Ref.

Ares(2018)2314007 - 01/05/2018
CONFIDENTIAL

D5.1 Imaging manual to standardise

image acquisition across all
participating sites

LITMUS

Liver Investigation: Testing Marker Utility in Steatohepatitis

Grant Agreement No. 777377

WP5 – Imaging

Lead contributor Paul Hockings (P33 – ANT)

paul.hockings@antarosmedical.com
Other contributors Michael Pavlides (P10 – UOXF)
Velicia Bachtiar (P11 – PERS)
Manuel Romero-Gomez (P12 – SAS)
Thersa Tuthill (P40 – PFE)
Lisa Jarl (P33 – ANT)

Due date 30 April 2018

Delivery date 30 April 2018
Deliverable type R
Dissemination level CO

Description of Work Version Date

1.0 30 April 2018
 CONFIDENTIAL

Document History

Version Date Description

0.1 26 Sept 2017 First Draft
0.2 23 Nov 2017 Second Draft
0.3 05 April 2018 Third draft
0.4 20 April 2018 Fourth draft
1.0 30 April 2018 Final version

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Table of Contents

1 Introduction ............................................................................................................................................................................... 5
Table of Contents for MRI Imaging Manual ....................................................................................................................... 7
2 Objectives of MRI imaging manual............................................................................................................................... 8
3 Site ................................................................................................................................................................................................ 8
4 Background .............................................................................................................................................................................. 8
Background to the LITMUS study ....................................................................................................................... 8
Objectives of the LITMUS imaging study ........................................................................................................ 9
5 Ethical/legal aspects ............................................................................................................................................................ 9
6 Incidental findings ................................................................................................................................................................. 9
7 Training.................................................................................................................................................................................... 10
8 Site Approval ........................................................................................................................................................................ 10
9 Procedure ............................................................................................................................................................................... 10
Subject referral........................................................................................................................................................... 10
Initial procedures at imaging site ...................................................................................................................... 11
Imaging protocol ........................................................................................................................................................ 11
10 Archiving ................................................................................................................................................................................. 17
11 Coding the examination .................................................................................................................................................. 17
12 Image File transfer to Quantitative Analysis Service (QAS) ......................................................................... 17
Timelines ....................................................................................................................................................................... 17
Transfer the image file to a USB memory .................................................................................................... 17
Transfer file to QAS ................................................................................................................................................. 18
Imaging e-CRF........................................................................................................................................................... 18
Table of Contents for FibroScan Manual ......................................................................................................................... 21
13 Read This First .................................................................................................................................................................... 22
13.1 Disclaimer ..................................................................................................................................................................... 22
14 Background to the LITMUS study .............................................................................................................................. 22
14.1 Background.................................................................................................................................................................. 22
14.2 Objectives with the LITMUS imaging study................................................................................................. 22
14.3 What Is the Purpose of Data Transfers (to USB and/or dedicated Cloud platform)?............. 23
14.4 How Will Patient Privacy Be Protected? ....................................................................................................... 23
14.5 Glossary of Acronyms ............................................................................................................................................ 24
15 Description of FibroScan® Technology .................................................................................................................... 25
15.1 How does it work? .................................................................................................................................................... 25
15.2 How is the exam conducted? ............................................................................................................................. 25
15.3 Is FibroScan Approved?........................................................................................................................................ 25

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16 How to setup a FibroScan® examination ................................................................................................................ 26

17 Output metrics from a FibroScan® examination.................................................................................................. 27
17.1 FibroScan® examination flow chart & quality guide ................................................................................. 28
18 FibroScan® examination time points in LITMUS Study ................................................................................... 30
19 How to map FibroScan® PDF report data into an electronic CRF ............................................................. 31
20 How to retrieve and export results from a previous examination ............................................................... 32
21 Other Frequency Asked Questions ........................................................................................................................... 33
22 References ............................................................................................................................................................................ 34
23 Appendix 1: FibroScan® FIBX data retrieval procedures ............................................................................... 35
23.1 Instructions for FibroScan® 502 / Touch, 530 Compact, 430 MINI.................................................. 35
24 Appendix 2: How to upload FIBX data to the dedicated QAS platform................................................... 37

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1 Introduction
Standardisation of data acquisition across all modalities will be vital for LITMUS to achieve
its goals as a robust assessment of image-based biomarker fidelity. LITMUS Imaging
Manuals have been produced in parallel to the scanning protocol. One covering the MRI
technical aspects and a second covering the ultrasound-based elastography technologies
(using manufacturer protocols for VCTE). These will be distributed to the participating sites
to ensure standardised operating practices are followed across all participating sites.

