Conditions: Non-alcoholic Fatty Liver Disease Nonalcoholic Steatohepatitis
Keywords: Non-alcoholic fatty liver disease NAFLD Non-alcoholic steatohepatitis NASH Platform design LYS006 LJN452 Tropifexor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.

Detailed description:
This was a Phase II, non-confirmatory, multicenter, open label, platform study in NAFLD participants with a NASH-like biomarker phenotype to examine the effects of single and combination therapies over 12 weeks of treatment. The study consisted of four distinct study periods:

* Screening Period (Day -60 to -28): Lasted up to a maximum of 33 days where participants were assessed for inclusion and exclusion criteria prior the baseline assessments.
* Baseline Period (Day -27 to -1): Lasted up to a maximum of 27 days and comprised baseline assessments and randomization.
* Treatment Period (Day 1 to 85): Participants were randomized in a 1:1 ratio to LYS006 20 mg (twice a day) arm or to LYS006 20 mg (twice a day) and tropifexor 200ug (once a day). Participants were treated daily during 12 weeks.
* Follow-up Period (Day 85 to 113): After completion of the treatment period, participants were observed until the End Of Study (EOS) visit at Day 113.

Arms:
arm 1: LYS006 20 mg was administered orally twice per day (b.i.d) for 12 weeks arm 2: LYS006 20 mg was administered orally twice per day (b.i.d) in addition to LJN452 200ug administered orally once daily for 12 weeks

Interventions: intervention 1: LYS006 intervention 2: Tropifexor
Intervention descriptions: intervention 1: 5 mg LYS006 capsules orally administered 20 mg b.i.d for 12 weeks intervention 2: 100 ug LJN452 capsules orally administered 200ug once daily for 12 weeks

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
PLATFORM / ADPT02
Clinical Trial Protocol CADPT02A12001 / NCT04147195
NASH EXploratory Single and COmbination Treatment 
(NEXSCOT): An open label, multicenter, platform study to 
evaluate the safety, tolerability, pharmacokinetics and 
efficacy of various single and combination treatments in 
patients with non-alcoholic fatty liver disease (NAFLD) who 
manifest a non-alcoholic steatohepatitis (NASH)-like 
biomarker phenotype
Document type:
Amended Protocol Version
EUDRACT number:
2019-000440-10
Version number:
04 (Clean)
Clinical trial phase:
II
Release date:
02-Jun-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................13
Protocol summary..............................................................................................................22
1
Introduction .......................................................................................................................26
1.1
Background............................................................................................................26
1.2
Purpose ..................................................................................................................26
2
Objectives and endpoints...................................................................................................27
3
Study design ......................................................................................................................28
4
Rationale............................................................................................................................30
4.1
Rationale for study design .....................................................................................30
4.1.1
Platform study.......................................................................................30
4.1.2
Study population ...................................................................................30
4.1.3
Objectives (Endpoints)..........................................................................32
4.1.5
Follow-up period...................................................................................34
4.2
Rationale for dose/regimen and duration of treatment ..........................................35
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................35
4.4
Purpose and timing of interim analyses.................................................................36
4.5
Risks and benefits..................................................................................................36
4.5.1
Blood sample volume............................................................................38
4.6
Rationale for public health emergency mitigation procedures..............................38
5
Population..........................................................................................................................38
5.1
Inclusion criteria ....................................................................................................39
5.2
Exclusion criteria...................................................................................................40
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44
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6.1.1
Investigational and control drugs..........................................................44
6.1.2
Additional study treatments ..................................................................44
6.1.3
Treatment arms/group ...........................................................................44
6.2
Other treatment(s)..................................................................................................44
6.2.1
Concomitant therapy.............................................................................44
6.2.2
Prohibited medication ...........................................................................45
6.2.3
Restriction for study participants ..........................................................46
6.3
Participant numbering, treatment assignment, randomization ..............................46
6.3.1
Participant numbering...........................................................................46
6.3.2
Treatment assignment, randomization ..................................................47
6.4
Treatment blinding.................................................................................................47
6.5
Dose escalation and dose modification..................................................................47
6.5.1
Permitted dose adjustments and interruptions of study treatment ........47
6.6
Additional treatment guidance...............................................................................48
6.6.1
Treatment compliance...........................................................................48
6.7
Preparation, dispensation, and management of investigational drug ....................49
6.7.1
Handling of study treatment..................................................................49
6.7.2
Accountability and monitoring .............................................................49
6.7.3
Preparation and dispensation.................................................................49
6.7.4
Instructions for administration..............................................................49
6.7.5
Remote delivery ....................................................................................50
7
Informed consent procedures ............................................................................................50
8
Visit schedule and assessments .........................................................................................52
8.1
Screening ...............................................................................................................57
8.1.1
Information to be collected on screening failures.................................57
8.1.2
Pre-screening.........................................................................................57
8.2
Participant demographics/other baseline characteristics .......................................57
8.3
Efficacy/Pharmacodynamics .................................................................................57
8.3.1
Liver function tests and liver and/or systemic inflammation 
markers..................................................................................................58
8.3.2
Markers of Liver Fibrosis......................................................................58
8.3.3
Magnetic Resonance Imaging (MRI)....................................................58
8.3.4
Anthropometric assessments.................................................................59
8.3.5
Cardiometabolic risk parameters...........................................................59
8.3.6
Appropriateness of biomarker assessments ..........................................59
8.4
Safety.....................................................................................................................59


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8.4.1
Safety-related laboratory evaluations....................................................59
8.4.2
Electrocardiogram (ECG) .....................................................................60
8.4.3
Pregnancy and assessments of fertility .................................................60
8.4.4
Appropriateness of safety measurements..............................................61
8.5
Additional assessments..........................................................................................61
8.5.1
Clinical Outcome Assessments (COAs) ...............................................61
8.5.2
Pharmacokinetics ..................................................................................61
8.5.5
Imaging .................................................................................................64
9
Discontinuation and completion........................................................................................64
9.1
Discontinuation from study treatment and from study..........................................64
9.1.1
Discontinuation from study treatment in individual participants..........64
9.1.2
Discontinuation from study...................................................................65
9.1.3
Lost to follow-up...................................................................................65
9.2
Withdrawal of informed consent/Opposition to use data/biological samples .......66
9.2.1
Study stopping rules..............................................................................66
9.2.2
Early study termination by the sponsor.................................................67
9.3
Study completion and post-study treatment ..........................................................67
10 Safety monitoring, reporting, and committees ..................................................................68
10.1
Definition of adverse events and reporting requirements......................................68
10.1.1
Adverse events ......................................................................................68
10.1.2
Serious adverse events ..........................................................................69
10.1.3
SAE reporting........................................................................................70
10.1.4
Pregnancy reporting ..............................................................................71
10.1.5
Reporting of study treatment errors including misuse/abuse................71
10.2
Additional safety monitoring.................................................................................72
10.2.1
Safety Assessment Committee..............................................................72
11 Data Collection and Database management......................................................................72
11.1
Data collection.......................................................................................................72
11.2
Database management and quality control............................................................73
11.3
Site monitoring ......................................................................................................73
12 Data analysis and statistical methods ................................................................................74
12.1
Analysis sets ..........................................................................................................74
12.2
Participant demographics and other baseline characteristics.................................74
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12.3
Treatments .............................................................................................................74
12.4
Analysis of the primary endpoint(s) ......................................................................75
12.4.1
Definition of primary endpoint(s).........................................................75
12.4.2
Statistical model, hypothesis, and method of analysis..........................75
12.4.3
Handling of missing values/censoring/discontinuations.......................76
12.4.4
Sensitivity and Supportive analyses......................................................76
12.5
Analysis of secondary endpoints ...........................................................................76
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................76
12.5.2
Pharmacokinetics ..................................................................................77
12.5.3
PK/PD relationships..............................................................................77
13 Ethical considerations and administrative procedures ......................................................80
13.1
Regulatory and ethical compliance........................................................................80
13.2
Responsibilities of the investigator and IRB/IEC..................................................80
13.3
Publication of study protocol and results...............................................................80
13.4
Quality Control and Quality Assurance.................................................................80
14 Protocol adherence ............................................................................................................81
14.1
Protocol Amendments ...........................................................................................81
15 References .........................................................................................................................82
16 Appendices ........................................................................................................................84
16.1
Appendix 1: Liver safety monitoring ....................................................................84
16.2
Appendix 2: Renal safety monitoring....................................................................90
17 Cohort-specific information ..............................................................................................91
17.1
Cohort 1 .................................................................................................................91
17.1.1
Cohort 1, Arm 1: LYS006.....................................................................91
17.1.2
Cohort 1, Arm 2: LYS006 and tropifexor.............................................98
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List of tables
Table 2-1
Objectives and related endpoints ..........................................................27
Table 4-1
Biomarker inclusion criteria compared to normal range.......................30
Table 4-2
Examples of placebo effect in published studies in NASH and 
NASH-like patient populations.............................................................33
Table 6-1
Permitted concomitant medications......................................................44
Table 6-2
Prohibited medication ...........................................................................45
Table 6-3
Dosing response to safety/tolerability events........................................48
Table 8-1
Assessment Schedule ............................................................................52
Table 8-2
Physical Assessments............................................................................59
Table 8-3
Safety-related Laboratory Assessments ................................................60
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................72
Table 16-1
Management of Participants with Confirmed ALP, ALT, AST, or 
Bilirubin Elevations With or Without Liver Related Clinical 
Symptoms..............................................................................................86
Table 16-2
Specific renal alert criteria and actions.................................................90
Table 17-3
Prohibited medications 
............................................97
Table 17-7
Prohibited medications 
..........................................109
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List of figures
Figure 3-1
Study design..........................................................................................28
Figure 4-1
Relationship of fibrosis state and ELF Test result ................................31
Figure 17-2
Potential efficacy of FXR agonism in NASH.....................................101
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List of abbreviations
5’NT
5’nucelotidase (5’riboncleotide phosphohydrolase)
ACEI
angiotensin-converting enzyme inhibitor
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
ARB
angiotensin II receptor blocker
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
body mass index
BUN
blood urea nitrogen
CDS
Core Data Sheet
CFR
Code of Federal Regulations
CI
confidence interval
CMO&PS
Chief Medical Office & Patient Safety
CNS
central nervous system
COA
Clinical Outcome Assessment
CRA
clinical research associate
CRF
case report/record form (paper or electronic)
CSR
clinical study report
CT
computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria Adverse Event
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DMC
data monitoring committee
ECG
electrocardiogram
EDC
electronic data capture
EDD
expected delivery date or estimated date of delivery
ELF
Enhanced Liver Fibrosis
EMA
European Medicines Agency
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EOS
End of Study
FDA
Food and Drug Administration
FIB4
Fibrosis-4
FIH
first-in-human
FSH
follicle-stimulating hormone
FXR
farnesoid X receptor
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
hour
HA
hyaluronic acid
HbA1c
Hemoglobin A1c (glycated hemoglobin)
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HDL
high-density lipoprotein
HGB
hemoglobin
HIV
human immunodeficiency virus
HOMA-IR
Homeostasis Model Assessment of Insulin Resistance
hsCRP
High-sensitivity C-reactive Protein
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IL
interleukin
IMP
investigational medicinal product
IN
Investigator Notification
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IU
international unit
IUD/S
intrauterine device/system
kPa
kilopascal
LC-MS/MS
liquid chromatography-mass spectrometry
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
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MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram(s)
mL
milliliter(s)
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRP
multidrug resistance protein
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NEXSCOT
NASH EXploratory Single and COmbination Treatment
nM
nanomolar
ng
nanogram
NOAEL
no observed adverse event level
OCA
obeticholic acid
OHP
off-site healthcare professional
PBC
primary biliary cholangitis
PBMC
peripheral blood mononuclear cell
PBPK
physiologically based pharmacokinetic (modelling)
PCR
protein-creatinine ratio
PD
pharmacodynamic(s)
PDFF
proton density fat fraction
pg
picogram
P-gp
P-glycoprotein
PIIINP
amino-terminal pro-peptide of procollagen type III
PK
pharmacokinetic(s)
PT
prothrombin time
QD
once a day
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RAP/SAP
Report and Analysis Plan (RAP) or Statistical Analysis Plan (SAP) is a regulatory 
document which documents preplanned statistical analyses
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RoW
Rest of World
R Value
ALT/ALP x ULN
SAC
Safety Assessment Committee
SAE
serious adverse event
SD
standard deviation
SE
standard error
SOM
Site Operations Manual 
SOP
standard operating procedure(s)
SSP
Safety Surveillance Plan
SUSAR
suspected unexpected serious adverse reactions
SVR
sustained virologic response
TIMP-1
tissue inhibitor of metalloproteinases
µg
microgram
ULN
upper limit of normal
US
ultrasound
VAS
Visual Analog Scale
WHO
World Health Organization 
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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g., any 
background therapy).
Assessment
A procedure used to generate data required by the study.
Biologic samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant. 
Clinical Outcome 
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, 
or survives.
Coded Data
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code.
Cohort
A set of one or more treatment arms bundled together for review and 
execution.
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug.
Core NEXSCOT 
protocol
Section 1 - Section 16. These are the sections of the NEXSCOT 
protocol that remain constant over the duration of this platform study.
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their samples 
or data.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the 
use of their samples or data.
Dosage
Dose of the study treatment given to the participant in a time unit 
(e.g., 100 mg once a day, 75 mg twice a day).
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from source
data/documents used at the point of care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last 
participant or at a later point in time as defined by the protocol.
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained. Also, the action of entering one or more participants 
into the study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant.
Investigational 
drug/treatment
The drug whose properties are being tested in the study.
Medication number
A unique identifier on the label of medication kits.


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Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study, or the participant allocated to 
an invalid stratification factor.
Off-site
Describes trial activities that are performed at remote location by an off-
site healthcare professional, such as procedures performed at the 
participant's home.
Off-site Healthcare 
Professional (OHP)
A qualified healthcare professional, such as a nurse, who performs 
certain protocol procedures for the participant in an off-site location such 
as a participant’s home.
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(e.g., concomitant or rescue therapy).
Participant
An individual with the condition of interest for the study. "Participant" 
terminology may be used in the protocol whereas term, "Subject" may 
be used in data collection.
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant 
and should be used to identify the participant throughout the study for all 
data collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-
up) which are described in the protocol. Periods define the study phases 
and will be used in clinical trial database setup and eventually in 
analysis.
Perpetrator drug
A drug which affects the pharmacokinetics of the other drug.
Personal data
Participant information collected by the investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes participant
identifier information, study information and biological samples.
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Randomization number
A unique identifier assigned to each randomized patient.
Re-screening
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol.
Remote
Describes any trial activities performed with the participant at a location 
that is not the investigative site where the investigator will conduct the 
trial, but is for example the participant’s home or another appropriate 
location.
Screen failure
A participant who did not meet one or more criteria that were required 
for participation in the study.
Source data/document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant.
Study treatment
Any single drug or combination of drugs or intervention administered to 
the participant as part of the required study procedures.


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Tele-visit
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial.
Treatment arm/group
A single or combination treatment regimen. 
Treatment specific 
information
Section 17. This section contains all the supporting information on the 
individual treatments to be studied in the NEXSCOT platform study.
Variable
A measured value or assessed response that is determined from 
specific assessments and used in data analysis to evaluate the drug 
being tested in the study.
Withdrawal of study 
consent (EoC) / 
Opposition to use of 
data/biological samples
Withdrawal of consent from the study occurs when a participant explicitly 
requests to stop use of their data and biological samples (opposition to 
use data and biological samples) AND no longer wishes to receive study 
treatment, AND does not agree to further protocol-required 
assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in countries where 
collection and processing of personal data is justified by a different legal 
reason than consent.


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Protocol summary
Protocol number
CADPT02A12001 (NEXSCOT)
Full Title
NASH EXploratory Single and COmbination Treatment (NEXSCOT): An 
open label, multicenter, platform study to evaluate the safety, tolerability, 
pharmacokinetics and efficacy of various single and combination
treatments in patients with non-alcoholic fatty liver disease (NAFLD) who 
manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype
Brief title
Study of safety, pharmacokinetics (PK), and efficacy of various single and 
combination treatments in patients with non-alcoholic fatty liver disease 
(NAFLD) who have characteristics of non-alcoholic steatohepatitis (NASH) 
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This platform study is designed to assess the safety, tolerability, PK, and 
early efficacy after administration of 
treatments for 12 weeks in NAFLD patients with a biomarker phenotype 
consistent with ongoing liver inflammation and fibrosis, and thus, NASH. 
Data from this study will enable efficient detection of high efficacy single 
drug and/or drug combinations, which will support the future development 
of optimal therapies for NASH.
Primary Objective
To determine the safety and tolerability of single or combination therapy 
during 12 weeks of treatment by monitoring safety endpoints (including vital 
signs, physical examination, laboratory measurements, electrocardiogram 
[ECG]) and adverse events.
Secondary Objectives

Objectives 1-4: To determine the effect of twelve weeks of single or
combination therapy on

1: Circulating markers of ongoing liver fibrosis as measured
by the Enhanced Liver Fibrosis (ELF) Test

2: Intrahepatic lipid content (percent liver fat) by measuring
Magnetic Resonance Imaging-Proton Density Fat Fraction
(MRI-PDFF)

3: Cardiometabolic risk parameters by measuring body
weight, waist and hip circumference, waist-to-hip ratio,
Homeostasis Model Assessment of Insulin Resistance
(HOMA-IR), hemoglobin A1C (HbA1c), fasting glucose,
fasting insulin, and fasting lipid profile

4: Circulating markers of liver and/or systemic inflammation
by measuring liver function tests (ALT) and high-sensitivity C-
reactive Protein (hsCRP)
And 

Objective 5: To evaluate the PK of each individual agent when
administered as a single or combination therapy by collecting and
analyzing blood samples to obtain plasma concentrations over 12
weeks of treatment.


