Conditions: Non-alcoholic Steatohepatitis (NASH)
Keywords: Steatohepatitis NASH NAFLD Fatty Liver Disease Liver Liver fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 193
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

Detailed description:

Arms:
arm 1: tropifexor 140 mcg, once daily; given orally arm 2: CVC 150 mg, once daily; given orally arm 3: tropifexor 140 mcg + CVC 150 mg, once daily; given orally arm 4: tropifexor 90 mcg + CVC 150 mg, once daily; given orally

Interventions: intervention 1: Tropifexor (LJN452) intervention 2: Cenicriviroc (CVC)
Intervention descriptions: intervention 1: Comparison with monotherapy and different combination doses intervention 2: Comparison with monotherapy and different combination doses

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 3 ...........................................................................................................................12
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................34
2
Study objectives and endpoints .........................................................................................34
2.1
Objectives and related endpoints...........................................................................34
3
Investigational plan ...........................................................................................................36
3.1
Study design...........................................................................................................36
3.2
Rationale for study design .....................................................................................38
3.3
Rationale for dose/regimen, route of administration and duration of treatment....38
3.4
Rationale for choice of comparator .......................................................................39
3.5
Purpose and timing of interim analyses/design adaptations..................................40
3.6
Risks and benefits..................................................................................................40
4
Population..........................................................................................................................42
4.1
Inclusion criteria ....................................................................................................42
4.2
Exclusion criteria...................................................................................................42
5
Treatment...........................................................................................................................45
5.1
Study treatment......................................................................................................45
5.1.1
Investigational and control drugs..........................................................45
5.1.2
Additional treatment..............................................................................46
5.2
Treatment arms......................................................................................................46
5.3
Treatment assignment and randomization.............................................................46
5.4
Treatment blinding.................................................................................................47
5.5
Treating the patient................................................................................................47
5.5.1
Patient numbering .................................................................................47
5.5.2
Dispensing the study drug.....................................................................48
5.5.3
Handling of study and additional treatment..........................................48
5.5.4
Instructions for prescribing and taking study treatment........................49
5.5.5
Permitted dose adjustments and interruptions of study treatment ........50


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5.5.6
Rescue medication ................................................................................50
5.5.7
Concomitant medication .......................................................................50
5.5.8
Prohibited medication ...........................................................................50
5.5.9
Emergency breaking of assigned treatment code..................................53
5.6
Study completion and discontinuation...................................................................53
5.6.1
Study completion and post-study treatment..........................................53
5.6.2
Discontinuation of study treatment .......................................................54
5.6.3
Withdrawal of informed consent...........................................................55
5.6.4
Loss to follow-up ..................................................................................55
5.6.5
Early study termination by the sponsor.................................................55
6
Visit schedule and assessments .........................................................................................56
6.1
Information to be collected on screening failures..................................................65
6.1.1
Pre-screening.........................................................................................65
6.2
Patient demographics/other baseline characteristics .............................................66
6.2.1
Demographic Information.....................................................................66
6.2.2
Medical history......................................................................................66
6.2.3
Alcohol history and assessments...........................................................66
6.2.4
Smoking history ....................................................................................66
6.2.5
Prior and concomitant medications.......................................................66
6.2.6
Liver evaluation ....................................................................................66
6.2.7
Other baseline characteristics................................................................67
6.2.8
Screening visit 2 – additional assessments............................................68
6.3
Treatment exposure and compliance .....................................................................68
6.4
Efficacy..................................................................................................................68
68
6.4.2
Liver tests..............................................................................................69
6.4.3
Coagulation tests...................................................................................69
69
69
70
70
70
6.4.9
Liver biopsy ..........................................................................................70
6.4.10
Appropriateness of efficacy assessments..............................................71
6.5
Safety.....................................................................................................................71
6.5.1
Physical examination ............................................................................71


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6.5.2
Vital signs..............................................................................................72
72
6.5.4
Laboratory evaluations..........................................................................72
6.5.5
Electrocardiogram (ECG) .....................................................................73
6.5.6
Pregnancy and assessments of fertility .................................................74
6.5.7
Appropriateness of safety measurements..............................................74
6.6
Other assessments..................................................................................................74
6.6.1
Clinical Outcome Assessments.............................................................75
6.6.2
Resource utilization...............................................................................77
77
78
78
7
Safety monitoring..............................................................................................................78
7.1
Adverse events.......................................................................................................78
7.2
Serious adverse events...........................................................................................80
7.2.1
Definition of SAE .................................................................................80
7.2.2
SAE reporting........................................................................................81
7.3
Liver safety monitoring .........................................................................................82
7.4
Renal safety monitoring.........................................................................................83
7.5
Reporting of study treatment errors including misuse/abuse ................................83
7.6
Pregnancy reporting...............................................................................................84
8
Data review and database management.............................................................................84
8.1
Site monitoring ......................................................................................................84
8.2
Data collection.......................................................................................................85
8.3
Database management and quality control............................................................85
8.4
Data Monitoring Committee..................................................................................86
8.5
Adjudication Committee........................................................................................86
9
Data analysis......................................................................................................................87
9.1
Analysis sets ..........................................................................................................87
9.2
Patient demographics and other baseline characteristics.......................................87
9.3
Treatments .............................................................................................................87
9.4
Analysis of the primary variable(s) .......................................................................88
9.4.1
Primary Variable(s)...............................................................................88
9.4.2
Statistical model, hypothesis, and method of analysis..........................88
9.4.3
Handling of missing values/censoring/discontinuations.......................88
9.4.4
Sensitivity analyses ...............................................................................89