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MRI Imaging Manual

Study title: LITMUS

Imaging site: <<>>

The original signature page is archived in the Imaging Trial Master File at Oxford University

Approved by:

Michael Pavlides Date (dd-MMM-yyyy)

LITMUS Project Manager,
University of Oxford

This manual N/A First version of this document

supersedes

Confidential

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Table of Contents for MRI Imaging Manual

1 Introduction ............................................................................................................................................................................... 5
Table of Contents for MRI Imaging Manual ....................................................................................................................... 7
2 Objectives of MRI imaging manual............................................................................................................................... 8
3 Site ................................................................................................................................................................................................ 8
4 Background .............................................................................................................................................................................. 8
Background to the LITMUS study...................................................................................................................... 8
Objectives of the LITMUS imaging study....................................................................................................... 9
5 Ethical/legal aspects ............................................................................................................................................................ 9
6 Incidental findings ................................................................................................................................................................. 9
7 Training.................................................................................................................................................................................... 10
8 Site Approval ........................................................................................................................................................................ 10
9 Procedure ............................................................................................................................................................................... 10
Subject referral ......................................................................................................................................................... 10
Initial procedures at imaging site .................................................................................................................... 11
Imaging protocol ...................................................................................................................................................... 11
10 Archiving ................................................................................................................................................................................. 17
11 Coding the examination .................................................................................................................................................. 17
12 Image File transfer to Quantitative Analysis Service (QAS) ......................................................................... 17
Timelines ..................................................................................................................................................................... 17
Transfer the image file to a USB memory .................................................................................................. 17
Transfer file to QAS ............................................................................................................................................... 18
Imaging e-CRF ......................................................................................................................................................... 18

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2 Objectives of MRI imaging manual

This manual describes the process to be followed at the Imaging site when performing MRI in the LITMUS
study. The workflow is described in the figure below:

Imaging
Subject Referral Transfer of images QAS Portal
site

Medical read (images

to UOXF)

3 Site
Local PI <<name>>
<<email/>>
<<telephone>>

MR Scanner: <<e.g. Philips Achieva 5.3>>

Scans Patches/WIPs/products
Proton Density Fat Fraction <<Multi echo GRE sequence>>
T1 Mapping << WIP or MyoMaps for Siemens/SmartT1 Map or
CardioMaps for GE/Molli Patch or CardiacQuant for
Philips>>
MR Elastography <<NA or describe>>
DEMILI <<NA or describe>>

4 Background

Background to the LITMUS study

The Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) study aims to identify and
validate biomarkers of non-alcoholic steatohepatitis (NASH) and across the spectrum of non-
alcoholic fatty liver disease (NAFLD). LITMUS is sponsored by the University of Newcastle (UNEW).
Connected to LITMUS and sponsored by the University of Oxford (UOXF) is an imaging study

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focusing specifically on the evaluation and validation of imaging biomarkers of NASH and NAFLD
and titled ‘Assessment & Validation of Imaging Modality Performance across the NAFLD Spectrum
in a Prospectively Recruited Cohort’.
The imaging study will:
 Establish a validated non-invasive imaging methodology that can detect NASH or its histological
components (steatosis, ballooning, and lobular inflammation) in patients with risk factors for NAFLD;
 Validate non-invasive imaging modalities that effectively stratify NAFLD patients based on severity of
fibrosis and portal hypertension;
 Validate non-invasive modalities that effectively stratify NAFLD patients according to their long-term
outcomes;
 Develop, evaluate and validate algorithms to stratify patients with NAFLD suitable for clinical
application;
 Build a digital repository of imaging biomarkers including all images and output together with
digitalised liver biopsies as gold standard.