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Study design
This is a non-confirmatory, multicenter, open label, platform study in 
NAFLD patients with a NASH-like biomarker phenotype to examine the 
effects of single and combination therapies over 12 weeks of treatment.
Each cohort consists of a 33-day screening period, 27-day baseline period, 
12-week treatment period, and a study completion visit (End of Study
[EOS] 1) approximately 28 days after the last drug administration.
For drugs with longer half-lives, the same study design will be followed,
however, an additional post-treatment follow-up visit (EOS2) will occur
56 days after the last drug administration, and study completion
evaluations will take place at this visit instead.
Population
The study population will be comprised of adult (18 years or older) male 
and female NAFLD patients with a NASH-like biomarker phenotype.
Approximately 25 participants per arm will be enrolled in the study and 20 
per arm are expected to be evaluable. Cohort 1 consists of two treatment 
arms. Multiple arms/cohorts are planned and future therapies will be 
introduced in subsequent protocol amendments.
Key Inclusion criteria
These criteria are applicable for all participants across all therapies/arms/
cohorts. 

Male and female participants 18 years or older (at the time of the
screening visit)

NAFLD patients with a NASH-like biomarker phenotype are defined
based on the presence of ALL FIVE of the following:

ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND

BMI ≥ 27 kg/m2 (in participants with a self-identified race other
than Asian) or ≥ 23 kg/m2 (in participants with a self-identified
Asian race) AND

History of Type 2 diabetes mellitus with HbA1c ≤9% at baseline
AND

ELF Test score ≥ 8.5 and ≤ 10.5 at either screening or baseline
AND

Liver fat ≥ 8% at baseline as determined by the reading of the
central MRI laboratory of locally produced images. The MRI
assessment should only be performed after eligibility has been
confirmed from all other baseline assessments.

Participants must weigh at least 40 kg (88 lbs.) and no more than 150
kg (330 lbs.)
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Key Exclusion criteria
These 
criteria 
are 
applicable 
for 
all 
participants 
across 
all 
therapies/arms/cohorts. Please also refer to the cohort-specific eligibility 
criteria for any additional factors to consider.

Use of other investigational drugs within 5 half-lives of randomization,
or within 3 months, whichever is longer; or longer if required by local
regulations.

Use of obeticholic acid (OCA) or pharmacologically-active weight loss
drugs within 1 month of randomization.

Use of strong CYP3A4/5 inhibitors or strong CYP3A4 inducers within
5 half-lives or 7 days of randomization, whichever is longer.

Participants on treatment with the following medicines UNLESS they
are on stable dosing for at least 3 months before randomization: anti-
diabetic medications, insulin, beta-blockers, thiazide diuretics,
fibrates, statins, niacin, ezetimibe, thyroid hormone, psychotropic
medications, estrogen or estrogen containing birth control.

Participants on treatment with vitamin E at doses > 200 IU/day and ≤
800 IU/day UNLESS they are on stable dosing for at least 6 months
before randomization, OR any participants on treatment with vitamin
E > 800 IU/day regardless of stable dosing.

Pregnant or nursing (lactating) women.

Women of child-bearing potential UNLESS they are using highly
effective methods of contraception during dosing and for a duration
equal to approximately 5 times the terminal half-life after stopping
study medication.

Sexually active males UNLESS they agree to use a condom during
intercourse while taking study medication and for a duration equal to
approximately 5 times the terminal half-life after stopping study
medication, and should not father a child in this period.

History of ongoing drug abuse within the 12 months prior to dosing, or
current or history of significant alcohol consumption for a period of
more than 3 consecutive months within 1 year prior to screening
(significant alcohol consumption is defined as ≥ 21 units of alcohol
per week in males and ≥ 14 units of alcohol per week in females; a
unit of alcohol is equivalent to 8 grams pure ethanol, 12 ounce (355
mL) beer, 4 ounce (118 mL) glass of wine, or 1 ounce (30 mL) shot of
hard liquor).

Type I diabetes or uncontrolled Type II diabetes (defined as
HbA1c > 9% at baseline).

Evidence of hepatic decompensation, severe liver impairment,
cirrhosis, or severe acute or chronic renal insufficiency.

History or presence of other concomitant liver diseases or liver
transplantation; current placement on a liver transplant list.

History or current diagnosis of ECG abnormalities indicating safety
concerns for participants.

Participants with contraindications to MRI imaging.


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Study treatment
Cohort 1 consists of two treatment arms:

Arm 1: LYS006

Arm 2: Tropifexor (LJN452)
+ LYS006
Participants will be randomized into any of the treatment arms open to 
enrollment for which the participant
meets the eligibility criteria. 
Randomization will be stratified by race and body mass index (BMI).
Multiple arms/cohorts are planned and future therapies will be introduced 
in subsequent protocol amendments.
Efficacy/ 
Pharmacodynamic 
(PD) assessments

Liver function tests and liver and/or systemic inflammation markers

Markers of liver fibrosis (including ELF Test)

Magnetic Resonance Imaging (MRI)

Cardiometabolic risk parameters
Pharmacokinetic 
assessments

Plasma concentrations for tropifexor and LYS006 (Cohort 1)
Key safety 
assessments

Vital signs

Physical examination

Laboratory measurements

ECG
Other assessments
Data analysis
Safety data will be summarized using descriptive statistics.
A mixed-effect model for repeated measures (MMRM) analysis will be 
conducted for log-transformed ratio to baseline ELF Test and ALT. 
The model will include effects for treatment, visit, treatment by visit 
interaction, stratification factor (race and BMI group), log-transformed 
baseline, and log-transformed baseline by visit interaction. An unstructured 
variance-covariance matrix will be used to account for correlation among 
multiple measurements from the same participant
and variance 
heterogeneity. If the unstructured covariance causes model convergence 
issues then other simpler covariance structures will be considered. Least 
squares mean, the associated 2-sided 80% confidence interval and the p-
value will be obtained for each treatment at each visit and back transformed 
to the original scale. Contrasts assessing trend over time will be 
constructed for each treatment using various functional forms as needed. 
Both cohort-wise and combined cohort analysis will be performed as 
appropriate. % liver fat as well as other secondary PD/biomarker endpoints 
will be analyzed similarly.
Key words
Non-alcoholic fatty liver disease, NAFLD, non-alcoholic steatohepatitis, 
NASH, platform design
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1
Introduction
1.1
Background
Non-alcoholic steatohepatitis (NASH)
The NASH EXploratory Single and COmbination Treatment (NEXSCOT) study is designed to 
measure the safety and efficacy of various single and combination drug treatments in patients 
with non-alcoholic fatty liver disease (NAFLD) who also manifest a non-alcoholic 
steatohepatitis (NASH)-like biomarker phenotype.
NASH is a severe and often lethal liver disease which is becoming increasingly prevalent 
throughout the world (Calzadilla and Adams 2016). It is anticipated that by 2024, NASH will 
become 
the 
most 
common 
cause 
of 
liver 
failure 
requiring 
liver 
transplant
(Zezos and Renner 2014). Three main features of the pathobiology of NASH are increased liver 
fat, inflammation and fibrosis.
There is no approved pharmaceutical treatment for NASH. This fact underscores the intractable 
nature of this disease which is in large part due to the contribution of multiple pathobiologic 
pathways, including increased de novo lipogenesis, inflammation and fibrosis. Based on these 
multiple contributing pathways it is reasonable to assume that regimens including more than 
one drug may be necessary to manage this disease effectively. This concept was recently 
supported by (Friedman et al 2018), who stated that, “...the possibility of drug combinations as 
a future therapeutic option is increasingly likely because of concern that attacking a single target 
will not be sufficiently potent...” in NASH.
Treatment specific background
NEXSCOT will study a number of investigational drugs as both single and combination 
treatment arms, with new treatment arms added during the conduct of the study. The specific 
background information for these particular treatment arms can be found in Section 17. 
Cohorts of new treatment arms will be added to Section 17 as amendments.
In contrast, the core parts of this protocol, Section 1 – Section 16, will remain constant over the 
duration of the NEXSCOT platform study.
1.2
Purpose
This platform study is designed to assess the primary objectives of safety and tolerability, and 
the secondary objectives of pharmacokinetics (PK) and biomarker efficacy after administration 
of 
 treatments for 12 weeks in NAFLD patients with a biomarker 
phenotype consistent with ongoing liver inflammation and fibrosis, and thus, NASH. Data from 
this study will enable efficient selection of high efficacy, single drug and/or drug combinations, 
which will support the rapid future development of optimal therapies for NASH.
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Primary Objective
Endpoints
To determine the safety and tolerability of 
single or combination therapy during 12 weeks 
of treatment
Safety endpoints (including vital signs, physical 
examination, laboratory measurements, ECG); 
Adverse events
Secondary Objectives
Endpoints
To determine the effect of single or 
combination therapy on circulating markers of 
ongoing liver fibrosis
Enhanced Liver Fibrosis (ELF) Test
To determine the effect of single or 
combination therapy on intrahepatic lipid 
content
Percent (%) liver fat as measured by Magnetic 
Resonance Imaging-Proton Density Fat Fraction 
(MRI-PDFF)
To determine the effect of single or 
combination therapy on cardiometabolic risk 
parameters
Body weight, waist and hip circumference, waist-to-
hip ratio, Homeostasis Model Assessment of Insulin 
Resistance (HOMA-IR), hemoglobin A1c (HbA1c), 
fasting glucose, fasting insulin, fasting lipid profile
To determine the effect of single or 
combination therapy on circulating markers of 
liver and/or systemic inflammation
Liver function test (ALT), high-sensitivity C-reactive 
Protein (hsCRP)
To evaluate the pharmacokinetics (PK) of each 
individual agent when administered as a single 
or combination therapy
Plasma concentrations
Exploratory Objectives
Endpoints
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3
Study design
This is a non-confirmatory, multicenter, open label, platform study in NAFLD patients with a 
NASH-like biomarker phenotype.
There is a maximum of five cohorts planned. Each cohort will consist of a 33-day screening 
period (Day -60 to Day -28), a baseline period of 27 days (Day -27 to Day -1), a treatment 
period of 12 weeks (Day 1 to Day 85), and a study completion evaluation (End of Study [EOS] 
1) approximately 28 days after the last drug administration (Day 113).
 Participants will be advised to maintain their recommended diet for NAFLD 
during the study. The study design scheme is shown below in Figure 3-1:
Figure 3-1
Study design
Participants who meet the eligibility criteria at screening will have baseline assessments 
performed, including determination of the percent liver fat content by MRI.
Once eligibility has been confirmed from screening and baseline assessments, participants will 
be randomized into any of the treatment arms open to enrollment for which the participant meets 
the eligibility criteria using an Interactive Response Technology (IRT) system. If a participant
does not meet the specific eligibility criteria of a particular treatment arm, the participant will 
be randomized to any open and actively enrolling arms for which the participant is eligible. 
Randomization will be stratified by race and BMI (refer to Section 6.3.2). In the event that there 
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is only one open treatment arm in a cohort or if participants are only deemed eligible for one 
treatment arm, participants will be enrolled using the same IRT system, but without 
randomization.
The first dose of study medications will be administered to participants during the visit on Day 
1, and scheduled assessments will be performed as defined in the Assessment schedule.
For orally-administered study medications, the first dose will be administered under fasted 
conditions at the visit on Day 1. Also, participants will be provided with a supply for -self 
administration during the treatment period on non-visit days. On visit days, study medication 
will be administered by study staff. In the event that multiple doses are needed per day, the 
participant can also self-administer subsequent doses after the initial dose is administered by 
study staff. For other types of study medications, such as injectable monoclonal antibodies, dose 
administration will be managed by study staff on designated visit days. Detailed instructions 
for taking/administering study treatment will be provided in the cohort-specific sections and/or 
the SOM. 
If adverse events or significant laboratory abnormalities are noted, in addition to dose reduction 
or interruption of the investigational drug(s), the investigator may choose to place the 
participant under a period of close observation until the participant is deemed to have returned 
to a satisfactory state of health in the opinion of the investigator. In the case of liver or renal 
laboratory abnormalities, please see Section 16.1 and Section 16.2, respectively, for additional 
information.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis), adverse event and serious 
adverse event monitoring.
Refer to the Assessment schedule for details of safety, PK, biomarker and PD assessments.
Please refer to Section 9.3 for details regarding the end of the study. 
Remote procedures
At the investigator’s discretion, and based on benefit-risk considerations of the participant’s 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures according to Table 8-1 performed at a remote location. Procedures may be 
performed remotely under the oversight of the Investigator, who retains accountability for 
oversight and all efficacy and safety decisions with delegation of tasks to an off-site healthcare 
professional (OHP). In addition to procedures performed by the OHP, the on-site staff may 
support certain assessments using tele-visits.
The remote procedures will only be offered in certain countries and sites as determined by 
Novartis based on national and local regulations. The OHPs will be provided by a third-party 
vendor sourced by Novartis. Where a site wishes to use OHPs that are not provided by Novartis, 
this must be agreed upon with Novartis prior to use.


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4
Rationale
4.1
Rationale for study design
The NEXSCOT study is designed to safely allow rapid and efficient determination of potential
high efficacy drugs and drug combinations in participants with NAFLD and a NASH-like 
(biomarker) phenotype. Rationale for key aspects of this design are provided below.
4.1.1
Platform study
The cohort-specific modules (Section 17) will contain the mechanism of action, non-clinical 
information, proposed dose and dosing regimen, and rationale for each treatment arm including 
anticipated safety, potential drug-drug interactions, unique inclusion or exclusion criteria, 
unique stopping rules or dose reduction criteria and other treatment specific information.
4.1.2
Study population
The study enrolls NAFLD patients with characteristics consistent with NASH:

Two risk factors for NASH: elevated BMI and history of Type II diabetes mellitus, and

Three phenotypic biomarkers for NASH as shown in Table 4-1: elevated liver fat content
diagnostic of NAFLD as measured by MRI-PDFF, liver inflammation as measured by
ALT, and liver fibrosis as measured by ELF Test. These phenotypic biomarkers are
consistent with the pathobiology of NASH and recent studies have supported these
biomarkers as being highly predictive of NASH (Harrison et al 2018a; Sanyal et al 2017).
Table 4-1
Biomarker inclusion criteria compared to normal range
ALT
Liver fat content (MRI-PDFF)
ELF Test
Normal value
29-33 IU/L (males)
19-25 IU/l (females)
< 5%
< 7.7
NEXSCOT inclusion 
criteria
≥ 43 IU/L and ≤ 5x ULN 
(males)
≥ 28 IU/L and ≤ 5x ULN 
(females)
≥ 8%
8.5-10.5
Reference
Kwo et al 2017
Petäjä and Yki-Järvinen 2016
Lichtinghagen et al 2013,
Vilar-Gomez and 
Chalasani 2018
In this study, ELF Test measurement will be conducted at screening (see Section 5.1
Inclusion criteria), and participants with an ELF Test result within the range of 8.5-10.5 will be 
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eligible for participation in the study. The goal of using these ELF Test inclusion criteria is to 
enrich the study population for those subjects with a high likelihood of an ongoing fibrotic 
process in the liver (disease stage F1-F3) but do not yet have severe fibrosis or cirrhosis
(stage F4). This ELF Test inclusion range is based on a weight-of-evidence analysis of the 
following reports:

In their review of the current state-of-the-art of soluble liver fibrosis biomarkers,
(Vilar-Gomez and Chalasani 2018) noted that the area under the receiver operating
characteristic curve (AUROC) for ELF Test using 8.5-10.18 cut-off values to detect liver
fibrosis (F≥2) was 0.82 in a meta-analysis of adult and pediatric patients (n=1329) with
chronic liver disease, including NAFLD.

(Lichtinghagen et al 2013) proposed the following ELF Test cut-off values based on the
results of this test in healthy volunteers (n=400) and the relationship of this test with liver
biopsy staged fibrosis in patients with hepatitis C (n=39):

≤7.7 excluded fibrosis with high sensitivity

≥9.8 had high specificity for identification of fibrosis

≥11.3 discriminated cirrhosis

(The National Institute for Health and Care Excellence 2016) proposed that NAFLD
patients should have ELF Test as a measure of advanced liver fibrosis and proposed that a
value of ≥10.51 was consistent with advanced liver fibrosis.

(Gungoren et al 2018) showed that using an ELF Test cut-off of ≥8.84 was associated with
a liver fibrosis score of F≥2 at an AUROC of 0.89 in 46 patients with auto-immune
hepatitis who have liver biopsy.

As shown in Figure 4-1, (Nobili et al 2009) reported a step-wise relationship of liver
biopsy measured fibrosis stage to ELF Test result in 121 patients with NAFLD.
Figure 4-1
Relationship of fibrosis state and ELF Test result
Source: (Nobili et al 2009).


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This study does not require the invasive procedure of liver biopsy in order to confirm NASH. 
However, based on the biomarkers evaluated at screening and respective inclusion criteria, in 
particular ELF Test scores, it can be reasonably assumed that a large proportion of participants
enrolled in this study will indeed have NASH (Lopez et al 2017). Patients with ELF 
Test > 10.5 and ALT > 5x ULN will not be enrolled given that these highly elevated values are 
consistent with severe and potentially intractable liver fibrosis / cirrhosis and/or inflammation.
4.1.3
Objectives (Endpoints)
Given that NEXSCOT will be studying investigational drugs used in combination for the first 
time, safety and tolerability will be the paramount and primary objective, assessed by safety 
endpoints (including vital signs, physical examination, laboratory measurements, ECG) and 
adverse events (see Section 12.4).
Secondary objectives are included in Table 2-1. The secondary endpoints are (see Section 12.5):

ALT, % liver fat (MRI-PDFF), and ELF Test: These biomarkers will provide evidence of
efficacy and are further described below.