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List of abbreviations
A14
Inducible cytokine Alpha - 14
A1AT
Alpha-1-antitrypsin
A2
Inducible cytokine Alpha - 2 
ACR
Albumin-creatinine ratio
AE
Adverse Event
AHA
American Heart Association
Alb
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AMA
Anti-mitochondrial antibodies
ANA
Anti-nuclear antibodies
ANIT
Alpha-Naphtha Isothiocyanate
APTT
Activated Partial Thromboplastin Time
ASMA
Anti-smooth muscle antibody
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical Classification
AUC
Area Under Curve
AUDIT
Alcohol Use Disorders Identification Test
AV block
Atrioventricular Block
b.i.d.
twice a day
BSEP
Bile Salt Export Pump
BSL
Baseline visit
BUN
Blood Urea Nitrogen
C5M
Neo-epitope of MMP-2,9 mediated degradation of type V collagen
C6M
Neo-epitope of MMP-2 mediated degradation of type VI collagen
CAP
Controlled attenuation parameter
CCR2
C-C Motif Chemokine Receptor Type 2
CCR5
C-C Motif Chemokine Receptor Type 5
CD14
Cluster of differentiation 14
CDT
Carbohydrate deficient transferrin
CFR
US Code of Federal Regulations 
Cmax
Maximum drug concentration
CPO
Country Pharma Organization
CRN
Clinical Research Network
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
Central Vein


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CVC
Cenicriviroc Mesylate
CYP3A4
Cytochrome P450 3A4
CYP7A1
Cytochrome P450 7A1
CYP2C8
Cytochrome P450 2C8
DBP
Diastolic Blood Pressure
DDI
Drug Drug Interaction
DMC
Data Monitoring Committee
EC50
eCRF
Half Maximal Effect Concentration
electronic Case Report Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EOT
End of treatment
EOS
End of study
eSource
Electronic Source
FAS
Full analysis set
FXR
Farnesoid X Nuclear Receptor
GCP
Good Clinical Practice
GGT
Gamma-glutamyl Transferase
GLP
Good Laboratory Practice
GLP-1 
Glucagon-like Peptide-1
HA 
Hyaluronic acid
Hb
Hemoglobin
HbA1c
Glycated hemoglobin
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C Virus
hCG
Human Chorionic Gonadotropin
HCVAb
Hepatitis C virus antibody
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form


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ICH
International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
Identification
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IQR
Interquartile range
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
LC-MS/MS 
Liquid chromatography coupled to tandem mass spectrometry
LLOQ
Lower limit of qualification
LT
Liver test
MCV
Mean Corpuscular Volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
MI
Myocardial Infarction
  
 
 
NAFLD
Non-alcoholic Fatty Liver Disease
NASH
Nonalcoholic Steatohepatitis
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
OCA
Obeticholic acid
PBC
Primary Biliary Cholangitis
PCR
Protein-creatinine ratio


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PRO
Patient Reported Outcomes
PSC
Primary Sclerosing Cholangitis
PT
Prothrombin Time/Portal Triad
PUFA
Polyunsaturated Fatty Acids 
QM
Quality Management
QTcF
Corrected QT interval (Fridericia method)
RAN
Randomized set
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAF
Safety set
SBP
Systolic Blood Pressure
sCD163
Soluble Cluster of differentiation 163
sCr
Serum Creatinine
SCR
Screened set
SHP
Small Heterodimer Partner
SAE
Serious Adverse Event
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T2DM
Type-2 Diabetes Mellitus
TBL
Total Bilirubin
TEAE
Treatment-emergent Adverse Event
TD
Treatment Discontinuation
TG
Triglycerides
TT
Thrombin Time
UGT1A1
UDP Glucuronsyltransferase 1 Family, Polypeptide A1
UGT
UDP Glucuronsyltransferase
ULN
Upper Limit Normal
WBC
White Blood Cells
WHO
World Health Organization 
WoC
Withdrawal of Study Consent
yGT
y-Glutamyltranspeptidase


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Glossary of terms
Control drug
Drugs(s) 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
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg 
once a day, 75 mg b.i.d).
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 paper source forms used at the point of 
care.
Enrollment
Point/time of patient entry into the study at which informed consent must be 
obtained (e.g. prior to starting any of the procedures described in the 
protocol).
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US Code of Federal Regulations (CFR) 21 Section 312.3 and 
is synonymous with “investigational new drug” or “investigational medicinal 
product.”
Medication pack number
A unique identifier on the label of each investigational drug package.
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients/subjects with 
established disease and in those with newly-diagnosed disease.
Patient/subject Identification 
(ID)
A unique number assigned to each patient upon signing the informed consent.
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.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Randomization number
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment.
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.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as part of 
the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy.
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the defined 
study treatment completion date.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study.
Withdrawal of study consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