Objectives of the LITMUS imaging study

The study is a multicentre imaging study conducted at up to 15 sites in around 5-10 countries.
Subjects will have a baseline scan and then a follow-up assessment 2 years after the initial
assessment with the same modalities. Oxford University (UOXF), Antaros Medical AB (ANT),
Perspectum Diagnostics Ltd (PERS), and Servicio Andaluz de Salud (SAS) are partners
responsible for carrying out this imaging study. The MRI measurements will be:
 Magnetic Resonance Elastography (MRE)
 LiverMultiScanTM (LMS) which includes the iron-corrected T1 Score (cT1), hepatic lipid content (%)
and liver iron (mg/g)
 Magnetic Resonance DWI for measurement of the Apparent Diffusion Coefficient (ADC)
 DEMILI MRI (detection of metabolic induced liver injury).

5 Ethical/legal aspects
The study is approved by the Ethics Committee at <<insert local ethical committee>>. All subjects
that will be referred to imaging have signed an informed consent at the Recruiting site.

6 Incidental findings
An incidental finding is an image feature of potential pathological nature that is discovered
unintentionally in addition to the study protocol required imaging endpoints. The incidental finding
can additionally not directly be discarded as caused by an imaging artefact.

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All MRI scans will be centrally read by an expert GI radiologist at UOXF for the presence of
incidental findings. The purpose of this central reading is not to provide a full clinical report of the
MR images, but to provide a report as to the presence or absence of any incidental findings. Only
findings that, in the judgment of the Radiologist, require further investigation will be flagged. This
reporting will take place within 10 working days of the scan being uploaded to the QAS study portal.
If an incidental finding is identified, a comment will be provided back to the imaging site through the
QAS study portal. It will be the responsibility of the local radiologist to then arrange for the findings
to be reported to the local PI at the recruiting centre, who will be responsible for any clinical follow
up that will be required.

7 Training
All imaging site staff acquiring data for the LITMUS imaging study need to be trained in the study
protocol. Study training will be conducted and documented according to the ANT, PERS and SAS
routines. Training documents and copies of site radiology staff certificates will be stored in the Trial
Master File (TMF) at UOXF. New staff who start working on the LITMUS imaging study during the
study will be trained by already trained staff. Training records will then be updated and sent to the
UOXF PM. Briefly:

 ANT: Web training of study personnel. Each center should submit one DWI and one MRE
study (if applicable) to check protocol adherence and image quality for site approval

 PERS: Site approval based on a site visit and QC data. On-line training and support team
are also available in addition.

 SAS: On-line training and an online support team will be available. After installation of
protocols, each center should submit at least two (2) DEMILI studies to check their adequacy

8 Site Approval
ANT will issue a Site Report summarising site status. An approved Site Report is necessary for
participation in the LITMUS imaging study.

9 Procedure

Subject referral
Recruiting site:

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 Will ask the subject if there is any contraindication for MRI, i.e. pace-maker, intra-cranial clip
 Retain an informed consent for the MRI procedure
 Will refer the subjects to the Imaging site and book an imaging slot. It is important that the timing of the
MRI procedure is in accordance with the protocol

Initial procedures at imaging site

 Schedule the MRI process
 Inform the referring Investigator immediately about any change to the MRI appointment date
 Identify the subject according to normal hospital procedure
 Perform routine check for all exclusion criterions for MRI, e.g. pace-makers, intra-cranial clips
 Breath-holding should be explained and practised before any data acquisition since variations in the depth
of a subject’s breathing can markedly alter the SNR and the consistency of the abdomen position between
acquisitions
 Set up the ECG or pulse oximeter and check the signal has clear R-wave triggering. Please set the
<entered heartrate> parameter to be about 5 over the patient’s actual heartrate
 Prepare Imaging eCRF or paper Scan Log to document scans

Imaging protocol

Scan preparation  Load the Measurement program from: <<>>

Subject positioning  Scanner isocentre should be landmarked on the xiphisternum of the

patient. The elastography driver is placed over the right lower chest
wall at the level of xiphisternum in midclavicular line (can be placed
in the right mid-axillary line if colon is present between the anterior
body wall and the liver)

Coils  Use the spine array and the large body flex coil

PLEASE NOTE:  Do not change the FOV or angle of the scans except as specified
below

3PlaneLocalizerBH  Perform a survey scan in breath hold

SURV (breathhold – end
exp.)