Cardiometabolic risk factors: NAFLD and NASH patients are at high risk for
cardiovascular morbidity and mortality. Therefore, it is important to characterize any
negative or positive effects of single drugs or drug combinations on cardiometabolic risk
factors including body weight, waist and hip circumference, waist-to-hip ratio,
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), hemoglobin A1C
(HbA1c), fasting glucose, fasting insulin, and fasting lipid profile.

Pharmacokinetics: The potential pharmacokinetic interactions of drugs used in
combination will be measured.
Currently, there are no approved treatments for NASH. However, over the last five years, the 
results of a number of studies in this indication have been reported in the medical literature 
(Sanyal et al 2017; Harrison et al 2018a; Harrison et al 2018b).
Based on these results, 
considerable knowledge of the magnitude of both placebo and active treatment effects in NASH 
studies now exists.
The placebo effects reported in four relatively short-term (≤ 16 week) NASH studies for three 
main efficacy endpoints, ALT, % liver fat (MRI-PDFF), and ELF Test, are summarized in 
Table 4-2.
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Table 4-2
Examples of placebo effect in published studies in NASH and NASH-
like patient populations
Investigational 
drug
Obeticholic 
acid (n=23)
Obeticholic acid 
(n=142)
NGM282 (n=27)
MGL3196 
(n=42)
BMS986036 
(n=26)
Duration 
(weeks)
6
12
12
12
16
%Δ ALT from 
baseline
35.5
-13.4
-2.2
-
-4.5
Relative %Δ 
liver fat from 
baseline
-
-
-3.0
-9.6
-
Δ ELF Test from 
baseline
0.3
-
0
0.1
-
Reference
Mudaliar et al 
2013
Neuschwander-
Tetri et al 2015
Harrison et al 
2018a
Harrison et al 
2018b, Abstract 
GS-009
Sanyal et al 
2017
Conversely, a review of multiple, recent studies in patients with NASH or a NASH-
like (biomarker) phenotype shows that high efficacy, active treatment is associated with relative 
percent decreases in % liver fat (MRI-PDFF) and ALT of ≥ 30% (Sanyal et al 2017; 
Harrison et al 2018a; Harrison et al 2018b). Similarly, a decrease in ELF Test by ≥ 0.3 units or 
3% can be considered evidence of a substantive, beneficial reversal in the ongoing liver fibrotic 
process (Harrison et al 2018a).
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4.1.5
Follow-up period
All participants receiving treatment in the NEXSCOT study should have safety evaluations and 
collection of concomitant treatments and/or adverse event data until at least approximately 
28 days (Day 113) or, if applicable, until at least approximately 56 days (Day 141) after the last 
dose of study treatment. Please refer to Section 9.1.1 for details pertaining to early study 
discontinuation and associated safety follow-up. 
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4.2
Rationale for dose/regimen and duration of treatment
Please refer to Section 17 (cohort-specific information) for a detailed rationale of each drug or 
drug combination treatment.
In general, the dose(s) of the drug(s) to be studied will be chosen based on an evaluation of all 
available preclinical and/or clinical data to ensure 1) a high likelihood of target or pathway 
modulation and 2) reasonable safety and tolerability.
Over the last five years, many exploratory studies in NASH have used a twelve-week duration of 
treatment, 
for 
example, 
(Mudaliar et al 2013)
and 
(Neuschwander-Tetri et al 2015). 
Twelve weeks is considered the shortest treatment period that will allow measurable changes 
in improvement of endpoints such as liver inflammation, liver fat content and liver fibrosis.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
There is currently no appropriate comparator for use in the NASH/NAFLD patients. 
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While the primary purpose of NEXSCOT is to detect high efficacy drug combinations, single
drug treatment arms may also be studied in those situations where the efficacy of the particular 
drug on the relevant endpoint biomarkers in the relevant patient population has not been 
previously measured. In this case, the treatment effects of the single drug treatment arm would 
be compared to both the combination drug effects and the historical placebo effects.
4.4
Purpose and timing of interim analyses
Please refer to Section 12.7.
4.5
Risks and benefits
Detailed descriptions of the expected safety, tolerability and efficacy characteristics of each of 
the proposed individual treatment arms can be found in Section 17.
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Based on 
 risk considerations, additional safety measures employed in NEXSCOT
include, but are not limited to:

The study employs safety management measures which are considered relevant and
appropriate for this patient population and protocol to facilitate safe conduct of the study.

The study will only be conducted by investigators who have broad experience with
patients who have multiple metabolic and/or liver comorbidities.

Patients with advanced liver disease, for example cirrhosis or more severe hepatitis, will
not be enrolled.

Patients with evidence of ECG abnormalities consistent with significant cardiovascular
risk will not be enrolled.

Participants will have a visit every two weeks during the first two months of treatment for
safety assessments, including ECGs and laboratory tests. Halfway through the final month
of treatment (Month 3), study staff will contact the participant by phone to inquire about
tolerability and safety.

This protocol pre-specifies both liver and renal events requiring intervention (Section 16.1
and Section 16.2, respectively).

The study will be also monitored by an internal Safety Assessment Committee (SAC),
which will provide an additional layer of oversight for safety events. For further details,
please refer to Section 10.2.1 and the standalone Safety Surveillance Plan (SSP).

Appropriate eligibility criteria and specific dose modification and stopping rules are
included in this protocol. The risk to subjects in this trial will be minimized by compliance
with the eligibility criteria and study procedures, as well as close clinical monitoring.
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Benefits
The key, potential benefits expected to be associated with participation in the NEXSCOT 
protocol include:
1. Participants will receive a potentially efficacious treatment where currently no approved
treatment is available. Over the duration of the study, patients may have the clinical
benefit of reductions in hepatic fat, inflammation and/or the ongoing fibrotic process.
2. The severity of the participant’s NAFLD will be staged by liver fat, ELF Test and liver
transaminases. Knowledge of these parameters may guide future treatment and behavior
modification for the particular participant.
3. Participants will contribute to the potential identification of high efficacy, combination
regimens for NASH treatment, where an unmet medical need exists.
Benefit:risk associated with the COVID-19 pandemic
The assessment of the benefit:risk for the study in the context of the COVID-19 pandemic 
concluded the absence of additional risks for the study population and/or related to the 
investigational medicinal product. As the COVID-19 situation evolves, investigators must use 
their best judgment to minimize risk to participants during the conduct of the study.
4.5.1
Blood sample volume
A volume of approximately 625 mL is planned to be collected over a period of up to 
approximately seven to eight months from each participant as part of the study. Additional 
samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Table 8-1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and the central laboratory manual.
See Section 8.5.4.1 on the potential use of residual samples.
4.6
Rationale for public health emergency mitigation procedures
Remote procedures are planned in this study to minimize burden on participants, and offer them 
increased flexibility to participate in the study from a remote location (as described in Section 
3 and defined in Section 8). During a public health emergency as declared by local or regional 
authorities (e.g., pandemic, epidemic, natural disaster), additional mitigation procedures to 
ensure participant safety and trial integrity may be considered. Notification of the public health 
emergency should be discussed with Novartis prior to implementation of mitigation procedures, 
and permitted/approved by local or regional Health Authorities and Ethics Committees as 
appropriate.
5
Population
The study population will be comprised of male and female NAFLD patients with a NASH-like 
biomarker phenotype.


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Approximately 25 participants per arm will be enrolled in the study, and around 20 participants 
per arm are expected to be evaluable. Based on the results of the ongoing data review, the 
sample size may be increased to an enrollment target up to approximately 50 total for a specific 
arm; for example, due to higher than anticipated variability of the biomarker data.
Please refer to Section 17 (cohort-specific information) for eligibility criteria specific to each 
treatment arm.
The investigator must ensure that all participants enrolled into the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order for the 
study population to be representative of all eligible patients.
Participant selection is to be established by checking through all eligibility criteria at both 
screening and baseline, unless otherwise specified. Please also refer to the Assessment Schedule
for the exact tests to be performed at either visit, but note that certain eligibility criteria may 
only need to be confirmed to be within the ranges specified at one of the two visits. A relevant 
record (e.g., checklist) of the eligibility criteria must be stored with the source documentation 
at the study site.
Deviation from any entry criterion excludes a participant from enrollment/randomization into 
the study.
Reference ranges for laboratory assessments are located in the standalone laboratory manual.
If any parameters are found to be outside of the range specified in the inclusion or exclusion 
criteria (where relevant) at screening or baseline, the assessment can be repeated once to 
rule-out laboratory error or anomaly.
Refer to Section 8.1 (Screening) for information regarding re-screening.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent(s) must be obtained prior to participation in the study.
2. Male and female participants 18 years or older (at the time of the screening visit).
3. NAFLD patients with a NASH-like biomarker phenotype are defined based on the 
presence of ALL FIVE of the following:
a. ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)* AND
b. BMI ≥ 27 kg/m2 (in participants with a self-identified race other than Asian) or 
≥23 kg/m2 (in participants with a self-identified Asian race) AND
c. History of Type 2 diabetes mellitus with HbA1c ≤9% at baseline AND
d. ELF Test score ≥ 8.5 and ≤ 10.5 at either screening or baseline AND
e. Liver fat ≥ 8% at baseline as determined by the reading of the central MRI laboratory 
of locally produced images. The MRI assessment should only be performed after 
eligibility has been confirmed from all other baseline assessments.
4. Participants must weigh at least 40 kg (88 lbs.) and no more than 150 kg (330 lbs.).
5. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.


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*Average of two independent results obtained approximately four weeks apart (e.g., once at 
screening and once at baseline) must be in this range AND both results must be within 30% of 
one another. Should the initial variance between the two baseline measures be > 30%, a third 
measure may be obtained 2 weeks after the second measurement. Such participants would be 
eligible for enrollment provided the variability between any two of these three samples is ≤30%.
5.2
Exclusion criteria
IMPORTANT
The exclusion criteria for the core protocol are located in this section (Section 5.2). 
These exclusion criteria apply to all participants enrolled into this study. However, there 
may also be additional treatment specific exclusion criteria which are provided in 
Section 17 for the individual treatment arms.
Participants meeting any of the following criteria and any criteria detailed in the cohort-specific 
information (Section 17) are not eligible for inclusion in this study.
1. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes.
2. Use of other investigational drugs within 5 half-lives of randomization, or within 3 
months, whichever is longer; or longer if required by local regulations.
3. Use of obeticholic acid (OCA) within 1 month of randomization.
4. Participants on treatment with the following medicines UNLESS they are on stable dosing 
for at least 3 months before randomization: anti-diabetic medications, insulin, beta-
blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, thyroid hormone, 
psychotropic medications, estrogen or estrogen containing birth control.
5. Participants on treatment with vitamin E at doses > 200 IU/day and ≤ 800 IU/day 
UNLESS they are on stable dosing for at least 6 months before randomization, OR any 
participants on treatment with vitamin E > 800 IU/day regardless of stable dosing.
6. Use of pharmacologically-active weight loss drugs such as lorcaserin, 
phentermine/topiramate, bupropion-naltrexone HCl, or orlistat within 1 month of 
randomization.
7. Use of strong inhibitors of CYP3A4/5 (for example; boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, fazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole) 
within 5 half-lives or 7 days of randomization, whichever is longer.
8. Use of strong CYP3A inducers (for example; avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort) within 5 half-lives or 7 days of randomization, whichever is 
longer.
9. Participants taking medications prohibited by the protocol, including cohort-specific 
guidance. See the ‘Prohibited Treatment’ sections in the core (Section 6.2.2) and cohort-
specific portions (Section 17) of the protocol for further details.
10. History of malignancy for which, based on the investigator assessment, would be 
reasonable grounds for exclusion.


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11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for a duration equal to approximately 5 times the terminal half-life after 
stopping study medication. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception;

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment;

Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant;

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception, or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example, hormone vaginal ring or transdermal hormone 
contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate 
history of vasomotor symptoms). Women are considered not of child bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential.
13. Sexually active males will be excluded UNLESS they agree to use a condom during 
intercourse while taking study medication and for a duration equal to approximately 
5 times the terminal half-life after stopping study medication, and should not father a child 
in this period. A condom is required to be used also by vasectomized men in order to 
prevent delivery of the drug via seminal fluid. In addition, male participants must not 
donate sperm for the time period specified above. If local regulations deviate from the 
contraception methods listed above to prevent pregnancy, local regulations apply and will 
be described in the ICF.
14. Current or history of significant alcohol consumption for a period of more than 
3 consecutive months within 1 year prior to screening. Significant alcohol consumption is 
defined as ≥ 21 units of alcohol per week in males and ≥ 14 units of alcohol per week in 


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females; a unit of alcohol is equivalent to 8 grams pure ethanol, 12 ounce (355 mL) beer, 4 
ounce (118 mL) glass of wine, or 1 ounce (30 mL) shot of hard liquor.
15. Inability to reliably quantify alcohol consumption based upon local study physician
judgment.
16. History of ongoing drug abuse within the 12 months prior to dosing.
17. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y
gastric bypass).
18. Type I diabetes or uncontrolled Type II diabetes (defined as HbAlc > 9% at baseline).
19. Evidence of severe acute or chronic renal insufficiency, such as participants with
eGFR < 60 mL/min/1.73m2.
20. Suspected or confirmed Gilbert's syndrome.
21. Evidence of hepatic decompensation or severe liver impairment or cirrhosis, as defined by
the presence of any of the following abnormalities (reminder that all lab ranges below
must be confirmed at both screening and baseline):

Serum albumin < 3.2 g/dL

INR > ULN

Total bilirubin > ULN

ALT or AST > 5x ULN*

Alkaline phosphatase > ULN

Platelets outside of normal reference range

History of esophageal varices, ascites, or hepatic encephalopathy

Splenomegaly
*Average of two independent results obtained approximately four weeks apart (e.g., once at
screening and once at baseline) in this range AND both results within 30% of one another.
Should the initial variance between the two baseline measures be > 30%, a third measure may
be obtained 2 weeks after the second measurement. Since this is an exclusion criterion, in order
for the participant to qualify, he/she must demonstrate an average ALT and AST ≤ 5x ULN
where the two individual measurements are ≤ 30% variable from one another.
22. History or presence of other concomitant liver diseases including, but not limited to:

Hepatitis B or C virus (HCV, HBV) infection, confirmed using standard laboratory
assays. Participants with a history of HCV who have appropriate documentation of
curative therapy per Investigator’s discretion (e.g., biopsy, sustained virologic
response [SVR] for more than 3 years prior to screening) are not excluded.

Primary biliary cholangitis (PBC)

Primary sclerosing cholangitis (PSC)

Alcoholic liver disease

Definite autoimmune liver disease or overlap hepatitis

Hemochromatosis

Known bile duct obstruction

Suspected or proven liver cancer
23. History of liver transplantation or current placement on a liver transplant list.


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24. Known positivity for Human Immunodeficiency Virus (HIV) infection, confirmed using
standard laboratory assays.
25. History of non-adherence to medical regimens, or participants who are considered by the
investigator to be unable to reliably comply with the requirements of the study.
26. History or current diagnosis of ECG abnormalities indicating safety concerns for
participants such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
27. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing,
or longer if required by local regulation.
28. Participants with contraindications to MRI imaging, including but not limited to:

Brain aneurysm clip

Implanted neural stimulator

Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires

Prosthetic heart valves

Cochlear implant

Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)

Other implanted medical devices (e.g., insulin pumps)

Metal shrapnel or bullets still in the body

Severe claustrophobia

Piercings or tattoos (as determined by the investigator and imager)

Weight in excess of MRI machine capacity
29. Signs or symptoms, in the judgment of the investigator, of a clinically significant systemic
viral, bacterial or fungal infection within 30 days prior to screening.

COVID-19 specific: It is highly recommended that PCR or antigen testing for
COVID-19 be completed within 1 week prior to first dosing. If testing is performed, a
positive test result would exclude a participant from enrollment into the study.
Additional testing may occur at the discretion of the investigating physician. COVID-
19 testing should be completed via nasal or throat swabs if available. If testing is not
performed, the investigator must document their discussion with the subject regarding
testing, and the rationale for not testing, in the source documentation. This
requirement may be ignored if the pandemic is declared ended by the country where
the site is located, and resumed if the pandemic recurs.