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Amendment 3 
Amendment rationale
The conduct of clinical trials has been impacted by the COVID-19 pandemic and related 
measures including national goverment mandates, closures of local hospitals and research
facilities, reassigment of research personnel, patient travel restrictions and delays in the 
shipment of study treatment and trial supplies.
The purpose of this amendment is to implement a plan for treatment continuity, patient safety 
monitoring and maintaining the integrity of the trial. The implemented measures are only for 
the period of the COVID-19 pandemic, and standard visit schedule and assessments as outlined 
in Table 6-1 should resume as soon as patients are able to visit study sites and undergo all end 
of treatment assessments
At the time of amendment (V03) release, enrollment is completed with 193 patients randomized. 
Changes to the protocol
This amendment provides the option to extend the study treatment for patients who are unable 
to come to site for the week 48 visit as scheduled due to COVID-19 pandemic restrictions.
The changes to specific sections of the protocol are as below:

Section 3.6: Updated to clarify the possible benefits and risks of longer study treatment 

Section 5.5.2: updated to include the stepwise approach to extend study treatment for 
patients who are unable to come to the study site for their Week-48, End of treatment 
(EOT) visit as scheduled per study protocol due to COVID-19 pandemic related 
restrictions

Section 6 and table 6.1: updated to include remote consultation for patients who are 
unable to come to the study site for their study visits (except week-48, End of treatment 
visit) as scheduled per study protocol due to COVID-19 pandemic related restrictions.
The footnotes revised to clarify the instructions for urine pregnancy test and study 
treatment extension. 

Section 9.5.1: updated to clarify analysis plan for the delayed Week 48, End of 
Treatment (EOT) visits due to COVID-19 pandemic related restrictions
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. This amendment is 
required to ensure trial continuity due to COVID-19 pandemic and related measures, therefore 
it will be implemented prior to Health Authority and IRB/IEC approval.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 






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Protocol summary
Protocol number
CLJC242A2201J
Full Title
A randomized, double-blind, multicenter study to assess the safety, 
tolerability, and efficacy of a combination treatment of tropifexor 
(LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic 
steatohepatitis (NASH) and liver fibrosis (TANDEM)
Brief title
Study of safety, tolerability, and efficacy of a combination treatment of 
tropifexor and cenicriviroc in adult patients with nonalcoholic 
steatohepatitis (NASH) and liver fibrosis
Sponsor and Clinical 
Phase
Novartis 
Phase 2b
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to assess the safety, tolerability, efficacy 
 
 of two regimens of tropifexor and cenicriviroc (CVC) 
(further described as tropifexor + CVC) compared to monotherapies 
tropifexor and CVC in patients with NASH and liver fibrosis. 
Primary Objective(s) 
The primary objective of this study is to evaluate the safety and 
tolerability of tropifexor + CVC in patients with NASH with fibrosis stage 
F2/F3 by monitoring adverse events, vital signs and laboratory values 
during 48 weeks of treatment as compared to monotherapy with each of 
tropifexor and CVC
Secondary Objectives
To characterize the efficacy of different doses of the combination drug 
tropifexor + CVC in patients with NASH with fibrosis stage F2/F3 as 
assessed by histological improvement after 48 weeks of treatment 
compared to monotherapies (tropifexor and CVC) compared to baseline 
biopsy.
Study design
This study is a randomized, double-blind, multicenter study to evaluate 
the safety and tolerability of tropifexor + CVC as compared to 
monotherapy with each of tropifexor and CVC.
Population
Adult male and female patients with histologic evidence of NASH with 
stage 2 or 3 fibrosis based on centrally-read liver biopsy.
The study will include a total of approximately 200 patients.
Key Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.

Male and female patients 18 years or older (at the time of the 
screening visit). Patients must weigh at least 50 kg (110 lb) and no 
more than 200 kg (440 lb) to participate in the study.

Adequate liver biopsy sample for evaluation by a central reader.

Presence of NASH as demonstrated by histologic evidence based on 
liver biopsy - NASH with fibrosis stage F2/F3, demonstrated on liver 
biopsy during the screening period. Alternatively, a historical biopsy 
can be used if performed within 6 months prior to screening, if:
the patient has been receiving any of the therapies listed in Table 
5-4, the dose must have been stable (since 1 month before the 
biopsy up to and including screening),

the patient’s weight has been stable (maximum weight loss of 
10% since biopsy up to and including screening).




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There is a single secondary objective in this study which is to 
characterize the efficacy of tropifexor + CVC as assessed by histological 
improvement after 48 weeks of treatment compared to monotherapies 
(tropifexor and CVC) relative to baseline biopsy. There are two estimands 
that will be used to evaluate this objective. 
The first estimand is the difference on the proportion of patients on the 
different tropifexor + CVC regimens who achieve at least a one point 
improvement in fibrosis at Week 48 compared to tropifexor and CVC 
monotherapy patients.
The second estimand is the difference in the proportion of patients on the 
different tropifexor + CVC regimens who achieve resolution of 
steatohepatitis at Week 48 relative to baseline compared to tropifexor 
and CVC monotherapy patients.
Differences between tropifexor + CVC combination therapy and 
monotherapy with tropifexor or CVC with respect to these proportions 
(response rates) will be evaluated using a Cochran-Mantel-Haenszel test 
controlling for baseline fibrosis stage (F2/F3). The estimand will be 
evaluated in the FAS population.
Key words
Tropifexor, LJN452, cenicriviroc, CVC, non-alcoholic steatohepatitis, 
NASH, phase 2, liver biopsy, randomized