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Shim Positioning
Hepatic MRE:
(2 x breathhold – end exp.)
5 slices
Remove elastography driver
LMS Base Slice
(breathhold – end exp.)
CONFIDENTIAL
The shim volume (red box in figure above) should be centred on
the slice(s). In the R-L and A-P directions the shim volume can
be adapted to include the entire abdomen in the transverse
view (liver and the spleen covered).
In the F-H direction, shim volume thickness should be left as set
in the protocol, and is thicker than the acquired slice.
 Position the axial scan in
the centre of the liver so
that equal amounts are cut
off in Head and Foot
directions
Check image quality to
ensure the breathhold
was successful. If not,
repeat and make a note
in the Scan Log
Single transverse slice should be positioned as above. It should
intersect the porta hepatis, and display the liver, spleen. If the
lungs are visible in the transverse slice, please re-centre and
localise the image lower on the patient’s abdomen as the lungs
will cause susceptibility artefacts.
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N.B. If susceptibility artefacts appear in the liver (Figure above), re-acquire after checking to
ensure scanning is done at magnet isocentre, and shim volume is positioned as described

LMS MOLLI MultiSlice
(breathhold – end exp.)
This scan acquires 4 transverse slices, one per breath-hold.
Each breath hold has a duration of approximately 11 seconds
with a small dependence on heart rate.
The slice stack should be positioned as shown above. The third
slice from inferior to superior should intersect the porta hepatis,
or as close as possible to it. It should display the liver, the
spleen, and may also contain the stomach. The lungs should be
excluded where possible as they may induce susceptibility
artefacts.
During the scan, it is imperative to monitor the physiological
recording trace to check no heart beats are missed by the
system’s triggering algorithm. A red line should appear below
every R-peak during the scanning,
It is important to check for motion and repeat the acquisition if
motion artefacts (typically from breathing) have occurred during
the acquisition. Motion artefacts can preclude accurate
parameter mapping.

LMS IDEAL Ensure the LMS IDEAL scan has the same geometry as LMS
(breathhold – end exp.) MOLLI (Figure above). This will ensure that slices and shim
volume will have the same location

LMS T2STAR DIXON
(breathhold – end exp.)
Single slice multi-echo gradient-echo transverse acquisition and
requires a breath hold of approximately 8-9 seconds. It must be
mapped on the previously acquired 4 slices. In order to do so
double click on the LMS MOLLI series and bring up the
transverse views in the viewing window of the planning

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interface. Scroll through the slices until slice 3 (which is the

second slice from the top of the liver) is shown. Then click on
the <Toggle 3 Point Plans Scan> icon as indicated by the red
circle in Figure below.
Click three times in three different points on the slice. The
image will then display the three points selected as indicated.
It doesn’t matter exactly where these points are placed as long
as they are on the slice.
In order to make the selection effective, please click on the icon
<Compute Plane> as seen in under the blue circle in Figure
below.

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DWI_4b_0_150_400_800:
(breathhold – end exp.)
5 slices (based on end exp.
localizer)
Same Geometry as MRE
DEMILI TSE-T2-BH
(breathhold – end exp.)
DEMILI STIR (respiratory
triggered
Scan duration approx. 4
minutes
DEMILI 3D-FFE-
T1(DINAMYC)
(breathhold – end exp.)
CONFIDENTIAL
 Position the axial scan in
the centre of the liver so
that equal amounts are
cut off in Head and Foot
directions
Check image quality to
ensure the breathhold
was successful. If not,
repeat and make a note
in the Scan Log
 Position the axial scan in
the centre of the liver so
that equal amounts are
cut off in Head and Foot
directions
Check image quality to
ensure the breathhold
was successful. If not,
repeat and make a note
in the Scan Log
 Position the axial scan in
the centre of the liver so
that equal amounts are
cut off in Head and Foot
directions
Check image quality to
ensure the breathhold
was successful. If not,
repeat and make a note
in the Scan Log
 Position the axial scan in
the centre of the liver so
that equal amounts are
cut off in Head and Foot
directions
Check image quality to
ensure the breathhold
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was successful. If not,

repeat and make a note
in the Scan Log

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10 Archiving
Image data should be archived to the hospital PACS according to normal hospital procedure