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Refer to cohort-specific information in Section 17.
6.1.2
Additional study treatments
No other treatment beyond the investigational drug(s) are included in this trial.
6.1.3
Treatment arms/group
Refer to cohort-specific information in Section 17.
6.2
Other treatment(s)
Refer to Section 17 for guidance for other treatments based on the specific treatment arm/cohort.
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms (CRFs).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Use of the treatments displayed in the below table is allowed for all treatment arms as long as 
the required minimum period of stable dosing is observed. However, if the minimum period of 
stable dosing cannot be observed, then these treatments are NOT allowed from randomization 
until the end-of-study visit. New initiation of these treatments during the study are not allowed.
Table 6-1
Permitted concomitant medications
Medication
Minimum period of stable dosing prior to 
randomization
Anti-diabetic medications
3 months
Insulin 
3 months
Beta-blockers
3 months
Thiazide diuretics
3 months
Fibrates
3 months
Statins
3 months
Niacin
3 months


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Medication
Minimum period of stable dosing prior to 
randomization
Ezetimibe
3 months
Thyroid hormone
3 months
Psychotropic medications
3 months
Estrogen or estrogen containing birth control
3 months
Vitamin E at doses < 800 IU/day
6 months
6.2.2
Prohibited medication
IMPORTANT
The prohibited medications for the core protocol are located in this section. These apply 
to all participants enrolled into this study. However, there may also be additional
treatment specific prohibited medications which are provided in Section 17 for the 
individual treatment arms.
Use of the treatments displayed in the below table is not allowed for all treatment arms for the 
duration of the prohibited period defined below:
Table 6-2
Prohibited medication
Medication
Prohibition period start
Prohibition period end
Other investigational drugs
Within 5 half-lives of 
randomization, or within 3 
months, whichever is longer; 
or longer if required by local 
regulations 
End-of-study visit
Obeticholic acid
Within 1 month of 
randomization
End-of-study visit
Anti-diabetic medications, insulin, 
beta-blockers, thiazide diuretics, 
fibrates, statins, niacin, ezetimibe,
thyroid hormone, psychotropic 
medications, estrogen or 
estrogen containing birth control†
Randomization
End-of-study visit
Vitamin E at doses > 200 IU/day 
and ≤ 800 IU/day‡
Randomization
End-of-study visit
Vitamin E at doses > 800 IU/day
Randomization
End-of-study visit
Pharmacologically-active weight 
loss medications (for example; 
lorcaserin, 
phentermine/topiramate, 
bupropion-naltrexone HCl, 
orlistat)
Within 1 month of 
randomization
End-of-study visit
Strong inhibitors of CYP3A4/5 
(for example; boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice, indinavir, 
itraconazole, ketoconazole, 
Within 5 half-lives or 7 days of 
randomization, whichever is 
longer
End-of-study visit


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Medication
Prohibition period start
Prohibition period end
lopinavir, fazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir, telaprevir, 
telithromycin, and voriconazole)
Strong CYP3A inducers (for 
example; avasimibe, 
carbamazepine, phenytoin, 
rifampin, St. John’s wort)
Within 5 half-lives or 7 days of 
randomization, whichever is 
longer
End-of-study visit
†These medications are prohibited UNLESS the participant has been on stable dosing for at least 3 
months prior to randomization. New initiations of these medications during the study are prohibited.
‡This medication is prohibited UNLESS the participant has been on stable dosing for at least 6 months 
prior to randomization. New initiations of this medication during the study are prohibited.
Please refer to the respective cohort-specific information (Section 17) prohibited medication 
section for additional restrictions, as applicable.
6.2.3
Restriction for study participants
For the duration of the study, the participants should be informed and reminded of the 
restrictions outlined in this section.
6.2.3.1
Dietary restrictions
On Day 1 and Day 85, all participants must fast (i.e., no food or liquid except water) for at least 
8 hours prior to administration of study treatment. Fasting is a requirement for certain samples 
(e.g., biomarkers) that are collected at these visits.
It is recommended that participants fast for at least 4 hours prior to any MRI or Fibroscan 
assessment. Please refer to the SOM for more details.
During the entire treatment period, it is recommended that study treatment should be 
administered with a light meal unless stated otherwise in the respective cohort-specific 
Section 17.
Participants can drink water ad libitum however, to ensure adequate hydration for urine 
collection (if applicable), participants should be encouraged to have a fluid intake of at least 
240 mL every 4 hours during waking hours in addition to fluid taken with meals and medication.
Alcohol consumption is to be strongly discouraged, and should not exceed 20 g/day in females 
and 30 g/day in males. Alcohol should be avoided for 8 hours prior to and after intake of study 
medication.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Upon signing the informed consent form, each participant is uniquely identified by a participant
number. The participant number assigned to a participant at screening remains the unique 
identifier for the participant throughout the study. For additional details on participant
numbering, please see the ‘Participant numbering’ section in the SOM.


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6.3.2
Treatment assignment, randomization
Once eligibility is confirmed from baseline assessments, all eligible participant will be 
randomized via Interactive Response Technology (IRT) to one of the treatment arms.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased: a participant randomization list will be produced by the IRT 
provider, or by a delegate under Novartis supervision, using a validated system that automates 
the random assignment of treatment arms to randomization numbers. These randomization 
numbers are linked to the different treatment arms.
Randomization will be stratified by race and BMI at baseline (Asian race with BMI < 30 kg/m2, 
or Asian race with BMI ≥ 30 kg/m2, or non-Asian race with BMI < 35 kg/m2, or non-Asian race 
with BMI ≥ 35 kg/m2). The race will be based on the race the participant self-reports as captured 
on the demography eCRF.
Participants will be enrolled without randomization if there is only one open treatment arm in a 
cohort, or if they are only deemed eligible for one treatment arm.
Please refer to the SOM for further details regarding the process of treatment assignment and 
randomization of participants.
6.4
Treatment blinding
This is an open label study. Treatment blinding is not applicable.
6.5
Dose escalation and dose modification
6.5.1
Permitted dose adjustments and interruptions of study treatment
The NEXSCOT study will start all participants on the initial, planned dose(s) of either the single 
or combination of drug(s). Change and/or interruption of dose is permitted based upon safety 
considerations. Dose adjustment for any reason other than for safety will be subject of a protocol 
amendment.
Safety and tolerability
If the treatment is not tolerated, the protocol allows reduction/interruption of dose(s), unless 
otherwise specified in the cohort-specific treatment information in Section 17. Please refer to 
Section 17 for the exact reduced dose(s) and the guidance below for more details. 
At the end of two weeks of reduced dosing, the investigator, weighing all the evidence, may 
consider increasing the dose(s) of the drugs in the regimen back to the starting dose(s). However, 
if the intolerability returns, the investigator should again decrease the dose(s) as before and 
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maintain the participant on these reduced dose(s) for the remainder of the study. If the 
participant cannot tolerate the reduced dose(s), then the investigator should consider stopping 
the experimental treatment.
Table 6-3
Dosing response to safety/tolerability events
First Action
Result
2nd Action
Result
3rd Action
Interrupt dosing for up to 
two days and/or decrease 
dose to approximately one-
half of the original starting 
dose for 2 weeks*†
Reduced dose 
tolerated
Consider 
increasing the 
dose back to the 
starting dose 
Starting 
dose 
tolerated
Continue at 
starting dose until 
study completion
Starting 
dose NOT 
tolerated
Decrease dose 
back to 
approximately one-
half of starting dose 
and remain at this 
dose until study 
completion†
Reduced dose 
NOT tolerated
Discontinue 
study 
treatment
*If the causative drug is unknown, the dose of all drugs in the combination should be reduced. If the
event is believed to be causally-related to one specific drug, only the dose of that drug may need to be
reduced while the other drug(s) in the combination may remain at the starting dose.
†Please refer to cohort-specific treatment information in Section 17 for the exact reduced dose(s).
For some drugs that may be used in the NEXSCOT study, adverse events thought to be related 
to treatment are included in their reference safety information as listed in their respective IBs. 
Cohort-specific information (Section 17) for that particular drug should be used to determine if 
the individual drug could be dose interrupted and/or reduced. An example would be "Drug A" 
for which diarrhea is a commonly reported adverse event. In this example, in the setting of new 
onset diarrhea with a drug combination which includes Drug A, it may be reasonable to only 
dose reduce Drug A, rather than reduce the dose of all drugs in the combination.
Liver and renal events
Certain liver and renal events as defined in Section 16.1 and Section 16.2, respectively, may 
necessitate dose modifications. The recommendations for the timing and duration of treatment 
discontinuation, adjustment and/or interruption, are also provided in Section 16.1 and 
Section 16.2. In the event that dose reduction is needed, please refer to cohort-specific treatment 
information in Section 17 for the exact reduced dose(s) to be used.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 


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Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts (if applicable) and information provided by the participant. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log.
Where applicable, remote treatment administration compliance will be assessed by the OHP 
and information will be provided to the Investigator and/or study personnel.
6.7
Preparation, dispensation, and management of investigational 
drug
6.7.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Unless specifically 
instructed by Novartis, the investigator must not destroy any drug labels, or any partly used or 
unused drug supply. Technical complaints are to be reported to the respective Novartis CO 
Quality Assurance.
Further details regarding the handling of study treatment are provided in the SOM; information 
will also be provided in Section 17 if the study treatment requires special handling 
(e.g., biologics, injectables).
6.7.2
Accountability and monitoring
The investigator must maintain an accurate record of the receipt and of dispensing of study 
treatment in a drug accountability log. Further details regarding accountability and monitoring 
are provided in the SOM.
6.7.3
Preparation and dispensation
Clinical supplies are to be dispensed only in accordance with the protocol. Medication labels 
will be in the local language and comply with the legal requirements of each country. 
Each study site will be supplied with study drug in packaging as described under the cohort-
specific treatment information in Section 17.
Further details regarding the preparation of study treatment are provided in the SOM; 
information will also be provided in Section 17 if the study treatment requires special 
preparation (e.g., biologics, injectables).
6.7.4
Instructions for administration
Study medication will be administered throughout the 12-week treatment period. 
As study treatments may vary depending on the specific arm, please refer to the respective 
cohort-specific information (Section 17) for further details on administering study treatment.


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6.7.5
Remote delivery
For remote visits, where delivery of study treatment directly to a participant’s remote location 
(e.g., home) is permitted by national and local governing regulations, dispatch of IMP from the 
site (or depot/pharmacy) to the participant will be performed under the accountability of the 
Investigator. Each shipment/provisioning will be for a maximum of 1-month’s supply.
Regular contact with the site and/or OHP will occur for instructional purposes, safety 
monitoring, and discussion of the participant´s health status until the next scheduled visit, as 
required. 
Study treatment for remote administration will be handled and shipped in line with the SOM 
and required procedures for shipping.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB or CDS for marketed drugs. This information will be included in the participant
informed consent and should be discussed with the participant during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
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The study includes the option for the participant to have certain study procedures performed 
off-site by an OHP instead of at the study site, for which a separate signature is required if the 
participant agrees. The Investigator may present this option to the participant, as permitted by 
national and local governing regulations. The process for obtaining consent should be exactly 
the same as described above for the main informed consent.A copy of the approved version of 
all consent forms must be provided to Novartis/sponsor after IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
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8
Visit schedule and assessments
Assessment schedule (Table 8-1) lists all of the assessments and when they are performed. All data obtained from these assessments must be 
supported in the participant’s source documentation.
Participants should be seen for all visits/assessments as outlined in the Assessment schedule (Table 8-1) or as close to the designated day/time 
as possible. Missed or rescheduled visits should not lead to automatic discontinuation. Please refer to the SOM for guidance regarding 
visit/assessment windows and other changes to scheduled visits/assessments.
Participants who discontinue from the study or withdraw their consent/oppose the use of their data/biological samples should be scheduled 
for a final evaluation visit (i.e., EOS1 or EOS2) if they agree, as soon as possible, at which time all of the assessments listed for the final visit 
will be performed. At this final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant 
medications not previously reported must be recorded on the CRF.
All assessments, except those marked with a “NR” footnote, may be performed remotely by an OHP in certain countries and sites, as allowed 
by national and local regulations.
Table 8-1
Assessment Schedule
Epoch
Screening
Treatment
Post-Treatment 
Follow-Up 11,2
Post-Treatment 
Follow-Up 21,2
Visit Name Screening Baseline
Treatment
EOS1
EOS2
Days -60 to -28
-27 to -1
13,4
85
153 225
293
433
573
715 853,4
113
141
Weeks
-9 to -4
-4 to -1
1
2
3
4
5
7
9
11
13
17
21
Time (post-dose)
-
-
-
-
-
-
0h3 1h
2h
3h
4h
-
0h3 1h
2h
3h 4h
-
-
-
-
Informed consent6
X
Inclusion / Exclusion 
criteria
X
X
Medical history/current 
medical conditions
X
X
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Epoch
Screening
Treatment
Post-Treatment 
Follow-Up 11,2
Post-Treatment 
Follow-Up 21,2
Visit Name Screening Baseline
Treatment
EOS1
EOS2
Days -60 to -28
-27 to -1
13,4
85
153 225
293
433
573
715 853,4
113
141
Weeks
-9 to -4
-4 to -1
1
2
3
4
5
7
9
11
13
17
21
Time (post-dose)
-
-
-
-
-
-
0h3 1h
2h
3h
4h
-
0h3 1h
2h
3h 4h
-
-
-
-
Demography
X
Hepatitis and HIV 
Screen8
S
COVID-19 Test8a
S
Pregnancy and 
assessments of fertility9
X
X
X
X
X
X
X
X
Physical examination10
S
S
S
S
S
S
S
S
S
Vital signs and body 
measurements11
X
X
X
X
X
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
Coagulation panel12
X
X
X
X
X
X
X
X
X
X
Fasting glucose, insulin, 
and lipids13
X
X
PK blood collection14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X15
X15
Conditional biomarker 
RNA16
X
X
X
X
X
X
Central lab biomarkers 17
X18
X
X
X
X
X
X
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Epoch
Screening
Treatment
Post-Treatment 
Follow-Up 11,2
Post-Treatment 
Follow-Up 21,2
Visit Name Screening Baseline
Treatment
EOS1
EOS2
Days -60 to -28
-27 to -1
13,4
85
153 225
293
433
573
715 853,4
113
141
Weeks
-9 to -4
-4 to -1
1
2
3
4
5
7
9
11
13
17
21
Time (post-dose)
-
-
-
-
-
-
0h3 1h
2h
3h
4h
-
0h3 1h
2h
3h 4h
-
-
-
-
Dose administration22
X
X23
X23
X23
X
X23
X
X23
X23
Fibroscan24,25,NR
X
X
X26
MRI/MRE27,NR
X
X
X26
VAS (Visual Analog 
Scale)28
X
X
Telephone follow-up
X
X
X
Concomitant therapies29
X
Adverse events
As required
Serious adverse events
As required
Comments
As required
Study completion 
information
X
X
X Assessment to be recorded in the clinical database
S Assessment to be recorded in the source documentation only
NR Non-remote, i.e. this assessment may not be performed remotely (i.e., must be performed at the originally qualified facilities).
1 For treatments with an extended half-life, EOS1 will be required as a standard, non-EOS post-treatment follow up visit, and EOS2 will serve as the EOS 
visit. For all other treatments, EOS1 will serve as the EOS visit.
2 If a participant discontinues study treatment early, the participant should be scheduled for a subsequent visit at which time all assessments at the EOS1 
visit should be performed. For treatments with an extended half-life, if a participant discontinues early after EOS1, then the participant should be 
scheduled for a subsequent visit at which time all assessments at the EOS2 visit should be performed.
3 Assessments to be performed pre-dose.
4 All participants must fast for at least 8 hours prior to administration of study treatment.
5 Visit will be conducted via telephone only. Participants are not required to present to the study site for assessments.
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6 Informed consent must be provided by all participants before any screening procedures are performed. The DNA assessment is optional and requires a 
separate informed consent to be signed.
8 Standard laboratory assays to be used for screening.
8aCOVID-19 test highly recommended to be completed within 1 week prior to first dosing, as defined in Exclusion Criterion #29.
9 Serum pregnancy tests will be performed at Screening and EOS; urine tests may be used at other time points.
10 A complete physical examination is required at Screening, Day 1, Day 85, and at the study completion visit. A focused physical examination can be 
performed at all other visits where a physical examination is required. Please see protocol Section 8.4 for more details.
11 Body height only measured at Screening. Waist and hip circumference (for waist-to-hip ratio calculation) only measured at Baseline and Day 85. Blood 
pressure and pulse rate will be measured in a sitting position at all marked visits.
12 Coagulation panel includes PT/INR and aPTT.
13 Fasting glucose and insulin used for Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) calculation. Fasting lipid panel includes total 
cholesterol, LDL, HDL, and triglycerides. Additional analyses of HDL and LDL sub-fractions, ApoC3, and lipoprotein(a) at these timepoints may be 
performed depending on the compound under investigation.
14 Trough PK samples will be collected at all visits during the treatment period (Day 1 to Day 85). On Day 29 and Day 57, additional samples will be 
obtained as marked.
15 Assessment is only to be performed at EOS if a participant discontinues study treatment and from the study early.
17 Assessment may include (
 CRP, 
 ELF Test).
18 ELF Test only.
22 For orally-administered study medications, participants will be provided with a supply to self-administer for 12 weeks (Day 2 to Day 84). 
Study medication will be administered by study staff on marked visit days. Participants should bring all used and unused medications, and diaries, to 
each visit. For other types of study medications, such as injectable monoclonal antibodies, dose administration will be managed by study staff on marked 
visit days. 
23 Orally-administered study medications only.
24 Optional assessment.
25 If Fibroscan is unavailable, alternative technology to assess liver stiffness may be considered upon consultation with the sponsor.
26 Assessment is only to be performed at this visit if a participant discontinues study treatment early on or after Week 8 for any reason and should be
scheduled as closely to the last dose of treatment as possible.
27 Assessment should be performed after eligibility is confirmed from all other screening/baseline assessments wherever possible. MRE is an optional 
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assessment. See Imaging Subject Scanning Guide for further instructions.
28 VAS assessments for itching of the skin.
29 A thorough review of any concomitant medications (including medication name, dose, unit, frequency, and route) should be performed at every visit.