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1
Introduction
1.1
Background
Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
in developed countries with a global prevalence of 25% (Younossi ZM 2011, Cohen JC 2011,
Younossi et al 2016). NAFLD is often a “silent” liver disease and usually associated with 
obesity, Type-2 diabetes mellitus (T2DM), dyslipidemia, hypertension and metabolic syndrome.  
Although most patients with NAFLD have a benign course, a subset of these patients may have 
the more severe and progressive form of NAFLD called nonalcoholic steatohepatitis (NASH), 
which is characterized by the presence of ballooning degeneration and lobular inflammation 
with or without perisinusoidal fibrosis in addition to steatosis. 
Figure 1-1
Schematic progression of NAFLD/NASH
The disease spectrum of nonalcoholic fatty liver disease. (A) Schematic of progression of NAFLD. The 
accumulation of Triglycerides (TG) within lipid droplets in hepatocytes causes steatosis. Steatosis 
associated with inflammation, cell death, and fibrosis is referred to as NASH, which can progress to 


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cirrhosis. Individuals with cirrhosis have an increased risk of hepatocellular carcinoma (HCC). (B) 
Histological sections illustrating normal liver, steatosis, NASH, and cirrhosis. Collagen fibers are 
stained blue with Masson’s trichrome stain. The portal triad (PT), which consists of the hepatic artery, 
portal vein, and bile duct, and the central vein (CV) are shown (Figure from Cohen JC 2011).
The projected estimate of NASH with advanced fibrosis is approximately 4.1 million adults in 
the US. (Kabbany MN 2017). Estimates vary due to the diagnostic modality used, study 
heterogeneity, but also the region of the world studied. Among NAFLD patients, NASH 
estimates are 29%-59% in North America.  In the overall global population, NASH prevalence 
is 3.8% (3-6.45%) (Foster et al 2012, Younossi et al 2016). Patients with NASH can progress 
to cirrhosis, liver decompensation, hepatocellular carcinoma (HCC), need for a liver 
transplantation, and are at increased risk of death from liver disease. The incidence of advanced 
liver disease, liver failure and HCC related to NAFLD/NASH are increasing dramatically and 
NASH is projected to become the most common indication for liver transplantation (Beste LA
2015, Wong 2015, Neuschwander and Tetri B 2003). NASH is the cause of progressive fibrosis 
in the patients with NAFLD. Fibrosis is the most important histological feature associated with 
all-cause mortality (e.g. cardiovascular disease) and liver complications in NASH (Angulo 2015, 
Ekstedt 2006). Despite recent improvements in soluble biomarkers, liver biopsy is still the gold 
standard for diagnosing NASH and assessing the stage of fibrosis in patients with NAFLD. Of 
note, rapid progressors may proceed to develop cirrhosis in only a 10-year period (Singh S 
2015). Reducing liver fibrosis is expected to improve the long-term clinical outcomes of 
patients with NASH (Ratziu V 2015).
There are no globally approved treatments for NASH. Several studies have been conducted with 
Vitamin E and thiazolidinediones, but no long-term benefits have been demonstrated. There are 
potential new therapies being evaluated, currently in phase II or III trials, but the reported 
efficacy from the available studies are still lacking substantial benefit. The significant global 
burden of NASH, the currently available study results especially when considered with 
multifactorial etiology of NAFLD/NASH suggests that combination therapy of different 
mechanisms of actions will be a more effective therapy for NASH patients. 
Farnesoid X receptor: tropifexor
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 (Figure 1-1) (Pattni et al 2012, Walters et al 2015). In the liver, 
FXR agonism modulates bile acid synthesis and detoxifying metabolism. FXR agonist increases 
expression of genes involved in canalicular and basolateral bile acid efflux and bile acid 
detoxifying enzymes while inhibiting basolateral bile acid uptake by hepatocytes and inhibiting 
bile acid synthesis (Calkin and Tontonoz 2012). FXR activation represses bile acid synthesis in 
the liver through induction of Small Heterodimer Partner (SHP), which is a negative regulator 
of CYP7A1, the rate-limiting enzyme of the neutral bile acid biosynthetic pathway (Goodwin 
et al 2000). Furthermore, FXR agonists increase excretion of bile acids through the kidney, 
increase bile acid binding proteins in the ileum and stimulate FGF15 (in rodents) or FGF19 (in 
humans) expression (a key regulator of bile acid metabolism).