11 Coding the examination

 Verify that the scan has been sent to PACS (Picture archiving and communication system)

 Select current subject in the Patient Browser

 Select “Remove Protection” from the right-mouse button menu

 Choose the Edit drop-down menu and select Correct

 Substitute the subject’s name with subject ID, e.g. UNEW_123_QUAN
(CENTRE_SEQUENTIAL NUMBER_INITIALS
 Substitute the subject’s Patient ID with the Visit code (MRI1 or MRI2)
 Remove the accession number
 Remove the referring physician
 Replace the month and day in the subject’s date of birth with 01-Jan. Example, a subject with
date of birth 29/10/1956 becomes 01/01/1956

 Select OK button and the information will be updated in the patient browser

12 Image File transfer to Quantitative Analysis Service (QAS)

Timelines
Image file should be uploaded to the QAS within 2 working days of acquisition.

Transfer the image file to a USB memory

 Insert USB-memory in the computer
 Open Patient Browser, select Local DataBase, select the desired patient data
 Select Transfer > Export to Offline
 Select the USB-drive using the Path drop down menu and select DICOM format. Check that the
Anonymise box is not ticked. Select OK
 From the Patient Browser select Transfer > Local Job Status. After data transferral is complete
eject the USB memory stick

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Transfer file to QAS

 Insert the USB-drive or CD on the computer used for file transfer
 Name the subject directory: ID_VC_YYYYMMDD where
o ID is Subject Identifier e.g. UNEW_123_QUAN (CENTRE_SEQUENTIAL
NUMBER_INITIALS),
o VC is Visit Code (MRI1 or MRI2), and
o YYYYMMDD is scan date

 Use a Web Browser to open page https://portal.perspectum-diagnostics.com/

 Username: person specific
 Password: person specific

 On the QAS Portal, click on the ‘Upload New Study’ link:

 Select the LITMUS Project
 Enter the Study ID
 Provide any additional details or requests for analysis in the comments window
 Drag and drop the patient study into the file upload window
 Press the Submit button

Imaging e-CRF
Information regarding the scan session, e.g. subject number, date, which method was performed
should be entered into the electronic imaging case report form (imaging eCRF). If no internet
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 CONFIDENTIAL

connection is available at the imaging site, a paper version of the imaging eCRF should be filled in
and information transferred to the imaging eCRF by the imaging site staff once internet connection
is available. The imaging eCRF should be filled in 2 days after the scan has been performed at the
latest.

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FibroScan Manual
Clinical Trial Sites in:
LITMUS study
Version: 27 April 2018

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Table of Contents for FibroScan Manual

Read This First ............................................................................................................................... 22

Disclaimer ................................................................................................................................... 22

Background to the LITMUS study ................................................................................................... 22

Background ................................................................................................................................. 22

Objectives with the LITMUS imaging study.................................................................................. 22

What Is the Purpose of Data Transfers (to USB and/or dedicated Cloud platform)? .................... 23

How Will Patient Privacy Be Protected? ...................................................................................... 23

Glossary of Acronyms ................................................................................................................. 24

Description of FibroScan® Technology ............................................................................................ 25

How does it work? ....................................................................................................................... 25

How is the exam conducted?....................................................................................................... 25

Is FibroScan Approved? .............................................................................................................. 25

How to setup a FibroScan® examination ......................................................................................... 26

Output metrics from a FibroScan® examination ............................................................................... 27

FibroScan® examination flow chart & quality guide ...................................................................... 28

FibroScan® examination time points in LITMUS Study .................................................................... 30

How to map FibroScan® PDF report data into an electronic CRF .................................................... 31

How to retrieve and export results from a previous examination ..................................................... 32

Other Frequency Asked Questions ................................................................................................. 33

References ..................................................................................................................................... 34

Appendix 1: FibroScan® FIBX data retrieval procedures ................................................................. 35

Instructions for FibroScan® 502 / Touch, 530 Compact, 430 MINI ............................................... 35

Appendix 2: How to upload FIBX data to the dedicated QAS platform ............................................ 37

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13 Read This First

13.1 Disclaimer
The intent of this document is to provide supplementary information pertaining to FibroScan use in the
context of LITMUS Study. Under no circumstances does this manual replace formalized training or supersede
instructions in the official clinical trial protocol. This document is to be used only after Echosens (or its
affiliates) have certified FibroScan operators at your practice.