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8.1
Screening
In general, it is permissible to re-screen a participant once if he/she fails the initial screening; 
however, each case must be discussed and agreed with the Sponsor on a case-by-case basis.
A participant may not be enrolled in more than one treatment arm.
Further information on re-screening is outlined in the SOM.
8.1.1
Information to be collected on screening failures
Certain limited data on screening failures will be collected. Further information on what data 
must be collected and further information on re-screening is outlined in the SOM.
8.1.2
Pre-screening
Prior to the screening visit, optional pre-screening assessments may be conducted, including 
laboratory tests for serum albumin, ALT, AST, ALP, bilirubin, creatinine, ELF (or one of its 
component measures such as hyaluronic acid), HbA1c, INR, and platelets, in order to assess 
participant eligibility for inclusion. Prior to any assessments being conducted, the pre-screening 
informed consent form must be signed by the participant.
Only data related to SAEs causally related to study procedures (i.e., blood sampling) will be 
reported. All other data related to pre-screening will be recorded only in the source 
documentation.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participant demographic and baseline characteristic data are to be collected on all participants. 
Relevant medical history/current medical condition present before signing the informed consent 
will be recorded. Investigators will have the discretion to record abnormal test findings on the 
appropriate CRF whenever in their judgment, the test abnormality occurred prior to the 
informed consent signature. 
8.3
Efficacy/Pharmacodynamics
Efficacy of the single or combination drug regimens will be assessed based on the following 
three general classes of assessments:

Liver function tests and liver and/or systemic inflammation markers (including ALT)

Markers of liver fibrosis (including ELF Test)

Magnetic Resonance Imaging (including MRI-PDFF)
In addition, the impact of treatment on cardiometabolic risk parameters including body weight, 
waist and hip circumference, waist-to-hip ratio, Homeostasis Model Assessment of Insulin 
Resistance (HOMA-IR), hemoglobin A1C (HbA1c), fasting glucose, fasting insulin, and fasting 
lipid profile will be assessed.


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Pharmacodynamic (PD) samples will be collected at the timepoints defined in the 
Assessment schedule (Table 8-1). Follow instructions outlined in the central laboratory manual 
regarding sample collection, numbering, processing and shipment.
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will 
not exceed those stated in the protocol. PD samples will be obtained and evaluated in all 
participants at all dose levels.
8.3.1
Liver function tests and liver and/or systemic inflammation markers
ALT, AST, GGT, ALP (total), total bilirubin, albumin, and high-sensitivity C-reactive Protein 
(hsCRP) will be assessed as indicated in the Assessment schedule. The methods for assessment 
and recording are specified in the laboratory manual.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reactive bilirubin will be quantified.
ALP isoenzymes and 5’nucelotidase (5’NT) will also be measured but will not form part of the 
screening requirements or safety data set.
The methods for assessment and recording are specified in the laboratory manual. Some of the 
liver function tests may be completed as part of the blood chemistry panel.
8.3.2
Markers of Liver Fibrosis

Enhanced liver fibrosis Test (ELF Test™) will assess: hyaluronic acid (HA), tissue
inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of procollagen
type III (PIIINP).

Fibroscan® (optional) to assess liver stiffness (in kPa) will be performed where available.
If Fibroscan is unavailable, alternative technologies to assess liver stiffness may be
considered upon consultation with the sponsor.

Fibrosis biomarker test (originally called Fibrotest®/ Fibrosure®) will assess:
α2-macroglobulin, apolipoprotein A1, total bilirubin, haptoglobin, GGT, and ALT.

Additional fibrosis markers may be assessed, including but not limited to FIB4 score,
APRI score, and NAFLD score.
Additional information is provided in the central laboratory manual. These markers will be 
assessed as indicated in Table 8-1 (Assessment schedule).
8.3.3
Magnetic Resonance Imaging (MRI)
Participants will undergo magnetic resonance imaging twice during the course of the study 
(at Baseline and End of Treatment) to quantitate liver fat. Optional exploratory MRI-based 
assessments will be performed in a subset of participants to evaluate the effect of treatment on 
exploratory MRI related endpoints as outlined in Table 2-1 (Objectives and related endpoints). 
All participants who discontinue prematurely on or after Week 8 must have an end of treatment 
MRI assessment scheduled as close to the last dose of treatment as possible.


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8.3.4
Anthropometric assessments
Height in centimeters (cm), waist and hip circumference (cm), and body weight (to the nearest 
0.1 kilogram [kg] in indoor clothing, but without shoes), will be measured as indicated in 
Table 8-1 (Assessment schedule). Additional details of these assessments will be provided in 
the SOM.
8.3.5
Cardiometabolic risk parameters
Blood samples will be collected for Homeostasis Model Assessment of Insulin Resistance 
(HOMA-IR), hemoglobin A1c (HbA1c), fasting glucose, fasting insulin, and fasting lipid 
profile including total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and 
lipoprotein A as per Table 8-1. Glucose and lipid measurements should be collected under 
fasted conditions. Detailed information will be provided in the central laboratory manual.
Note: Body weight, waist and hip circumference, and waist-to-hip ratio are also considered 
cardiometabolic risk parameters.
8.3.6
Appropriateness of biomarker assessments
As described in Section 4.1, the three biomarkers supporting the secondary objectives of this 
study, liver fat content using MRI-PDFF, ALT and ELF Test are well established, platform 
technologies which are frequently used in both clinical practice and research in liver disease. 
Multiple studies in NAFLD and NASH conducted over the last five years have used some or 
all 
of 
these 
biomarkers
as 
endpoints
(Sanyal et al 2017; 
Harrison et al 2018a; 
Harrison et al 2018b).
8.4
Safety
Safety assessments are specified below with the Assessment schedule (Table 8-1) detailing 
when each assessment is to be performed.
The methods for each assessment and data recording details are located in the SOM.
For details on AE collection and reporting, refer to the AE Section 10.1.1.
Table 8-2
Physical Assessments
Assessment
Specification
Physical 
examination
Complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, 
and/or pelvic exams may be performed.
Focused physical examination will include the examination of general 
appearance, skin, throat, lungs, heart, abdomen, and extremities.
Vital signs
Includes body temperature, pulse, and blood pressure.
8.4.1
Safety-related laboratory evaluations
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 


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until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
Table 8-3
Safety-related Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin (HGB), Ery. Mean Corpuscular Hemoglobin (MCH), 
Ery. Mean Corpuscular HGB Concentration (MCHC), Ery. Mean Corpuscular 
Volume (MCV), Platelets, Erythrocytes, Leukocytes, Erythrocyte Morphology, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Bands, Other)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphate, Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL Cholesterol, 
HDL Cholesterol, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or 
Urea, Uric Acid, Amylase, Lipase, HbA1c, Glucose
Urinalysis
Microscopic Panel (Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, 
Epithelial cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
Prothrombin time (PT), International normalized ratio (INR), Activated partial 
thromboplastin time (aPTT)
Pregnancy Test
Serum / Urine pregnancy test
8.4.2
Electrocardiogram (ECG)
Single 12 lead ECGs will be collected at the time points indicated in the Assessment schedule
(Table 8-1).
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc will be assessed.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated by study staff, unless auto-calculated by the 
ECG machine.
Clinically significant abnormalities must be reported as adverse events.
Additional details pertaining to ECG collection and reporting are included in the SOM.
8.4.3
Pregnancy and assessments of fertility
Pregnancy testing
See the Assessment schedule (Table 8-1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements*. A positive urine 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.
Refer to Section 10.1.4 for details on Pregnancy reporting.


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Assessments of Fertility
Refer to Section 5.2 for criteria to determine a female participant’s childbearing potential status.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. surgical bilateral oophorectomy without a hysterectomy
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant, regardless of reported reproductive/menopausal status at screening/baseline.
Vasectomized partners of female participants should provide supporting documentation, which 
is to be kept as source, as applicable per local Health Authority regulations.
8.4.4
Appropriateness of safety measurements
Other than possible treatment specific safety measures (Section 17), the safety assessments 
selected are standard for this indication/ participant population.
8.5
Additional assessments
No additional tests will be performed on patients entered into this study.
8.5.1
Clinical Outcome Assessments (COAs)
8.5.1.1
Visual Analog Scale (VAS)
A 100 mm visual analogue scale (VAS) will be used to assess the severity of participants’ itch 
(ranging from 0 = no itch at all to 100 = the worst imaginable itch). The score (distance from 
left) on the VAS will be recorded by the participant marking with a line. 
The scale will be completed by participants as indicated in Table 8-1 (Assessment schedule).
8.5.2
Pharmacokinetics
PK samples will be collected at the visits defined in the Assessment schedule (Table 8-1). 
Follow instructions outlined in the central laboratory manual regarding sample collection, 
numbering, processing and shipment. See the potential use of residual samples for more 
information.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data and the expected PK for the drug(s) being tested.
Pharmacokinetic (PK) samples will be collected in all participants.
Concentrations will be expressed in mass per volume units and will refer to the free base.
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8.5.4.1
Use of residual biological samples
Residual blood samples may be used for another protocol specified endpoint.
8.5.5
Imaging
Magnetic resonance imaging (MRI) and magnetic resonance elastography 
(MRE)
Participants will undergo magnetic resonance imaging twice during the course of the study 
(Baseline and End of Treatment) to quantitate liver fat. Optional exploratory MRI-based 
assessments (including MRE) will be performed in a subset of participants to evaluate the effect 
of treatment on exploratory MRI related endpoints as outlined in Table 2-1 (Objectives and 
related endpoints).
All participants who discontinue prematurely on or after Week 8 must have an end of treatment 
MRI assessment.
MRI acquisition sequences, including MRE, are described in MRI Participant Scanning Guide.
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers.
9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation from study treatment in individual participants
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration) and can 
be decided by either the participant or the investigator.
Study treatment must be discontinued under the following circumstances:
1. Participant decision
2. Pregnancy
3. Use of prohibited treatment(s)
4. Any situation in which study participation might result in a safety risk to the participant
5. The investigator believes that continuation would negatively impact the safety of the
participant or the risk/benefit ratio of trial participation
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6. Hypersensitivity (CTCAE Grade 2 or higher) reaction to study medication
7. An adverse event that is CTCAE Grade 4 or higher, regardless of whether the event is
suspected to be related to study drug(s)
8. An adverse event that is CTCAE Grade 3 and suspected to be related to study drug(s)
(apart from liver and renal events - see below)

If a liver or renal event occurs, follow guidelines outlined in Section 16.1 and
Section 16.2, respectively, regarding discontinuation of study treatment
9. Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the participant’s overall status, prevents the participant from continuing
participation in the study
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue from study treatment agree to return for the end of treatment 
assessments (i.e., EOS1 or EOS2) indicated in the Assessment schedule (Table 8-1; and refer
to Section 8).
If the participant cannot or is unwilling to attend any visit(s), the study staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
9.1.2
Discontinuation from study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
occurs should be made as detailed in the assessment table (refer to Section 8).
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g., 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study.


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9.2
Withdrawal of informed consent/Opposition to use 
data/biological samples
Withdrawal of consent/opposition to use data/biological samples occurs when a participant:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples), and

No longer wishes to receive study treatment, and

Does not want any further visits or assessments (including further study-related contacts)
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of Personal and Coded Data is not required in a certain country’s legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the 
Assessment schedule (please also refer to Section 8).
Novartis will continue to retain and use all research results (data) that have already been collected for 
the study evaluation, including processing of biological samples that has already started at the time of 
consent withdrawal/opposition. No new Personal Data (including biological samples) will be 
collected following withdrawal of consent/opposition.
9.2.1
Study stopping rules
Treatment arm stopping rules
If any of the following events occur, all ongoing treatment arms sharing the same suspect drug(s)
will be placed on hold to further enrollment, and no new participants may be dosed, however 
dosing of those without safety concerns may continue. In addition, a full review of all available 
clinical safety data and discussion with the investigators will take place.

One participant on study drug experiences any adverse event that is CTCAE Grade 4 or 
higher that is suspected to be related to study drug(s)

Two participants on study drug experience a similar adverse event that is a CTCAE Grade 
3 or higher other than ALT elevation regardless of whether the events are suspected to be 
related to study drug(s)

Two participants are discontinued due to a liver event as defined in Section 16.1

Two participants are discontinued due to a renal event as defined in Section 16.2


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
Two participants meet the same individual participant stopping rule 6, 7, or 8
(Section 9.1.1)

One participant experiences any adverse event that is CTCAE Grade 5 regardless of 
whether the event is suspected to be related to study drug(s)

One participant experiences an SAE that is suspected to be related to study drug(s)

The Principal Investigator and Sponsor consider that the number and/or severity of 
adverse events justify discontinuation of the suspect drug(s)

The Sponsor unilaterally requests it
Safety reviews for treatment arm stopping will be conducted cooperatively between medically 
qualified representatives of the sponsor and investigator and a joint decision will be made.
The treatment arm may resume following the safety review, if the investigator and sponsor 
agree it is safe to proceed.
9.2.2
Early study termination by the sponsor
The study can be paused or terminated by Novartis at any time for any reason. This may include 
reasons related to the benefit/risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. In taking the decision to 
terminate, Novartis will always consider the participant’s welfare and safety. Should early 
termination be necessary, participants must be seen as soon as possible and treated as a 
participant who discontinued from study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.3
Study completion and post-study treatment
Each participant will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
For participants who discontinue the study early and do not return for a study completion visit, 
a safety follow-up call will be conducted 30 days after last administration of study treatment. 
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3 and the SOM. Documentation of 
attempts to contact the participant should be recorded in the source documentation.
Trial-level study completion is defined as when final data analysis and reporting, and 
appropriate closeout activities are completed, following either triggering event: 
1. When the final participant in the fifth cohort finishes his/her Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator, or
2. When an early study termination decision is finalized.


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10
Safety monitoring, reporting, and committees
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious, refer to
Section 10.1.2):
1. the Common Toxicity Criteria (CTC) AE grade (version 5.0 or higher) for the adverse 
event. If CTC-AE grading does not exist for an adverse event, use:

1 = mild

2 = moderate

3 = severe

4 = life threatening* (see Section 10.1.2 for definition of a serious adverse event 
[SAE])
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may 
not necessarily be an SAE (e.g., certain laboratory abnormalities in the absence of 
meeting other seriousness criteria).

5 = death
2. its relationship to the study treatment
3. its duration (start and end dates or ongoing) and the outcome must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
6. its outcome i.e., its recovery status or whether it was fatal
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed


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
Dose reduced/increased

Drug interrupted/permanently discontinued
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 5 half-lives following the last dose 
of study treatment or until the final study visit, whichever is longer.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants
with the underlying disease. 
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for participants that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event (appearance of [or worsening of any pre-existing])
undesirable sign[s], symptom[s] or medical conditions[s]) which meets any one of the following 
criteria:

fatal

life-threatening

Life-threatening in the context of a SAE refers to a reaction in which the participant
was at risk of death at the time of the reaction; it does not refer to a reaction that
hypothetically might have caused death if it were more severe (please refer to the
ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:


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
routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g., defined as an event that jeopardizes the participant or may
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. Please see Section 10.1.5 for more details.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, under no circumstances later than within 24 
hours of learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report.
For patients who sign the pre-screening informed consent form, SAEs which occur after 
signature of this consent will only be captured if they are reported to be causally related to study 
procedures (i.e., blood sampling).
SAEs occurring after the participant has provided informed consent until the time the participant
is deemed a screen failure must be reported to Novartis.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 


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different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical 
Office and Patient Safety (CMO&PS) associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment, unless 
otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment must be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review, and sign the pregnancy consent form. This consent form 
is necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS
department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery (EDD).
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant, or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in 
Dosing CRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the
respective sections.
10.2
Additional safety monitoring
Refer to Section 16.1 for liver safety monitoring, and Section 16.2 for renal safety monitoring.
10.2.1
Safety Assessment Committee
As described in the FDA Draft Guidance for Industry: Safety Assessment for IND Safety 
Reporting (CDER 2015), this study will include a Safety Assessment Committee (SAC) which 
will include both study team members and also members not directly related to the conduct of 
the study. The SAC will function independently of site investigators participating in the study. 
The SAC will assess at frequent intervals the progress of the NEXSCOT treatment arms and
the safety data and will continue, modify or terminate treatment arms based on these reviews.
The rationale for using a SAC rather than an external DMC and specific details regarding 
composition, responsibilities, data monitoring, meeting frequency, and documentation of SAC
reports, minutes, and recommendations is described in the Safety Surveillance Plan.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web--enabled software that conforms to 21 CFR Part 11 requirements, and study staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
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The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
study staff via the EDC system. Designated study staff are required to respond promptly to 
queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Randomization codes will be tracked using IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/moved to restricted 
area to be accessed by independent programmer and statistician. Any changes to the database 
after that time can only be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/
delegated CRO representative will review the protocol and data capture requirements 
(i.e., eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to GCP, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/delegated CRO/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 


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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the participants will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
All data will be listed, summarized and analyzed by cohort and treatment. Combined cohort 
analysis will be performed as appropriate.
12.1
Analysis sets
The safety analysis set will include all participants that received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The efficacy/PD analysis set will include all participants with available efficacy/PD data and 
no protocol deviations with relevant impact on efficacy/PD data.
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment for the safety analysis set.
Categorical data will be presented as frequencies and percentages. For continuous data, sample 
size (n), mean (arithmetic), standard deviation, median, minimum, and maximum will be 
presented. For selected parameters, 25th (Q1) and 75th (Q3) percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be listed by treatment, 
participant, system organ class (SOC) and preferred term (PT).
12.3
Treatments
The safety analysis set will be used for the analyses below. Categorical data will be summarized 
as frequencies and percentages. For continuous data, mean, standard deviation, median, 25th 
and 75th percentiles, minimum, and maximum will be presented.