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Part 1 of the CLJN452X2201 study in PBC patients is ongoing. No safety concerns were 
identified with doses ranging from 30 to 90 µg orally once daily for 4 weeks.
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.
C-C chemokine receptor type 2 and type 5 inhibitor: cenicriviroc
Cenicriviroc mesylate (CVC) is an oral, dual antagonist of C-C motif chemokine receptor types 
2 and 5 currently in clinical development for the treatment of liver fibrosis in adult patients with 
NASH. The Investigator’s Brochure (CVC IB) provides a detailed review of the pre-clinical 
and clinical information on CVC available to date.
Human pharmacokinetic and pharmacodynamic as well as safety and tolerability data are 
further described in the CVC IB. Briefly, CVC has demonstrated antifibrotic activity in animal 
models of liver and renal fibrosis (Lefebvre et al 2016). Preclinical (Lefebvre et al 2016,
Puengel et al 2016, Tacke et al 2015, Mossanen et al 2016) and clinical evidence (Friedman et 
al 2017, Lefebvre et al 2016, Thompson et al 2016) support its anti-inflammatory and 
antifibrotic properties, which are mediated by C-C motif chemokine receptor types 2 and 5 
blockade. 
The mechanism of action of CVC, as an anti-inflammatory and anti-fibrotic agent, supports its 
use in liver diseases, such as liver fibrosis associated with NASH. CVC treatment decreases the 
recruitment and migration of CCR2-expressing monocytes to the site of liver injury, mainly via 
CCR2 antagonism, thereby reducing the infiltration of pro-inflammatory, monocyte-derived 
macrophages into the liver (Krenkel O 2017). In addition, CCR5 antagonism by CVC is 
expected to impair the migration, activation, and proliferation of collagen-producing activated 
hepatic stellate cells and myofibroblasts, therefore reducing fibrogenesis.
Assessment of cenicriviroc in non-clinical studies
In vitro data with CVC have demonstrated that it blocks the binding of C-C motif chemokine 
ligand 2 (CCL2; also known as monocyte chemotactic protein 1 [MCP-1]) to CCR2, and also 
blocks the binding of CCR5 ligands, CCL3 (also known as macrophage inflammatory protein 
[MIP]-1, CCL4 (also known as MIP-1and CCL5 (also known as regulated on activation 
normal T-cell expressed and secreted [RANTES]), to CCR5. Ex vivo experiments showed that 
nanomolar concentrations of CVC achieved 98% receptor occupancy of CCR2 on human 
monocytes and ~90% receptor occupancy for CCR5 on human CD4+ and CD8+ T-cells. 
Additionally, CVC was an efficient inhibitor of monocyte and human lymphocyte (primarily 
T-cells) migration in vitro. CVC’s anti-inflammatory and antifibrotic effects have been 
evaluated in a range of nonclinical models of inflammation and fibrosis, and has demonstrated 
activity in multiple animal fibrosis models.
The effects of CVC on the central nervous, cardiovascular, and respiratory systems were 
examined in a core battery of safety pharmacology studies. CVC at oral doses up to 1600 mg/kg 
had no effects on the general physical condition or behavior of rats. CVC had no significant  
effects  on  blood  pressure,  heart  rate,  body  temperature,  or  electrocardiogram (ECG) 
parameters (including PR interval, QRS duration, QT interval, and corrected QT interval) at 


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oral doses up to 2000 mg/kg in cynomolgus and no effects on the respiratory rate, tidal volume, 
minute volume, or enhanced pause (Penh) up to 24 hours post-dose.
Toxicology studies showed no target organ toxicity, thus no adverse liver findings, in mice or 
monkeys. In rats, the liver was the primary target organ identified in repeat dose studies, with 
biliary hyperplasia being the primary finding. Overall, the risk for hepatobiliary effects due to 
CVC appears to be low. The nonclinical data suggest that CVC will not adversely affect the 
liver at or near clinical exposures. Liver findings were present in only 1 of 3 species and when 
present, a high safety margin was apparent (>27-fold). CVC was not genotoxic, and did not 
adversely affect fertility or embryofetal development (refer to CVC IB for further details).
Assessment of cenicriviroc in clinical studies
Overall, as of January 2018, approximately 1154 participants have been exposed to CVC in 
completed and ongoing clinical studies (January 2018 Development Safety Update Report 
cutoff). CVC doses ranged from 25 mg to 900 mg across all CVC studies. There was no 
apparent dose- or exposure-relationship for safety.

Overall, CVC was generally well tolerated in the Phase 1 studies evaluating single 
doses of CVC up to 900 mg and at multiple daily doses of up to 900 mg for ≥7 days.

In participants with mild to moderate hepatic impairment, CVC 150 mg QD for 14 
days was generally well tolerated regardless of level of hepatic impairment, and no 
safety concerns were identified in this population.

In the Phase 1 studies, most adverse events (AEs) were mild or moderate in severity.
The most commonly observed AEs (≥ 2%) with CVC in single-dose studies were 
headache, nasopharyngitis, all abdominal pain, nausea, vomiting, diarrhea, contact 
dermatitis, and somnolence. The most commonly observed AEs (≥ 2%) with CVC in 
multiple-dose studies were headache, and constipation.

In the CENTAUR Phase 2b study in adult participants with NASH with liver fibrosis, 
CVC appears to be safe with no notable differences observed compared to previous 
clinical studies in incidence of treatment-emergent AEs and laboratory abnormalities, 
including liver transaminase elevations, which were generally similar between 
treatment groups. Safety findings in CENTAUR were consistent with that of the 
extensive clinical experience with CVC, including the Phase 2 HIV studies.
Study 652-2-203 (CENTAUR) is a 2-year placebo-controlled Phase 2b study in 289 adult 
participants with liver fibrosis and NASH. Enrollment completed in June 2015 and Year 2 
database lock was performed on 22 August 2017. In CENATUR, the Year 1 primary endpoint 
of NAFLD Activity Score (NAS) improvement by at least 2 points (and no worsening of 
fibrosis) in the intent-to-treat (ITT) population and the key secondary endpoint of resolution 
of steatohepatitis (and no worsening of fibrosis) was achieved in a similar proportion of 
subjects on CVC (N = 145) and placebo (N = 144) (16% vs 19%, p = 0.52 and 8% vs 6%, p
=0.49, respectively). However, the fibrosis endpoint (i.e., improvement in fibrosis by at least
1 stage and no worsening of steatohepatitis) was met in twice as many subjects on CVC 
than placebo in the ITT population (20% vs 10%; p = 0.02). At Year 1, a higher proportion of 
participants in the CVC group (29%) compared with the combined placebo group (19%) had 
an improvement of at least 1 stage at Year 1 per the NASH CRN staging system. Similarly, a 
higher proportion of participants in the CVC group (35%) compared with the combined 