14 Background to the LITMUS study

14.1 Background
The study Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) is a study aiming to identify
and validate biomarkers of non-alcoholic steatohepatitis (NASH) and across the spectrum of non-alcoholic
fatty liver disease (NAFLD). LITMUS is sponsored by the University of Newcastle (UNEW).

Connected to LITMUS and sponsored by the University of Oxford (UOXF) is an imaging study focusing
specifically in the evaluation and validation of imaging biomarkers of NASH and across the spectrum of
NAFLD and titled ‘Assessment & Validation of Imaging Modality Performance across the NAFLD Spectrum in
a Prospectively Recruited Cohort’.

The imaging study will:

 Establish a validated non-invasive imaging methodology that can detect NASH or its histological
components (steatosis, ballooning, and lobular inflammation) in patients with risk factors for NAFLD;
 Validate non-invasive imaging modalities that effectively stratify NAFLD patients based on severity of
fibrosis and portal hypertension;
 Validate non-invasive modalities that effectively stratify NAFLD patients according to their long-term
outcomes;
 Develop, evaluate and validate algorithms to stratify patients with NAFLD suitable for clinical
application;
 Build a digital repository of imaging biomarkers including all images and output together with
digitalised liver biopsies as gold standard.

14.2 Objectives with the LITMUS imaging study

The study is a multicentre imaging study conducted at up to 15 sites in around 5-10 countries. Subjects will
have a baseline scan and then a follow-up assessment 2 years after the initial assessment with the same
modalities. The image acquisitions will be performed at baseline and at 2 years and use the following

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 CONFIDENTIAL

modalities:

(i) Ultrasound including:

a. VCTE (Fibroscan®);
b. Point quantification shear wave elastography (pSWE)/ARFI;
c. 2d Shear Wave elastography – 2d-SWE/SSI

(ii)MRI including:
a. Magnetic Resonance Elastography (MRE)
b. LMS which includes the Liver Inflammation and Fibrosis Score (LIF), hepatic lipid content (%) and liver iron
(mg/g),
c. Magnetic Resonance DWI for measurement of the Apparent Diffusion Coefficient (ADC)
d. DEMILI MRI (detection of metabolic induced liver injury).

This manual will only describe the VCTE (Fibroscan) imaging part of the imaging study.

14.3 What Is the Purpose of Data Transfers (to USB and/or dedicated
Cloud platform)?
Multiple sections within this document describe methods for extracting FibroScan examination data (PDF,
FIBX) to USB and then transferring these data to Perspectum’s Quantitative Analysis Service (QAS). The
purpose is two-fold:
1. Data Protection – Since there is always a chance of a hardware failure, periodic data back-up should
occur to prevent an irreversible loss of examination data. Ideally, data should be backed to USB after
each examination. Data transfer to QAS provides an additional layer of protection by maintaining a
duplicate copy in the cloud.
2. Quality Assurance – FibroScan data (PDF/FIBX) will be periodically transferred to the dedicated QAS
platform to allow Echosens to perform blinded analyses of examinations. In doing so, Echosens and
the Sponsor can provide feedback to clinical trial sites to help maintain high quality of all FibroScan
examinations in the study.

14.4 How Will Patient Privacy Be Protected?

Patient privacy is of utmost importance to all parties involved in the clinical trial. In order to ensure patient
privacy, multiple steps have been taken:
1. Exam Setup – p. 6 recommends entry of specific parameters upon initiation of a FibroScan exam such
that no information about the patient is stored on the system.

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2. Anonymization Step – p. 6, p. 15 to 17 describe processes that strip all patient information at the time
of extracting PDF and FIBX files, respectively. Afterwards, only FibroScan-specific parameters remain
(e.g. kPa, CAP).

By following the guidelines outlined in this document, there will be no patient-specific information transferred
from clinical trial sites to the Sponsor (or its delegates). If there are any questions pertaining to this process,
please contact clinical@echosens.com.