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by treatment, participant and the Anatomical Therapeutic 
Chemical (ATC) classification system.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to evaluate the safety and tolerability of single or 
combination therapy during 12 weeks of treatment. Safety and tolerability data will be 
summarized using descriptive statistics. Details are provided in Section 12.4.2.
12.4.1
Definition of primary endpoint(s)
All safety data collected, including laboratory measurements, vital signs, adverse events and 
ECG, represent the primary endpoints of this study and will be used to support the assessment 
of the primary objective.
12.4.2
Statistical model, hypothesis, and method of analysis
Formal statistical analysis will not be performed on the safety and tolerability data.
Adverse events
All information obtained on adverse events will be displayed by treatment and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication, or present prior to start of treatment but increased 
in severity based on preferred term, or changed from being not suspected to being suspected of 
study drug relationship, or developed into SAEs after the start of the treatment period) will be 
summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum CTCAE grade.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment, participant, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time and will include sample size (n), mean (arithmetic), 
SD, median, 25th percentile (Q1), 75th percentile (Q3), minimum and maximum.
Standard 12-lead ECG
All ECG data will be listed by treatment, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time and will include 
sample size (n), mean (arithmetic), SD, median, 25th percentile (Q1), 75th percentile (Q3),
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Clinical laboratory evaluations
All laboratory data will be listed by treatment, participant, and visit/time and if normal ranges 
are available abnormalities will be flagged. A separate listing will be provided presenting all 
parameters in a participant with any abnormal values. Summary statistics will be provided by 
treatment and visit/time and will include sample size (n), mean (arithmetic), SD, median, 25th
percentile (Q1), 75th percentile (Q3), minimum and maximum.
12.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed.
12.4.4
Sensitivity and Supportive analyses
Not applicable.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
A mixed-effect model for repeated measures analysis (MMRM) will be conducted for log-
transformed ratio to baseline ELF Test and ALT.
An 
unstructured
variance-covariance matrix will be used to account for correlation among multiple 
measurements from the same participant and variance heterogeneity. If the unstructured 
covariance causes model convergence issues, then other simpler covariance structures will be 
considered. Least squares mean, the associated 2-sided 80% confidence interval and the p-value 
will be obtained for each treatment at each visit and back transformed to the original scale. 
Contrasts assessing trend over time will be constructed for each treatment using various 
functional forms as needed. Both cohort-wise and combined cohort analysis will be performed
as appropriate.
Log-transformed ratio to baseline % liver fat, hsCRP, HOMA-IR, HbA1c, fasting glucose, 
fasting insulin, and fasting lipid profile, as well as change from baseline ELF Test, ALT, % 
liver fat, waist circumference, hip circumference, waist-to-hip ratio, and % change from 
baseline weight will also be analyzed. Parameters with more than one post-treatment 
measurement will be subjected to the same MMRM analysis described above for ELF Test and 
ALT using untransformed baseline in lieu of log-transformed baseline as a covariate for the 
untransformed data analysis. For parameters with only one post-treatment measurement such 
as % liver fat, an ANCOVA with treatment and stratification factor (race and BMI group) as 
classification factors and baseline (or log-transformed baseline if applicable) as a covariate will 
be employed.
Additionally, a multivariate ANCOVA will be done for the three-dimensional endpoint: 
log-transformed ratio to baseline ELF Test, ALT and % liver fat at Week 12. The model will 
include treatment and stratification factor (race and BMI group) as classification factors and 
log-transformed baseline as a covariate. An arbitrary 3 by 3 covariance matrix will be assumed 
for the three-dimensional endpoint.
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Proportion of participants with at least 30% relative reduction and 5% absolute reduction in % 
liver fat will be tabulated separately by treatment. If there are sufficient data, then a subgroup 
analysis (ANCOVA) in participants with baseline liver fat ≥10% will be performed to compare % 
liver fat between treatments.
Baseline participant characteristics will be monitored 
closely and compared across cohorts to assess population drift which may occur because of 
improved general care and enrollment of either less or more healthy participants over time. The 
population drift, if present, will be accounted for using a modeling approach as appropriate.
Missing data will not be imputed in the MMRM analysis. Assuming data is missing at random, 
a participant with missing value at a visit will still contribute to the estimation of the treatment 
effect at that particular visit as the likelihood-based MMRM borrows information from non-
missing values of this participant and other participants. For the Week 12 multivariate 
ANCOVA, an additional analysis with the last post-treatment observation carried forward for 
missing ELF Test and ALT values may be performed.
12.5.2
Pharmacokinetics
Plasma concentration data will be listed by treatment, participant, and visit/sampling time point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point, 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. 
Summary statistics (mean, SD, geometric mean, CV, median, min and max) per analyte, per 
time point will be reported. The concentration data may be integrated with data from other 
studies for population PK analysis in the future and will be reported separately.
12.5.3
PK/PD relationships
The relationships between individual PK profiles or derived PK parameters and various 
efficacy/PD measurements or derived variables (including, but not limited to ELF Test, ALT 
and % liver fat) may be explored using graphical approaches (e.g., scatter plots) and regression 
analysis as appropriate. Similarly, the relationship between % liver fat reduction and ALT 
reduction vs. weight loss as well as ALT decrease vs. % liver fat reduction may be explored as 
needed.
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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures 
(e.g., advertisements) and any other written information to be provided to participants. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as the global last 
participant last visit) and finalization of the study report, the results of this trial will be submitted 
for publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required Health Authority websites 
(e.g., Clinicaltrials.gov, EudraCT). For details on the Novartis publication policy including 
authorship criteria, the Investigators are requested to refer to the Novartis publication policy 
training materials provided at the trial investigator/initiation meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
New cohorts will be added to the protocol using substantial amendments.
Urgent safety measures that are required for participant safety may be implemented 
immediately provided that Health Authorities are subsequently notified by protocol amendment 
and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request.
Calzadilla Bertot L, Adams LA (2016) The Natural Course of Non-Alcoholic Fatty Liver 
Disease. Int J Mol Sci; 17(5).
CDER (2015) US Department of Health and Human Services, Food and Drug Administration, 
Guidance for Industry: Safety assessment for IND safety reporting. Rockville, MD.
Friedman SL, Neuschwander-Tetri BA, Rinella M, et al (2018) Mechanisms of NAFLD 
development and therapeutic strategies. Nat Med, 24(7):908-922.
Gungoren MS, Efe C, Kav T, et al (2018) Diagnostic accuracy of enhanced liver fibrosis 
(ELF) test for significant fibrosis in patients with autoimmune hepatitis. J Lab Precis Med, 
3(21):1-7.
Harrison S, Moussa S, Bashir M, et al (2018a) MGL-3196, a selective thyroid hormone 
receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the 
primary endpoint in a 36 week serial liver biopsy study. J Hepatol Suppl, 68(1): S38.
Harrison SA, Rinella ME, Abdelmalek MF, et al (2018b) NGM282 for treatment of non-
alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 
trial. Lancet, 391(10126):1174-1185.
Kwo PY, Cohen SM, Lim JK (2017) ACG Clinical Guideline: Evaluation of Abnormal Liver 
Chemistries. Am J Gastroenterol, 112(1):18-35.
Lichtinghagen R, Pietsch D, Bantel H, et al (2013) The Enhanced Liver Fibrosis (ELF) score: 
normal values, influence factors and proposed cut-off values. J Hepatol; 59(2):236-42.
López IC, Aroca FG, Bernal MDF, et al (2017) Utility of the ELF Test for Detecting 
Steatohepatitis in Morbid Obese Patients with Suspicion of Nonalcoholic Fatty Liver Disease. 
Obes Surg; 27(9):2347-53.
Mudaliar S, Henry RR, Sanyal AJ, et al (2013) Efficacy and safety of the farnesoid X receptor 
agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. 
Gastroenterology; 145(3):574-82.e1.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al (2015) Farnesoid X nuclear receptor 
ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet; 385(9972):956-65.
National Institute for Health and Care Excellence (2016) Non-alcoholic fatty liver disease 
(NAFLD): assessment and management. London, UK.
Nobili V, Parkes J, Bottazzo G, et al (2009) Performance of ELF serum markers in predicting 
fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology;136(1):160-7.
Pattni SS, Brydon WG, Dew T, et al (2012) Fibroblast Growth Factor 19 and 7α-Hydroxy-4-
Cholesten-3-one in the Diagnosis of Patients With Possible Bile Acid Diarrhea. Clin Transl 
Gastroenterol; 3(7): e18.
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Petäjä EM, Yki-Järvinen H (2016) Definitions of Normal Liver Fat and the Association of 
Insulin Sensitivity with Acquired and Genetic NAFLD-A Systematic Review. Int J Mol Sci;
17(5):633.
Sanyal A, Charles ED, Neuschwander-Tetri B, et al (2017) BMS-986036 (pegylated FGF21) 
in patients with non-alcoholic steatohepatitis: a phase 2 study. J Hepatol Suppl;
66(1):S89-S90.
Schaap FG, Trauner M, Jansen PL (2014) Bile acid receptors as targets for drug development. 
Nat Rev Gastroenterol Hepatol; 11(1):55-67.
Vilar-Gomez E, Chalasani N (2018). Non-invasive assessment of non-alcoholic fatty liver 
disease: Clinical prediction rules and blood-based biomarkers. J Hepatol; 68(2):305-15.
Walters JR, Johnston IM, Nolan JD, et al (2015) The response of patients with bile acid 
diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharmacol Ther;
41(1):54-64.
Zezos P, Renner EL (2014) Liver transplantation and non-alcoholic fatty liver disease. World 
J Gastroenterol; 20(42):15532-8.
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16
Appendices
16.1
Appendix 1: Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a process for identification, monitoring and evaluation of liver events 
has to be followed. For this study in participants likely to have altered liver function at baseline, 
an adapted monitoring process will be followed.
Participants who develop elevations in liver-related laboratory parameters and/or clinical signs 
and symptoms suggestive of liver disease, such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (< 5%), should be managed 
according to Table 16-1.

If ALP, ALT, AST, or bilirubin elevations reach the specified thresholds listed below and
outlined in Table 16-1, the participant must be re-evaluated within 48-72 hours after the
laboratory results becoming available, at which time confirmatory laboratory testing will
be performed. This includes ALP, ALT, AST, total and direct bilirubin and INR.

At the same time repeat clinical laboratory samples are drawn, an ad-hoc PK sample
should be taken. The date and time of the PK draw and the last study medication
administration over at least the preceding 2 days shall be recorded in the eCRF.

If prompt evaluation is not possible within 48-72 hours following receipt of abnormal
laboratory results, study drug should be interrupted immediately (date of last study drug
dose must be recorded in the eCRF) and the participant must be re-evaluated as soon as
possible.

The sponsor should be notified of laboratory abnormalities and any clinical symptoms
within 48 hours of available laboratory results and/or assessment of clinical symptoms.
Liver chemistry repeats should be performed using the central laboratory, with the results 
provided via the standard electronic transfer. If results will not be available from the central 
laboratory within 24 hours, then the repeats can also be performed at a local laboratory to 
monitor the safety of the participant. Should this occur, a sample should also be sent to the 
central laboratory for analysis. Any local liver chemistry tests previously conducted that are 
associated with this event should have results maintained in source documents. The result from 
the central laboratory will be provided via the standard electronic transfer. 


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If the elevation is confirmed, close observation of the participant will be initiated, including 
consideration of treatment interruption or discontinuation (as described in Table 16-1) if 
deemed appropriate, close monitoring, causality and clinical evaluation should be performed as 
below:

Repeating the liver tests to confirm elevation as described in Table 16-1.

Discontinuation of the investigational drug, if appropriate. Note that discontinuation is
mandatory in the case of decompensated cirrhosis as defined by ascites, bleeding
esophageal varices, hepatic encephalopathy, jaundice or any other liver decompensation
related symptom.

Hospitalization of the participant, if appropriate.

An investigation of the liver event which needs to be followed until resolution, such as by:

Obtaining a more detailed history of symptoms and prior or concomitant diseases.

Obtaining a history of concomitant drug use (including nonprescription or over-the-
counter medications and herbal and dietary supplement preparations), alcohol use,
recreational drug use, and special diets.

Excluding acute viral hepatitis Types A, B, C, D, and alcoholic hepatitis;
hypoxic/ischemic hepatopathy; autoimmune hepatitis and biliary tract disease.

Imaging such as abdominal US, CT or MRI, as appropriate.

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.

Conducting pathology and serology tests, and/or liver biopsy, based on investigator’s
discretion.
Participants who permanently discontinue study drug due to potential liver toxicity must be 
followed for close monitoring until abnormalities stabilize to baseline levels or baseline grade 
of abnormality and the participant is asymptomatic.
All follow-up information, and the procedures performed must be recorded on the appropriate 
CRFs, including SAE forms when appropriate.
The baseline value will be calculated as the mean of the last two assessments before first 
administration of the study drug.


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Table 16-1
Management of Participants with Confirmed ALP, ALT, AST, or Bilirubin Elevations With or Without Liver Related 
Clinical Symptoms
Baseline
Treatment-Emergent (Confirmeda)
Liver-Related Clinical 
Symptomsb
Action taken
Monitoringc
Study Drug
ALT and/or AST
Baseline ALT and/or AST < 2
× ULN
ALT and/or AST 
> 3 × ULN but ≤5 × baseline
None
Laboratory monitoring and causality evaluation Continue dosing
Present
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALT and/or AST
> 3 × ULN but ≤5 × ULN AND
total bilirubin > 2 × ULN 
(in Gilbert’s syndrome, see footnotef)
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALT and/or AST 
> 3 × ULN and > 5 × baseline
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Permanently 
discontinue
Baseline ALT and/or AST ≥2
× ULN
ALT and/or AST 
> 2 × baseline but ≤3 × baseline
None
Laboratory monitoring and causality evaluation Continue dosing
Present
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALT and/or AST 
> 2 × baseline but ≤3 × baseline 
AND
total bilirubin > 2 × ULNf 
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALT and/or AST
> 3 × baseline 
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Permanently 
discontinue
Baseline normal or elevated 
ALT and/or AST values
ALT and/or AST
> 3 × ULN and > 2 × baseline AND 
either
total bilirubin > 2 × baseline OR
INR increase by >0.3 to a value >1.5
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALP


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Baseline
Treatment-Emergent (Confirmeda)
Liver-Related Clinical 
Symptomsb
Action taken
Monitoringc
Study Drug
Baseline ALP ≤ ULN
ALP > 1.5 × ULN
(not due to known bone pathology)
None
Laboratory monitoring and causality 
evaluationc
Continue dosing
Present
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALP > 1.5 × ULN 
(not due to known bone pathology) 
AND
total bilirubin > 2 × ULNf
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
Baseline ALP > ULN
ALP > 2 × baseline 
(not due to known bone pathology)
None
Laboratory monitoring and causality 
evaluationc
Continue dosing
Present
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALP > 2 × baseline 
(not due to known bone pathology) 
AND
total bilirubin > 2 × ULNf
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge


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Baseline
Treatment-Emergent (Confirmeda)
Liver-Related Clinical 
Symptomsb
Action taken
Monitoringc
Study Drug
Total or Direct Bilirubin
Baseline total bilirubin ≤ ULN
Total bilirubin > 2 × ULNf
With or without liver-
related clinical symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
Baseline total bilirubin > ULN
Total bilirubin > 1.5 × baselinef
With or without liver-
related clinical symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
Baseline normal or elevated
direct bilirubin
Direct bilirubin > 1.5 mg/dL
With or without liver-
related clinical symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, and PK sampling
Interrupt dosinge
ALT, AST, ALP and Total Bilirubin
Baseline normal or elevated 
values
Normal or elevated values
Present
Laboratory monitoring and causality 
evaluationc
Continue or 
Interrupt dosing 
as appropriateg


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ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eCRF = electronic case report form; INR = international normalized ratio; PK = pharmacokinetics; 
ULN = upper limit of normal
a  The required confirmatory measurement should be obtained within 48-72 hours after the 
laboratory results become available. If prompt evaluation is not possible, study drug should be 
interrupted immediately (date of last study drug dose must be recorded in the eCRF).
b  Combination of clinical signs and symptoms of right upper quadrant pain or tenderness, worsening 
or new fatigue, anorexia, nausea, rash, vomiting, diarrhea, fever, pruritus, and/or eosinophilia (> 
5%).
c  Frequent hepatic laboratory testing and clinical assessments, including a thorough causality 
evaluation, should be performed every other week at minimum, in consultation with the sponsor, until 
resolution of clinical symptoms and/or stabilization of liver biochemistries to baseline levels or 
baseline grade of abnormality. 
d  The sponsor should be notified of laboratory abnormalities and any clinical symptoms, and 
participants should be closely monitored until resolution of clinical symptoms/stabilization of liver 
biochemistries to baseline levels or baseline grade of abnormality.
e  Study drug must be interrupted (date of last study drug dose must be recorded in the eCRF). 
The sponsor should be notified of laboratory abnormalities and any clinical symptoms, and 
participants should be closely monitored until resolution of clinical symptoms/stabilization of liver 
biochemistries to baseline levels or baseline grade of abnormality. In participants with elevations in 
liver biochemistry but who do not meet permanent drug discontinuation criteria, study drug may be 
resumed if it is determined that complete resolution to normal or clinically comparable to baseline 
levels or baseline grade of abnormality (baseline value will be calculated as the mean of the last two
assessments before first administration of the study drug) has occurred and it is not considered that 
the deterioration in liver function was related to study drug. This must be documented based on 
biochemical parameters and clinical symptoms, per the discretion of the investigator and in 
consultation with the sponsor. Restarting study drug is only permitted following an interruption of less 
than 10 days. The investigator should consider restarting study drug treatment at a reduced dose if 
possible. If significant liver abnormalities recur at any time after restarting study drug, then study 
drug must be permanently discontinued.
f In participants with emerging evidence of Gilbert’s syndrome, in place of the total bilirubin criterion, 
use direct bilirubin > 2 × baseline.
g Development of liver-related clinical symptoms in absence of biochemical abnormalities is an 
indication for prompt biochemical and physical evaluation to decide whether continued dosing is 
appropriate. If prompt evaluation is not possible, study drug should be interrupted and participant
followed for laboratory monitoring and causality evaluation.