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placebo group (22%) had an improvement of at least 1 stage at Year 1 per the Ishak fibrosis 
staging system. Treatment benefits were greater in those with higher disease activity and 
fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. In 
summary, CVC showed a clinically meaningful antifibrotic benefit and anti-inflammatory 
activity in NASH patients with liver fibrosis.
To determine the durability of histological improvement achieved after 1 year of treatment, 
improvement in fibrosis by ≥1 stage was assessed in subjects with available biopsy results at
all 3 timepoints (baseline, Year 1, and Year 2). Results from this analysis showed that the 
proportion of subjects in the CVC group who achieved improvement in fibrosis by ≥1 stage 
at the end of Year 1 and maintained this benefit at Year 2 was twice the proportion of subjects
in the placebo group (60% versus 30%, respectively). The durable antifibrotic effect of CVC
was also more apparent in the subgroup of subjects with Stage 3 fibrosis at baseline, for which
the antifibrotic benefit at Year 2 was maintained in 86% of subjects in the CVC group 
versus 60% in the placebo group. Furthermore, in the subgroup of subjects with fibrosis Stage 
2 or 3 at baseline, a higher proportion of subjects receiving CVC achieved a ≥2-stage 
improvement in fibrosis (and no worsening of steatohepatitis) at Year 2 relative to subjects 
receiving placebo (9.3% in the CVC group versus 2.7% in the placebo group, from baseline to 
Year 2). When only subjects with Stage 3 fibrosis at baseline were included in the analysis,
14.0% of subjects receiving CVC versus 4.2% of subjects receiving placebo for 2 years 
achieved a ≥2-stage improvement in fibrosis (and no worsening of steatohepatitis) at Year 2. 
CVC had a generally comparable safety and tolerability profile to placebo over 2 years. Overall, 
the results from the final Year 2 analysis confirmed the clinically meaningful antifibrotic effect 
of CVC treatment observed in the Year 1 primary analysis (Ratziu et al 2018).
Given that severity of fibrosis stage has been shown to be the only histological feature 
independently associated with clinical outcomes over the long term, these results provide 
additional evidence of the potential of CVC as a safe and efficacious pharmacologic treatment 
for liver fibrosis in adults with NASH.
In CENTAUR, the safety profile of CVC (150 mg QD) was comparable to that in participants
treated with placebo and was well tolerated over 2 years. The types, severity, and frequency 
of TEAEs reported after 2 years of CVC treatment was consistent with those reported after 1
year of treatment. The overall incidence of TEAEs during the study was similar  across  the  
treatment  groups  (≥ 95.0%  of  participants  in each  group).  No deaths occurred during the
study. The frequency and types of TEAEs reported were comparable between treatment groups 
during Year 1 and Year 2.

The frequency of treatment-related events reported after 2 years of CVC treatment 
was comparable to that reported after 1 year of treatment (41.7% vs 42.1%).

The most frequently reported drug-related TEAEs of at least Grade 2 severity through
1 year of treatment were fatigue (2.8%) and diarrhea (2.1%) in the CVC arm 
and headache (3.5%) in the placebo arms.

The most frequently reported study drug-related TEAEs of at least Grade 2 severity 
through 2 years of treatment were fatigue (5.0%) in the CVC/CVC group, headache


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in the placebo/CVC group (6.6%), and ALT increased (3.3%) in the placebo/placebo 
group.

For participants who crossed-over from placebo and received CVC for 1 year, the 
frequency of TEAEs reported (44.3%) was similar to that reported in participants who 
received 1 year CVC during Treatment Period 1 of the study (41.7%). A smaller 
number of participants experienced TEAEs that resulted in discontinuation of study
drug.

After 2 years of CVC treatment, the number of participants who discontinued the study 
due to a TEAE was greater than that reported for participants treated with 2 years of 
placebo (4.1% vs 0), but was comparable to that reported after 1 year of treatment (6.3%).

The only AE leading to discontinuation, regardless of causality, reported in at least 
2 participants in the CVC/CVC group was ALT increased (3 participants, 2.5%); 
all were Grade 3 severity.

Although the number of participants who experienced serious adverse events (SAEs) 
increased after 2 years of CVC treatment compared to placebo (18.2% vs 11.8%), 
almost all were considered not-related to study drug and did not lead to study
discontinuation.

Only 1 participant experienced a study drug-related event (Grade 3 heart arrhythmia), and 
only 1 event led to discontinuation (Grade 3 congestive heart failure considered not 
related to study medication).

With the exception of treatment-emergent Grade 3 and 4 amylase elevations and Grade 
4 lipase elevations observed more frequently in the CVC arms versus the placebo arm 
(3.3% versus 1.7%, 2.2% versus 0.0%, and 21.1% versus 16.7%, respectively), the 
incidence of treatment-emergent Grade 3 or 4 laboratory results were generally similar
between the CVC arms and the placebo arm
   No meaningful changes in vital signs or anthropometric parameters were observed.