14.5 Glossary of Acronyms

Acronym Description
CAP Controlled Attenuation Parameter
CE European Conformity
ECRF Electronic case report form
FDA Food and Drug Administration
FIBX FIBroscan® eXamination file
FS FibroScan®
IQR Inter-quartile range
LSM Liver Stiffness Measurement
LTT Liver targeting tool
NAFL Non-alcoholic fatty liver
NASH Non-alcoholic steatohepatitis
PDF Portable document format
SCD Skin to capsule distance
TM Time Motion
USB Universal serial bus
VCTE Vibration controlled transient elastography

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15 Description of FibroScan® Technology

15.1 How does it work?

The FibroScan® device uses proprietary technology to simultaneously assess liver stiffness and
ultrasound attenuation, which are correlated to liver fibrosis and steatosis, respectively [1, 2]. Liver
stiffness is derived from Vibration Controlled Transient Elastography (VCTE) measurements, which
involve mechanically inducing a shear wave in the liver and determining shear wave propagation
speed using pulse echo ultrasound tracking. Liver ultrasound energy attenuation rate is determined
by an algorithmic analysis termed Controlled Attenuation Parameter (CAP). The VCTE and CAP
analysis techniques synergistically quantify key aspects of liver health.

15.2 How is the exam conducted?

The patient examination is painless and requires only 5-
10 minutes. During the test procedure, the patient lies
comfortably, shirt raised slightly, with the right arm raised
behind their head to reveal the rib cage (Figure 1). The
FibroScan® operator applies a water-based gel to the skin
and positions the probe over the center of the liver prior to
Figure 1. Dorsal decubitus position testing. Once the probe is correctly positioned, a series of
10 measurements (at minimum) are taken at this position while the patient breaths normally. The
FibroScan® operator’s screen provides feedback which assures the test is being performed
successfully and accurately. Test results are reported for liver stiffness, CAP, and quality control
metrics.

15.3 Is FibroScan Approved?

FibroScan® technology has been granted market approval by regulatory bodies in multiple
countries including European Union, United States of America (incl. Puerto Rico), Canada,
Australia, New Zealand, Serbia, Switzerland, Israel, Taiwan, China, Japan, and other
countries. The FibroScan® is a medical device manufactured by Echosens (Paris, France).
The instrument is designed to measure non-invasive stiffness (E) and CAP in the liver. The
operating instructions and the labeling accompanying the device can be provided upon
request to Echosens (clinical@echosens.com).

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16 How to setup a FibroScan® examination

To maintain consistency across the clinical trial, please use the following guidelines to enter subject
information into the FibroScan® instrument. Figure 2 is applicable for current FibroScan® systems
[502/T, 530C, and 430MINI].

Figure 2. Sample subject information input screen for current FibroScan®

systems

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17 Output metrics from a FibroScan® examination

Figure 3 is applicable for current FibroScan® systems [502/T, 530C, and 430 MINI1].

Figure 3. Sample output with key metrics for current FibroScan® systems

1
System is not compatible with CAP software
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17.1 FibroScan® examination flow chart & quality guide

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18 FibroScan® examination time points in LITMUS Study

Visit Visit # FS Data Collected Comments
Baseline V1 VCTE, CAP [1], [2],[3]
Visit 2 V2 VCTE, CAP [1], [2],[3]

1. Assessment to be performed following > 4-hour fast

2. VCTE and CAP should be obtained when available
3. FibroScan® PDF2 reports and FIBX3 source files should be saved after each examination
(when possible) and submitted to the Sponsor (or assigned delegate) upon request.4

2
See p. 13 for details on how to save PDF reports
3
See Appendix 1 for details on how to extract FIBX source data
4
See Appendix 2 for details on how to upload data
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19 How to map FibroScan® PDF report data into an electronic

CRF
Figure 4 is applicable for current FibroScan® systems [502/T, 530C, and 430MINI1].