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16.2
Appendix 2: Renal safety monitoring
Recommended actions and follow-up assessments regarding renal function data are shown in 
Table 16-2. If evaluation of a renal event reveals a reversible etiology not related to study drug, 
the study drug may be restarted as long as the period of interruption is less than 10 days. 
Note that the day to day variability of a particular participant’s serum creatinine is reflected in 
the different values measured at screening versus baseline. Because of this, the investigator 
should use the higher of these two values as the reference against which to compare on-
treatment serum creatinines.
Table 16-2
Specific renal alert criteria and actions
Renal Event
Actions
Serum creatinine increase 25 –
49% compared to screening or 
baseline (whichever is higher)
Confirm 25% increase after 2-5 days. If creatinine does not 
increase to ≥ 50% compared to screening or baseline, revert 
to original scheduled sampling schedule.
Collect urinalysis.
Follow up within 2-5 days thereafter.
Serum creatinine increase ≥50 % 
compared to screening or baseline
(whichever is higher)
Confirm > 50 % within 2-5 days after receipt of the abnormal 
value.
If confirmation of abnormal value is not possible in this 
timeframe, study drug must be withheld until further 
evaluation is possible.
Collect urinalysis.
Consider drug interruption.
Assess participant for other causes of increased serum 
creatinine including: starting an ACEI or ARB, starting a 
nonsteroidal anti-inflammatory, new onset hypovolemia and 
new onset low blood pressure.
Consider participant hospitalization / specialized treatment.
New onset dipstick proteinuria, 
typically +3 or +4, with a protein-
creatinine ratio (PCR) ≥ 1g/g or 
≥90 mg/mmol
Confirm value after 2-5 days.
Collect urinalysis.
Assess participant for other causes of increased urine protein 
including: urinary tract infection, diabetes, strenuous 
exercise.
Consider drug interruption / discontinuation.


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17
Cohort-specific information
This section contains details that pertain to specific cohorts and treatment arms and should be 
considered as supplementary to information presented in the preceding core protocol sections
and respective Investigator’s Brochures. If there are no cohort- or treatment-specific details 
presented for a given topic (e.g., cohort- or treatment-specific eligibility criteria, study 
restrictions, dose adjustment rules), then the information in the corresponding section in the 
core protocol for that topic should be implemented without further adjustment.
17.1
Cohort 1
Cohort 1 will evaluate the use of LYS006 alone and tropifexor (LJN452) in combination with 
LYS006 for the treatment of elevated liver fat, liver inflammation and liver fibrosis in NAFLD 
participants who manifest a NASH-like biomarker phenotype. The drug combination of 
LYS006 and tropifexor (LJN452) may provide clinical benefit beyond that of either drug alone, 
considering different, complementary mechanisms of action of these drugs. 
Approximately 50 participants will be randomized in a 1:1 ratio to one of the following treatment 
arms:

Arm 1: LYS006

Arm 2: Tropifexor (LJN452)
+ LYS006
17.1.1
Cohort 1, Arm 1: LYS006 
17.1.1.1 Introduction
This treatment arm will evaluate LYS006 alone.
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17.1.1.3 Rationale for the single treatment
The LYS006 
single treatment arm will allow assessment of LYS006 safety, 
tolerability and efficacy and comparison of data to LYS006 combination in order to determine 
whether the single agent effects are additive, synergistic or antagonistic.
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17.1.1.6 Drug-drug interaction
Not applicable for this treatment arm. 
17.1.1.7 Specific restrictions for study participants
17.1.1.7.1
Prohibited medications
Use of the treatments displayed in Table 17-3 is NOT allowed for this treatment arm for the 
duration of the prohibited period defined below. 
Table 17-3
Prohibited medications
Medication
Prohibited period start
Prohibited period end
OAT3 inhibitors
Within 5 half-lives or 7 days of 
randomization, whichever is 
longer
End-of-study visit
17.1.1.7.2
Dietary restrictions
There are no specific dietary restrictions.
17.1.1.7.3
Other restrictions
Not applicable.
17.1.1.8 Specific safety stopping rules
Not applicable.
17.1.1.10 Specific study design considerations
As this treatment does not have an extended half-life, the EOS1 visit will serve as the end-of-
study visit for participants randomized to this treatment arm.
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17.1.2
Cohort 1, Arm 2: LYS006 and tropifexor
17.1.2.1 Introduction
This treatment arm will evaluate a free combination of LYS006 and tropifexor.
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17.1.2.2.2
Tropifexor
Tropifexor, also known as LJN452, is a highly potent, specific and orally available non-bile 
acid agonist of the bile acid receptor FXR and is currently being evaluated in early phase healthy 
subject and patient studies.
17.1.2.2.3
Background on FXR receptor
The bile acid receptor, farnesoid X receptor (FXR), is a nuclear receptor expressed in liver, 
intestine and kidney. FXR acts as a sensor of elevated bile acids and initiates homeostatic 
responses to control bile acid levels and modulate other metabolic processes such as 
gluconeogenesis and lipogenesis (Pattni et al 2012, Walters et al 2015). FXR agonism 
modulates bile acid synthesis and detoxifying metabolism. In the setting of NASH, as shown in 
Figure 17-2 below, FXR agonism in both the liver and the gut has the potential to provide 
multimodal benefits which, in brief, include: reduction of fat accumulation in liver via 
decreased de novo lipogenesis, reduction of hepatic inflammation, anti-fibrotic effects mediated 
by stellate cells via decreased oxidative stress, and reduction of bacterial and lipopolysaccharide 
translocation from gut which induces inflammation (Schaap et al 2014).
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Figure 17-2
Potential efficacy of FXR agonism in NASH
Adapted from Schaap et al 2014.
Clinical validation of a FXR agonist for the treatment of NASH has been shown in clinical trials 
with obeticholic acid (OCA), a semi-synthetic variant of the natural bile acid chenodeoxycholic 
acid. In a small study in 20 patients with NAFLD and type 2 diabetes mellitus in which OCA 
was given for 6 weeks, OCA 25 mg improved insulin sensitivity and reduced circulating alanine 
aminotransferase (ALT) concentrations (Mudaliar et al 2013). In a larger trial (n=219), it was 
shown that 45% of NASH patients receiving 25 mg OCA QD for 72 weeks had improved liver 
histology compared to 23% of NASH patients receiving placebo in the same period 
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17.1.2.2.5
Tropifexor clinical data
Tropifexor human safety and tolerability
Currently participants are receiving monotherapy tropifexor in ongoing studies CLJN452X2201 
(Primary Biliary Cholangitis [PBC]), CLJN452X2202 (primary Bile Acid Diarrhea [pBAD]) 
and CLJN452A2202 (non-alcoholic steatohepatitis [NASH]). Patients are also receiving 
tropifexor in combination with cenicriviroc in study CLJC242A2201J (NASH) at multiple sites 
across the world. 
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In summary, in clinical studies tropifexor has been well tolerated to date, with doses currently 
being tested up to 200 μg orally in the ongoing phase 2 NASH program.
Please see the tropifexor Investigator’s Brochure for more information on other potential or 
hypothetical safety risks.
Tropifexor human efficacy in NASH
Preliminary data from the ongoing Novartis CLJN452A2202 study in patients with NASH 
provides evidence that tropifexor 90 µg daily for 12 weeks improved liver fat and ALT versus 
placebo. 140 µg and 200 µg daily doses of tropifexor are under evaluation in this study at the 
present time.
17.1.2.2.6
Tropifexor dose rationale
The current non-clinical safety profile of tropifexor (tropifexor IB), the DMC’s 
recommendation based on first NASH clinical data and pharmacokinetic data, and clinical data 
in NASH patients to date from study CLJN452A2202, support evaluation of a tropifexor
 in this study as outlined below. 
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17.1.2.7 Specific restrictions for study participants
17.1.2.7.1
Prohibited medications
Use of the treatments displayed in Table 17-7 is NOT allowed for this treatment arm for the 
duration of the prohibited period defined below:
Table 17-7
Prohibited medications
Medication
Prohibited period start
Prohibited period end
OAT3 inhibitors
Within 5 half-lives or 7 days of 
randomization, whichever is 
longer
End-of-study visit
17.1.2.7.2
Dietary restrictions
There are no specific dietary restrictions. 
17.1.2.7.3
Other restrictions
Not applicable.
17.1.2.8 Specific safety stopping rules
Not applicable.
17.1.2.10Specific study design considerations
As these treatments do not have extended half-lives, the EOS1 visit will serve as the end-of-
study visit for participants randomized to this treatment arm.
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SAP_001.pdf: 
(') NOVARTIS
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research 
PLATFORM 
CADPT02A12001 / NCT04147195 
NASH EXploratory Single and combination Treatment 
(NEXSCOT): An open label, multicenter, platform study to 
evaluate the safety, tolerability, pharmacokinetics and 
efficacy of various single and combination treatments in 
patients with non-alcoholic fatty liver disease (NAFLD) who 
manifest a non-alcoholic steatohepatitis (NASH)-like 
biomarker phenotype 
Statistical Analysis Plan (SAP) 
Author(s): 
Document type: 
SAP Documentation - NIBR 
Document status: 
Amendment 1 Final 
Release date: 
09-Feb-2022
Number of pages: 
27 
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For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
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Table of contents
Table of contents .................................................................................................................5
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Scope of document ..................................................................................................7
1.2
Study reference documentation ...............................................................................7
1.3
Study objectives and related endpoints....................................................................7
1.3.1
Primary objective(s) and related endpoints.............................................7
1.3.2
Secondary objective(s) and related endpoints.........................................7
1.4
Study design and treatment......................................................................................8
2
First interpretable results (FIR) ...........................................................................................9
3
Interim analyses...................................................................................................................9
4
Statistical methods: Analysis sets......................................................................................10
4.1
Cohort-specific information: .................................................................................11
4.1.1
Cohort 1:................................................................................................11
4.1.2
Protocol deviation codes .......................................................................11
5
Statistical methods for Pharmacokinetic (PK) parameters................................................13
5.1
Variables................................................................................................................13
5.2
Descriptive analyses ..............................................................................................13
5.2.1
Graphical presentation ..........................................................................14
5.3
Statistical model, assumptions and hypotheses .....................................................14
6
Statistical methods for Efficacy/Pharmacodynamic (PD) parameters ..............................15
6.1
Primary efficacy objectives ...................................................................................16
6.2
Secondary efficacy objectives ...............................................................................16
6.2.1
Variables ...............................................................................................17
6.2.2
Descriptive analyses..............................................................................18
6.2.3
Statistical model, assumptions and hypotheses.....................................18
7
PK/PD relationships ..........................................................................................................22
8
Statistical methods for safety and tolerability data............................................................22
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8.1
Variables................................................................................................................23
8.2
Descriptive analyses ..............................................................................................23
8.2.1
Graphical presentation ..........................................................................24
8.3
Statistical model, assumptions and hypotheses .....................................................24
10 Derivations ........................................................................................................................26
10.1.1
HOMA-IR .............................................................................................26
11 SAP deviations from protocol ...........................................................................................27
12 Reference list.....................................................................................................................27
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................11
List of figures
Figure 1-1 
Study design............................................................................................9
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1
Introduction 
1.1
Scope of document
The Reporting Analysis Plan (RAP) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CADPT02A12001”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
Tables, Figures, Listings (TFL) detail the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR outputs.
1.2
Study reference documentation
Final study protocol, version v04, 02 Jun 2021 and final SOM, version v02, 17 Aug 2021 are
available at the time of finalization of Statistical Analysis Plan.
1.3
Study objectives and related endpoints
1.3.1
Primary objective(s) and related endpoints
Primary objective
Endpoints related to primary objective
To determine the safety and tolerability of
single or combination therapy during 12 weeks
of treatment.
Safety endpoints (including vital signs,
physical
examination, 
laboratory
measurements, ECG); Adverse events.
1.3.2
Secondary objective(s) and related endpoints
Secondary objective(s)
Endpoints related to secondary objectives
To determine the effect of single or 
combination therapy on circulating markers 
of ongoing liver fibrosis
Enhanced Liver Fibrosis (ELF) Test
To determine the effect of single or 
combination therapy on intrahepatic lipid 
content
Percent (%) liver fat as measured by 
Magnetic 
Resonance 
Imaging-Proton 
Density Fat Fraction (MRI-PDFF)
To determine the effect of single or 
combination therapy on cardiometabolic risk 
parameters
Body weight, waist and hip circumference,
waist-to-hip 
ratio,
Homeostasis 
Model 
Assessment of Insulin Resistance (HOMA-
IR), hemoglobin A1c (HbA1c), fasting 
glucose, fasting insulin, fasting lipid profile
To determine the effect of single or 
combination therapy on circulating markers 
of liver and/or systemic inflammation
Liver function test (ALT), high-sensitivity C 
reactive Protein (hsCRP)


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To evaluate the pharmacokinetics (PK) of 
each individual agent when administered as a 
single or combination therapy.
Plasma concentrations
1.4
Study design and treatment
This is a non-confirmatory, multicenter, open label, platform study in NAFLD patients with a
NASH-like biomarker phenotype to examine the effects of single and combination therapies 
over 12 weeks of treatment.
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There is a maximum of five cohorts planned. Each cohort will consist of a 33-day screening 
period (Day -60 to Day -28), a baseline period of 27 days (Day -27 to Day -1), a treatment 
period of 12 weeks (Day 1 to Day 85), and a study completion evaluation (End of Study [EOS] 
1) approximately 28 days after the last drug administration (Day 113).
 Participants will be advised to maintain their recommended diet for NAFLD 
during the study. The study design scheme is shown below in Figure 1-1:
Figure 1-1
Study design
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial at each IA and at the end of study 
(CSR).
The study FIR template (mock slides) can be found in CREDI in the study RAP folder.
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list.
3
Interim analyses 
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4
Statistical methods: Analysis sets
The safety analysis set will include all participants that received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e., not 
flagged for exclusion) PK concentration measurement, who received any study drug and with 
no protocol deviations that impact on PK data.
The efficacy/PD analysis set will include all participants with available efficacy/PD data and 
no protocol deviations with relevant impact on efficacy/PD data.
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
Throughout this document, ‘treatment’ refers to the treatment arm of a cohort that each 
participant is assigned to.
For treatments with an extended half-life, EOS1 will be required as a standard, non-EOS post-
treatment follow up visit, and EOS2 will serve as the EOS visit. For all other treatments, EOS1 
will serve as the EOS visit. If a participant discontinues study treatment early, the participant
should be scheduled for a subsequent visit at which time all assessments at the EOS1 visit 
should be performed. For treatments with an extended half-life, if a participant discontinues 
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early after EOS1, then the participant should be scheduled for a subsequent visit at which time 
all assessments at the EOS2 visit should be performed.
The Day 113 (EOS1) visit for treatments with no extended half-lives and the Day 141 (EOS2) 
visit for treatments with extended half-lives will be pooled and reported/analyzed together 
under a common EOS visit, labeled as ‘EOS’, in the reporting/analysis. The Day 113 (EOS1) 
visit for treatments with extended half-lives will be reported/analyzed as a distinct visit, labeled 
as ‘Day 113’, in the reporting/analysis.
For the End of Study (EOS) visit, only data from study completers will be included in the 
efficacy summary/analysis tables/figures.  Safety summary/analysis tables/figures will include
data from all participants, i.e., both study completers and non-study completers for the End of 
Study (EOS) visit.
4.1
Cohort-specific information:
4.1.1
Cohort 1:
Cohort 1 will evaluate the use of LYS006 alone and tropifexor (LJN452) in combination with 
LYS006 for the treatment of elevated liver fat, liver inflammation and liver fibrosis in NAFLD
participants who manifest a NASH-like biomarker phenotype. The drug combination of 
LYS006 and tropifexor (LJN452) may provide clinical benefit beyond that of either drug alone, 
considering different, complementary mechanisms of action of these drugs. 
Approximately 50 participants will be randomized in a 1:1 ratio to one of the following 
treatment arms:

Treatment arm 1: LYS006

Treatment arm 2: Tropifexor (LJN452)
 + 
LYS006 
The treatments used in cohort 1 (i.e. LYS006 and Tropifexor) do not have extended half-lives, 
so the EOS1 visit will serve as the end-of-study visit for participants randomized to any of the 
two treatment arms of cohort 1 (i.e. for all cohort 1 participants).
4.1.2
Protocol deviation codes
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of 
deviation
Data exclusion
Participants are excluded from safety
analysis in case of these PDs: 
Exclude participant from safety analysis set 
INCL01
Written informed consent 
must be obtained prior to 
screen procedures 
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Category
Deviation code
Text description of 
deviation
Data exclusion
Participants are excluded from PK analysis in 
case of these PDs:
Exclude participant from PK analysis set
INCL01
Written informed consent 
must be obtained prior to 
screen procedures
OTH13
Additional data collected is 
not as per effective ICF/ 
Protocol requirement
Exclude only the PK data that 
the protocol deviation relates to 
from the visit the protocol deviation 
occurred on
Participants are excluded from efficacy/PD 
analysis in case of these PDs:
Exclude participant from efficacy/PD analysis
set
INCL01
Written informed consent 
must be obtained prior to 
screen procedures
OTH12
Follow up end of study 
MRI was not completed 
within 7 days of treatment 
discontinuation
Exclude participant from imaging 
data analyses from the visit the
protocol deviation occurred on (for
imaging data, visit can be either
Day 85 or EOS)
OTH13
Additional data collected is 
not as per effective ICF/ 
Protocol requirement
Exclude only the efficacy/PD data that 
the protocol deviation relates to 
from the visit the protocol deviation
occurred on
COMD01
Following randomization 
initiation of new 
antidiabetic, insulin, 
betablockers, thiazide 
diuretics, fibrates, statins, 
niacin, ezetimibe, thyroid 
hormone, psychotropic, 
estrogen, birth control
Exclude participant from all
efficacy/PD analyses from the
protocol deviation’s study day
(i.e., prohibited medication’s start
day) onwards