Overall, the proportion of participants with confirmed liver transaminase elevations that 
met protocol-defined biochemical criteria for suspected drug-induced liver injury was 
9.7% in the CVC group and 7.6% in the placebo group during the first year of treatment. 
The frequency did not increase in CVC-treated participants in Arm A after an additional 
year of treatment with CVC. No cases of Hy’s law were observed in the study. Among 
the participants who met the criterion for suspected drug induced liver injury, 2 
hepatobiliary adverse events of autoimmune hepatitis were reported during Year 1 (1 
participant in the CVC Arm A and 1 participant in the placebo Arm C). These 
participants did not continue onto treatment during Year 2. In addition, a case of possible 
autoimmune hepatitis was observed upon liver biopsy (1 subject in CVC Arm A, event 
not reported as an AE or SAE by the investigator). No cases of autoimmunehepatitis 
were observed during Year 2 of the study.
   There have been no deaths related to CVC treatment.
Based on the results of CENTAUR, the Phase 3 AURORA study was initiated in April 2017 to 
study the antifibrotic benefit of CVC as compared with placebo in adults with NASH and Stage 
2 or 3 fibrosis. CVC is currently also in Phase 2 development in subjects with primary sclerosing 
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In over 1000 subjects treated, including those with NASH and liver fibrosis, HIV-1 infection, 
and cirrhotics with hepatic impairment, CVC demonstrated good safety and tolerability
(Abdelmalek M et al 2017, CVC IB), supporting evaluation in combination therapy with 
tropifexor for the treatment of liver fibrosis associated with NASH.  
This study is the first study with a combination of tropifexor and CVC in patients with 
biopsy confirmed NASH and it aims to assess safety and tolerability as well as efficacy after
daily dosing for 48 weeks.
Tropifexor and cenicriviroc (combination) pre-clinical data
A preclinical animal study investigating the potential additive effects of CVC and tropifexor in 
STAM mouse models of diet induced NASH, shows that combination therapy of tropifexor and 
CVC further improved steatosis, ballooning, and inflammation as measured by NAS vs. vehicle 
when compared to either agent as monotherapy (Laffitte B, AASLD 2017 abstract # P-2052). 
The combination of tropifexor and CVC was associated with more pronounced reductions in 
lobular inflammation and hepatocellular ballooning. Tropifexor, CVC, and the combination all 
reduced fibrosis to a similar extent vs. vehicle. These preclinical combination data supports 
further evaluation in humans.
Tropifexor and cenicriviroc (combination) toxicology data
In accordance to the International Conference on Harmonization (ICH) guidance on non-
clinical safety studies (ICH) M3 (R2) section XVII (combination drug toxicity testing), 4 and
13 week GLP combination studies were performed in rats to support the long term clinical 
development of the 2 investigational drugs CVC and tropifexor as combination therapies for 
NASH.
CVC and/or LJN452 were administered separately or in combination, daily via oral gavage to 
rats for 28 days (Study 652-9-1059).  The groups and doses were as indicated in the Table 1-1
below:
Table 1-1
Study design 28 day oral gavage combination study
Group
No. of 
Animals
CVC Dose 
Level
(mg/kg/ 
day)
CVC Dose 
Concentration
(mg/mL)
LJN452 
Dose Level
(mg/kg/ 
day)
LJN452 Dose 
Concentration
(mg/mL)
M
F
1 (Control)
10
10
0
0
0
0
2 (CVC low)
10
10
30
6.0
0
0
3 (CVC high)
10
10
100
20.0
0
0
4 (LJN452 low)
10
10
0
0
0.03
0.006
5 (LJN452 High)
10
10
0
0
1.0
0.2
6 (CVC+LJN452) (low)
10
10
30
6.0
0.03
0.006
7 (CVC+LJN452) (high)
10
10
30
6.0
1.0
0.2
Source: Study 652-9-1059
CVC = Cenicriviroc; F = Female; M = Male


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Administration of CVC alone or in combination with LJN452 was generally well-tolerated
when administered via oral gavage for 28 days. The only effects noted during in-life phase were 
slightly decreased mean body weight and body weight change for males administered 1.0 
mg/kg/day LJN452, alone or with 30 mg/kg/day CVC and slightly decreased food consumption 
for males administered 1.0 mg/kg/day LJN452 with 30 mg/kg/day CVC. 
Clinical pathology changes were seen primarily in animals administered LJN452 and consistent 
with the changes reported in previous studies with LJN452 and with the expected pharmacology 
of the drug. Most of the test-article related clinical chemistry effects may be associated with 
expected pharmacology of the test article(s). 
Clinical pathology changes in animals administered CVC included minimally to mildly lower 
absolute monocyte counts which was attributed to the pharmacology of CVC (CCR2 
antagonism) and was not noted in animals administered LJN452 alone. 
Based on the microscopic findings, primary target tissues for LJN452 were the liver, kidney, 
and intestines as previously reported in other studies with LJN452 alone. These findings may 
be attributable to the pharmacologic activity of LJN452, as FXR is highly expressed in the liver, 
kidney, and intestines. Secondary findings, consistent with stress, were observed in the thymus 
and prostate in animals administered LJN452, which correlated with decreased individual 
and/or group thymus and prostate weights, respectively, as well as decreased individual 
terminal body weights. 
In conclusion, administration of CVC alone caused no microscopic findings indicative of 
toxicity and administration of CVC in combination with of LJN452 had no impact on toxicity 
of LJN452.
CVC and LJN452 were administered in combination daily via oral gavage to rats for at least 13 
weeks to assess the reversibility, persistence, or delayed occurrence of any effects after an 8-
week recovery phase (Study 1984-T01-052).
The groups and doses are presented in the Table 1-2 below:
Table 1-2
Study design 13 weeks oral gavage combination study
Group
Sub-
group
No. of 
Animals
CVC 
Dose 
Level
(mg/kg/ 
day)
CVC Dose 
Concentration
(mg/mL)
LJN452 
Dose 
Level
(mg/kg/ 
day)
LJN452 Dose 
Concentration
(mg/mL)
M
F
1 (Control)
1 (Tox)
15
15
0
0
0
0
2 (TK)
3
3
2 (Low)
1 (Tox)
15
15
3
0.6
0.03
0.006
2 (TK)
6
6
3 (High)
1 (Tox)
15
15
30
6
0.5
0.1
2 (TK)
6
6
Source: Study 1984-T01-052
CVC = Cenicriviroc; F = Female; M = Male; Tox = Toxicity; TK = Toxicokinetic.


