval 01 April 2022

Meeting
IEC Submission
28Apr2022
10 April 2022

IEC Approval Pending – CEIm H. Clínico U de Valencia

“Conselleria - Generalitat
June 2022
Valenciana” Approval

Data Collection Start July 2022

Data Collection End September 2022

Final Statistical Report January 2023

Clinical Study Report March 2023

Publications 2023-2024

40
Proprietary

3. Start-up: Regulatory/ethics approvals

CEIm H. Clínico U de Valencia

APRIL 2022 MAY 2022

10 28 12 ¿? ¿?

Submission IEC meeting Clarifications Response to IEC approval

requested by IEC clarifications

41
4. Safety

42
Proprietary

4. Safety – Pharmacovigilance Training

Specific training to be performed by the supplier:

Adverse Event and Product quality complaint Reporting for Non-Interventional Studies:
Supplier Training for Secondary Data Collection using structured data

Sent by MSD annually

43
Proprietary

4. Safety – Pharmacovigilance Training

This is a non-interventional database study based on secondary use of data collected for other purposes.

• No reporting of individual adverse events or product quality complaints to regulatory agencies is planned for this
database study because there is no access to individual patient/subject records and it is not possible to assess the
causality of individual cases.

• Study-specific health outcomes of interest, including any that qualify as adverse events, will be summarized as part of
any interim analysis, including any that qualify as adverse events, will be summarized as part of any interim analysis
(including safety analysis, if required) and in the final study report, which will be provided to regulatory agencies by the
sponsor as required.

INVESTIGATOR RESPONSIBILITY:

If an investigator elects to spontaneously report any suspected adverse reactions or product quality complaints, they should be reported
in English using an AE and PQC report form as outlined in the approved protocol for reporting to worldwide regulatory agencies as
appropriate.

44
Proprietary

4. Safety – AE and PQC form What Information Needs to be Reported ?

NASH_External Adverse Event and

Product Quality Complaint Form
(v1.0_10Feb2022)

Once completed, to be sent to the

PV fax: + 34 91 5716466
(in English )

45
5. Next Steps

46
Proprietary

NEXT STEPS

MSD INCLIVA

To send specific documents: Documentation:

- AE and PQC training • CVs team & Trainings logs
- AE and PQC reporting form • Protocol Signature pages
- Training log PV and Protocol

IEC decision: APPROVAL

Other?

47
 Questions?

MSD
Address: C/Josefa Valcárcel, 38 28027 Madrid
Thanks