Figure 4. Mapping report parameters to eCRF (current FibroScan® systems)

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20 How to retrieve and export results from a previous

examination
This section is applicable to current FibroScan® systems [502/T, 530C, and 430 MINI]. In order to
transfer a PDF report to the USB device, please perform the following steps:

1. Plug the USB drive into the FibroScan® 5

2. Enter the Archives mode from the main FibroScan® window by clicking on:

or

3. Select the subject ID in the list (Figure 5), or use the search function by clicking on :

Figure 5. Data log screen

4. Once the exam is selected, click on to export the report to the USB device
5. Select “No” to anonymize the PDF:

6. Transfer report to Sponsor upon request

5
USB port can reside on either front of back of system
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21 Other Frequency Asked Questions

Q: What should I do if I have some issues in completing a FibroScan® examination?
A: FibroScan® can be completed successfully in approximately 95% of subjects according to literature
[ref 3]. However, severe obesity and presence of ascites are known causes of invalid results. Should
you have any other training issue, contact our dedicated training team: clinical@echosens.com

Q: What should I do if I perform repeat FibroScan® examinations on a subject and get very different
results?
A: Double check that the scan has been correctly performed and that the technical risks of mistakes
have been ruled out. If problem persists, contact our dedicated team: clinical@echosens.com

Q: Who should I contact if I have any questions related to the FibroScan® instrumentation,
maintenance or service?
A: Contact our dedicated teams:
Service Portal (All Countries): https://support.echosens.com

Q: Who should I contact if I am having issues extracting data from the FibroScan® instrument?
A: Contact our dedicated team: clinical@echosens.com and please add “LITMUS Study” to the
Subject Line

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22 References
1. Sandrin, L., B. Fourquet, et al. Transient elastography: a new noninvasive method
for assessment of hepatic fibrosis. Ultrasound in Medicine and Biology
2003;29(12):1705-1713.
2. Sasso, M., M. Beaugrand, et al. Controlled attenuation parameter (CAP): a novel
VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic
steatosis: preliminary study and validation in a cohort of patients with chronic liver
disease from various causes. Ultrasound in Medicine and Biology 2010;36(11):1825-
1835.
3. Myers, R. P., G. Pomier-Layrargues, et al. Feasibility and diagnostic performance of
the FibroScan XL probe for liver stiffness measurement in overweight and obese
patients. Hepatology 2012;55(1):199-208.

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23 Appendix 1: FibroScan® FIBX data retrieval procedures

Definitions
 FIBX file – FIBroscan® eXamination file (.FIBX) containing exam data (results, shear wave
maps). Each FIBX file corresponds to a single exam, is approximately 6 to 10 MB in size and

has a unique file name:

Prerequisites
 Access to FibroScan® instrument
 Internet-connected personal computer

Who Should Do This

 FibroScan® operator or designate

When Should This Be Done

 FIBX data should be transferred to USB at the end of each examination; Upload to Sponsor
(or delegate) upon request

23.1 Instructions for FibroScan® 502 / Touch, 530 Compact, 430 MINI
STEPS TO BE FOLLOWED CORRESPONDING ILLUSTRATION
1. Turn on the FibroScan (Button D)

2. Plug the USB drive into the FibroScan® (USB

socket, F)
**Never start the 530 Compact System with
USB drive plugged**

3. Enter Archives Mode from software main

window:

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4. Select study-specific FibroScan exams (circle

them in orange) to be exported manually from
the database

Alternatively, use the search function, filter

exams by using “XXX” in the code field to
display them on the software interface

5. Click on « FIBX export » button to export all

selected exams

6. Click « No » to ensure that exported data

exported is anonymized

7. FIBX file shall now be copied on the USB

device; After transfer is complete, remove
USB device from the FibroScan®

8. Follow instructions in Appendix 2 (p. 37) to

transfer data to the Sponsor.

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24 Appendix 2: How to upload FIBX data to the dedicated QAS

platform
Who Should Do This
 Study coordinator, data manager or equivalent at clinical trial site (or delegate)

When Should This Be Done

 Within 2 working days

STEPS TO BE FOLLOWED

1. Plug the USB drive into an internet-connected PC

2. Open web browser and go here: https://portal.perspectum-diagnostics.com/

3. Enter login and password that was provided by Perspectum; If you do not have a login/password, please
contact Perspectum at support@perspectum-diagnostics.com

4. Open « My files » and then « FibroScan FIBX FILES XXXX FOLDER »

5. On the QAS Portal, click on the ‘Upload New Study’ link:
6. At the Upload MRI Patient Study page choose the LITMUS Project
7. Enter the Subject ID
8. Provide any additional details or requests for analysis in the comments window
9. Drag and drop the FIBX files into the file upload window
10. Press the Submit button

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