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Category
Deviation code
Text description of 
deviation
Data exclusion
TRT03
Treatment modification 
guidelines per protocol not 
followed
Exclude participant from all
efficacy/PD analyses from the
protocol deviation’s study day
onwards – PD is exclusionary
only under specific criteria*
*TRT03 PD is exclusionary if dose interruption is > 2 days and/or decreased dose is continued for > 2
weeks.
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All participants within the PK analysis set will be included in the PK data analysis.
For participants with protocol deviations affecting the PK analyses, the data will be excluded 
as described in Table 4-1 above.
The evaluation of the pharmacokinetics (PK) of each individual agent when administered as a 
single or combination therapy is one of the secondary objectives of this study.
5.1
Variables 
PK samples will be collected in all participants at the visits defined in the Assessment schedule 
(see protocol section Table 8-1). 
Each study drug will be determined by a validated LC-MS/MS method; the anticipated Lower 
Limit of Quantification (LLOQ) and method specifics will be listed in the central laboratory 
manual.
Concentrations will be expressed in mass per volume units and will refer to the free base.
PK parameters will be determined using the actual recorded sampling times and 
noncompartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher). Cmax, Tmax, 
AUC0-t and other parameters as appropriate will be estimated and reported from the plasma 
concentration-time data if feasible.
5.2
Descriptive analyses
Plasma concentration data will be listed by cohort, treatment, participant, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point.
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Summary statistics per analyte, per time point will be reported. Summary statistics will include 
sample size (n), mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, 
minimum, maximum
 The geometric mean and its CV will not be reported if the data includes 
zero values.
The concentration data may be integrated with data from other studies for population PK 
analysis in the future and will be reported separately.
Pharmacokinetic parameters will be listed by cohort, treatment
and participant.
Pharmacokinetic parameters will be summarized by treatment and visit. Summary statistics will 
include sample size (n), mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum. An exception to this is Tmax where sample size (n), median, 
minimum and maximum will be presented. A geometric mean will not be reported if the data
set includes zero values.
5.2.1
Graphical presentation 
Arithmetic mean (SD) plasma concentration by time will be plotted on linear-linear scale (all 
treatments in the same graph).
Overlaying individual plasma concentration by time profile, by treatment will be plotted (one 
graph per treatment, all participants in the same graph) on linear-linear scale.
Individual plasma concentration by time profile, by participant will be plotted on linear-linear 
scale (one graph per treatment and participant).
5.3
Statistical model, assumptions and hypotheses
An unstructured variance-
covariance structure will be used. If the unstructured covariance causes model convergence 
issues, then other simpler covariance structures will be considered in the following sequence: 
TOEP, AR(1) and CS. The least squares mean differences between treatments and the 
associated 2-sided 90% confidence intervals in the logarithmic scale will be obtained at each 
visit and will then be back-transformed to the original scale to produce the geometric mean ratio 
(GMR) between treatments and associated 90% CIs at each visit and for each PK parameter. 
The associated p-value will also be obtained at each visit and for each PK parameter.
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6
Statistical methods for Efficacy/Pharmacodynamic (PD) 
parameters
All participants within the efficacy/PD analysis set will be included in the efficacy/PD data 
analysis.
Data will be excluded from the efficacy/PD analyses in the following cases:

For participants with protocol deviations affecting the efficacy/PD analyses, the data
will be excluded as described in Table 4-1 above.

For participants that discontinued treatment early, the following programming rule will
be applied: Any efficacy assessments that occurred on or after the treatment
discontinuation study day, will be excluded from all efficacy/PD data analyses. An
exception to this is the Day 85 visit or EOS visit imaging data (MRI and MRE
assessments), that will be excluded only if they occurred prior to study day 56 (i.e.,
imaging assessments that occurred on or after study day 56, will not be excluded from
the imaging analyses).

Participants with <80% treatment compliance
Treatment compliance calculation
For each subject, the treatment compliance (%) will be calculated using the following formula:
100 ∗	
  	     	  ℎ  
  – 	
  	 
 	 ℎ 
 
	
  	     	  ℎ  
 

where,
Number of capsules expected to be taken up to the last treatment day =
last treatment day * 
, if treated with LYS006
          OR
last treatment day * 
, if treated with LJN452
Number of capsules missed during the treatment period =
Sum (Number of capsules expected to be taken in the dosing modification period x - Number 
of capsules actually taken in the dosing modification period x)
Notes:

The treatment compliance will be calculated separately for each treatment (LYS006
and LJN452).

The last treatment day is defined as the last available start or end treatment day, as
reflected in the dosing dataset.
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
A dose modification period is a period with either a dose change or a dose
interruption. These periods will be identified in the dosing dataset under records with
TYPE OF CHANGE=’DOSE CHANGED’ and TYPE OF CHANGE=’DOSE
INTERRUPTED’, respectively.

For the dose modification periods:
o
Only the dosing records with non-missing dose administered, non-missing start
date and non-missing end date will be considered in the calculations.
o
Dose administered = Number of capsules administered
o
The number of capsules expected to be taken in a dosing modification period =
(period end day – period start day +1) * 
, if treated with LYS006
OR
(period end day – period start day +1) * 
, if treated with LJN452
o
The number of capsules actually taken in a dosing modification period =
(period end day – period start day +1) * dose administered
o
The frequency of dose administered will not be considered in the calculations, only
the dose administered itself.
6.1
Primary efficacy objectives
There are no primary efficacy objectives for this study.
The primary objective of this study is related to the safety and tolerability of single or 
combination therapy during 12 weeks of treatment and is described in Section 8.
6.2
Secondary efficacy objectives
The secondary efficacy objectives are:
1. To determine the effect of single or combination therapy on circulating markers of
ongoing liver fibrosis
2. To determine the effect of single or combination therapy on intrahepatic lipid content
3. To determine the effect of single or combination therapy on cardiometabolic risk
parameters
4. To determine the effect of single or combination therapy on circulating markers of liver
and/or systemic inflammation.
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6.2.1
Variables
The secondary efficacy variables/endpoints related to the secondary efficacy objectives are:
1. Markers of liver fibrosis:
o
Enhanced Liver Fibrosis Test (ELF Test™):

Hyaluronic acid (HA)

Tissue inhibitor of metalloproteinases (TIMP-1)

Amino-terminal pro-peptide of procollagen type III (PIIINP)
2. Magnetic Resonance Imaging (MRI):
o
Percent (%) liver fat as measured by Magnetic Resonance Imaging-Proton
Density Fat Fraction (MRI-PDFF)
3. Cardiometabolic risk parameters:
o
Body weight
o
Waist circumference
o
Hip circumference
o
Waist to hip ratio
o
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
o
Hemoglobin A1c (HbA1c)
o
Fasting glucose
o
Fasting insulin
o
Fasting lipid profile:

Total cholesterol

HDL-cholesterol

LDL-cholesterol

Triglycerides

Lipoprotein A
4. Liver function tests and liver and/or systemic inflammation markers:
o
Alanine aminotransferase (ALT)
o
High-sensitivity C-reactive Protein (hsCRP)
Baseline definition:
Baseline for ALT is defined as the mean of the last 2 non-missing measurements taken prior to 
the first dose of study drug administered at the Day 1 visit.
For all other secondary efficacy endpoints, baseline is defined as the last non-missing 
measurement prior to the first dose of study drug administered at the Day 1 visit.


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All assessments (scheduled and unscheduled) will be considered into the derivation of the 
baseline.
6.2.2
Descriptive analyses
The raw measurements, the change from baseline measurements and the percentage change 
from baseline measurements of the above secondary efficacy endpoints will be listed by cohort, 
treatment, participant and visit/time.
Descriptive statistics will be provided for the raw measurements, the change from baseline 
measurements and the percentage change from baseline measurements of the above secondary 
efficacy endpoints by treatment and visit/time and will include sample size (n), mean (arithmetic
and geometric), SD, CV (arithmetic and geometric), median, minimum, maximum 
The geometric mean and its 
CV will not be reported if the data includes non-positive values. For the change from baseline 
data summary, the geometric mean and its CV will be based on log-transformed ratio to baseline 
(i.e., change from baseline in the log scale).
In addition, the proportion of participants with at least 30% relative reduction and 5% absolute 
reduction in % liver fat (i.e. percentage change from baseline <= -30% and change from baseline 
<= -5% respectively) will be tabulated separately by treatment.
6.2.2.1
Graphical presentation
Arithmetic mean (+/- SE) of the raw measurements, the change from baseline measurements 
and the percentage change from baseline measurements of the above secondary efficacy 
endpoints will be plotted over time and by treatment (all treatments in the same graph). In 
addition, geometric mean (+/- 80% CI) of the raw measurements and the ratio to baseline 
measurements of the above secondary efficacy endpoints will be plotted over time and by 
treatment (all treatments in the same graph).
Overlaying individual (spaghetti) plots of the raw measurements, the change from baseline 
measurements and the percentage change from baseline measurements of the above secondary 
efficacy endpoints will be provided over time and by treatment (one graph per treatment, all 
participants of each treatment in the same graph).
6.2.3
Statistical model, assumptions and hypotheses
A mixed-effect model for repeated measures (MMRM) analysis will be conducted for log-
transformed ratio to baseline in ELF Test and ALT. 
 An 
unstructured variance-covariance matrix will be used to account for correlation among multiple 
measurements from the same participant and variance heterogeneity. If the unstructured 
covariance causes model convergence issues, then other simpler covariance structures will be 
considered. Least squares mean, the associated 2-sided 80% confidence interval and the p-value 
will be obtained for each treatment at each visit and back transformed to the original scale, 
meaning that the least squares means will be expressed as geometric means after the back-
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transformation on the original scale. Contrasts assessing trend over time will be constructed for 
each treatment using various functional forms as needed. Both cohort-wise and combined 
cohort analysis will be performed as appropriate.
Log-transformed ratio to baseline in % liver fat, hsCRP, HOMA-IR, HbA1c, fasting glucose, 
fasting insulin and fasting lipid profile as well as change from baseline in ELF Test, ALT and % 
liver fat, waist circumference, hip circumference, waist to hip ratio and percentage change from 
baseline in body weight will also be analyzed. Parameters with more than one post-treatment 
measurement will be subjected to the same MMRM analysis described above for ELF Test and 
ALT using untransformed baseline in lieu of log-transformed baseline as a covariate for the 
untransformed data analysis. 
Additionally, a multivariate ANCOVA will be done for the three-dimensional endpoint: log-
transformed ratio to baseline in ELF Test, ALT and % liver fat at Week 12. The model will
include treatment and stratification factor (race and BMI group at baseline) as classification 
factors and log-transformed baseline as a covariate. An arbitrary 3 by 3 covariance matrix will 
be assumed for the three-dimensional endpoint.
If there are sufficient data, then a subgroup analysis (ANCOVA) in participants with baseline 
liver fat >=10% will be performed to compare % liver fat between treatments.
 Baseline participant characteristics
will be monitored closely and compared across cohorts to assess population drift which may
occur because of improved general care and enrollment of either less or more healthy 
participants over time. The population drift, if present, will be accounted for using a modeling 
approach as appropriate.
6.2.3.1
Handling of missing data
Missing data will not be imputed for the univariate MMRM analysis. Assuming data is missing 
at random, a participant with missing value at a visit will still contribute to the estimation of the 
treatment effect at that particular visit as the likelihood-based MMRM borrows information 
from non-missing values of this participant and other participants.
For the Week 12 multivariate ANCOVA, an additional analysis with the last post-treatment 
observation carried forward for missing ELF Test and ALT values may be performed.
6.2.3.2
Graphical presentation of results
Not applicable.
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7
PK/PD relationships
The relationships between individual PK profiles or derived PK parameters and various 
efficacy/PD measurements or derived variables (including, but not limited to ELF Test, ALT 
and % liver fat) may be explored using graphical approaches (e.g., scatter plots) and regression 
analysis as appropriate. Similarly, the relationship between % liver fat reduction and ALT 
reduction vs weight loss as well as ALT decrease vs % liver fat reduction may be explored as 
needed.
8
Statistical methods for safety and tolerability data
The primary objective of this study is to determine the safety and tolerability of single or 
combination therapy during 12 weeks of treatment.
All participants within the safety analysis set will be included in the safety data analysis.
For participants with protocol deviations affecting the safety analyses, the data will be excluded 
as described in Table 4-1 above.
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8.1
Variables
All safety data collected including adverse events, body height, body weight, BMI, vital signs 
(blood pressure, pulse rate and body temperature), ECG intervals (PR interval, QRS duration, 
heart rate, RR interval, QT interval, QTcF and QTcB), laboratory measurements (Hematology, 
Chemistry, Urinalysis, Coagulation and Pregnancy Test), as well as participant demographics, 
baseline characteristics, relevant medical history, current medical conditions, concomitant 
medications and significant non-drug therapies, and treatment information.
8.2
Descriptive analyses
Participant demographics and other baseline characteristics
All data for demographic and other baseline characteristics including disease characteristics
(including but not limited to age, gender, race, ethnicity, country, height, weight, BMI, ALT, 
AST, GGT, hepatic fat fraction (%) and ELF) will be listed by cohort, treatment and participant. 
Summary statistics will be provided by treatment. Categorical data will be presented as 
frequencies and percentages. For continuous data, sample size (n), mean (arithmetic), SD, 
median, minimum and maximum will be presented. For selected parameters, the 25th percentile
(Q1) and 75th percentile (Q3) will also be presented.
Relevant medical histories and current medical conditions at baseline will be listed by cohort, 
treatment, participant, system organ class (SOC) and preferred term (PT).
Treatment
Data for study drug administration (rescue medication) will be listed by cohort, treatment and
participant.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by cohort, treatment, participant and the Anatomical Therapeutic 
Chemical (ATC) classification system.
Vital signs
All vital signs data will be listed by cohort, treatment, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time and will include sample size (n), mean 
(arithmetic), SD, median, 25th percentile (Q1), 75th percentile (Q3), minimum and maximum.
ECG evaluations
All ECG data will be listed by cohort, treatment, participant, and visit/time, and abnormalities 
will be flagged. Summary statistics will be provided by treatment and visit/time and will include 
sample size (n), mean (arithmetic), SD, median, 25th percentile (Q1), 75th percentile (Q3),
minimum and maximum.
Clinical laboratory evaluations
All laboratory data will be listed by cohort, treatment, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing will be provided presenting 


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all parameters in a participant with any abnormal values. Summary statistics will be provided 
by treatment and visit/time and will include sample size (n), mean (arithmetic), SD, median, 
25th percentile (Q1), 75th percentile (Q3), minimum and maximum.
Adverse events
All information obtained on adverse events will be listed by cohort, treatment and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication, or present prior to start of treatment but increased 
in severity based on preferred term, or changed from being not suspected to being suspected of
study drug relationship, or developed into SAEs after the start of the treatment period) will be
summarized in the following ways:

by treatment, primary system organ class (SOC) and preferred term (PT).

by treatment, primary system organ class (SOC), preferred term (PT) and maximum
CTCAE grade.
Separate summaries will be provided for study medication related adverse events, death, serious
adverse events, other significant adverse events leading to discontinuation.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
8.2.1
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vital signs, ECG intervals and 
laboratory measurements) will be created by treatment.
8.3
Statistical model, assumptions and hypotheses
Formal statistical analysis will not be performed on the safety and tolerability data. The 
statistical evaluation of all safety and tolerability data will be descriptive.
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10
Derivations
10.1.1
HOMA-IR
Depending on the units which fasting glucose and fasting insulin are given in, HOMA-IR will 
be calculated as:
HOMA-IR = [Fasting glucose (mmol/L) x (fasting insulin (pmol/L)/6)] / 22.5
HOMA-IR = [Fasting glucose (mg/dL) x fasting insulin (uIU/mL)] / 405
Reference: https://www.thebloodcode.com/homa-ir-calculator/
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where age is given in years, BMI in kg/m2, platelets in 109/L, albumin in g/dL.
11
SAP deviations from protocol
2. In the study protocol V03 sections 12.5.1 and 12.6, the model used for analyzing secondary
parameters with more than one post-treatment measurement is
named as ‘repeated measures analysis of covariance (ANCOVA)’, whereas in the current
SAP sections 6.2.3 and 6.3.3 it is named as ‘mixed-effect model for repeated measures
(MMRM)’, since this is a more appropriate wording for this model.
3. In the study protocol V03 section 8.5.1.1, it is stated that: ‘A 100 mm visual analogue scale
(VAS) will be used to assess the severity of participants itch (ranging from 0 = no itch at all
to 10 = the worst imaginable itch).’. However, 100 is the correct VAS value corresponding
to the worst imaginable itch, so in the current SAP section 6.3.1 this has been corrected
accordingly to ‘100 = the worst imaginable itch’.
12
Reference list
1. Clinical Trial Protocol, CADPT02A12001, Protocol Version 04, dated 02 Jun 2021.
2. Site Operations Manual, SOM Version 02, dated 17 Aug 2021.
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