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No LJN452 or CVC related effects on mortality, clinical observations, ophthalmic observations, 
functional observational battery (neurobehavioral observations, elicited behaviors, or open field 
observations) occurred.
During the dosing phase, males administered ≥ 3/0.03 mg/kg/day (CVC/LJN452) gained 
slightly less weight compared to controls, while females gained more. Both effects reversed 
during the recovery phase.  
Several relatively minor, CVC- and LJN452-related clinical pathology findings were observed 
at the terminal sacrifice in animals administered ≥ 3/0.03 mg/kg/day CVC/LJN452. These 
findings were attributed to the pharmacologic activity of CVC (CCR2 antagonism/decreased 
monocytes) or LJN452 (FXR agonism); those changes were similar to the one observed with 
the single agents (see above).
At the terminal sacrifice, CVC- and LJN452-related microscopic findings occurred in the liver, 
kidney, intestine (cecum, duodenum, and ileum) and the spleen. In the liver, minimal to 
moderate hepatocyte hypertrophy and periportal vacuolation was observed microscopically in
animals administered 30/0.5 mg/kg/day. Higher liver weights correlated with hepatocellular 
hypertrophy and hepatocyte vacuolation in animals administered 30/0.5 mg/kg/day, 
hepatocellular hypertrophy in females administered ≥3/0.03 mg/kg/day.  In the intestine, an 
increased incidence of crypt/gland ectasia was noted in the cecum, duodenum, and ileum of 
animals administered 30/0.5 mg/kg/day. In the kidney, a CVC and LJN452-related increased 
incidence of basophilic tubules was noted in the cortex of males administered 30/0.5 mg/kg/day. 
Higher spleen weights correlated with the microscopic finding of increased marginal zone size 
in animals administered 30/0.5 mg/kg/day; this change is consistent with the effect of a 
pharmacological inhibition of CCR2 by CVC in the spleen (Flaishon 2004 et al). At the recovery 
sacrifice, no CVC and LJN452-related microscopic findings were observed, indicating 
reversibility of the changes observed during the dosing phase. The NOAEL is 30/0.5 mg/kg/day 
CVC/ LJN452).
Overall, the toxicity findings observed during the single agent studies and the combination 
studies were similar. The changes in clinical pathology were either due to the CCR2 
pharmacology (decreased monocytes) or FXR agonism and were similar in the combination 
studies compared to the single agent studies. The primary target organs observed 
microscopically were the liver, kidney and gastrointestinal tract and were similar in the 
combination studies compared to the single agent studies. The nature and the severity of the 
findings in these organs were also similar. In addition, minimal to mild increased marginal zone 
in the spleen was observed after 13 weeks of treatment at 30/0.5 mg/kg/day CVC/LJN452. 
Although the mechanism of action has not been determined, this change is consistent with a 
pharmacological inhibition of CCR2 in the spleen (Flaishon 2004 et al). The NOAEL in the 13 
week study was the high dose of 30/0.5 mg/kg/day CVC/LJN452.
In conclusion, the findings in the 4- and 13- week combination therapies were aligned with the 
findings observed in similar studies with the single agents and/or with their expected 
pharmacology.
Clinical tropifexor and cenicriviroc – drug-drug interaction results 
A single site, randomized, parallel 3-arm, double-blind, double-dummy drug-drug interaction 








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with CVC in clinical trials.
Tropifexor and cenicriviroc – clinical DDI and food 
The tropifexor + CVC drug-drug interaction study CLJC242A2101 in healthy subjects 
suggested that co-administration of CVC reduces tropifexor exposure (both Cmax and AUC 0-
24h) by about 35%. No safety concerns were identified at the doses of 60 µg tropifexor alone, 
150 mg CVC alone or their combination, administered once daily with a standard breakfast for 
14 days. In addition, an across-study exploratory comparison indicated that tropifexor plasma 
exposure (both Cmax and AUC) at 60 µg administered fasted (study CLJN452X2101) is similar 
to that at the same dose administered following a standard breakfast (study CLJC242A2101).
In summary, as compared to the fasted status, a high-fat meal increases tropifexor exposure but 
a standard meal appears not to. It is recommended that NASH patients, in this study, will be 
dosed following a standard meal without high fat (i.e. per AHA diet see appendix 17).
Tropifexor and cenicriviroc (combination) - safety considerations
In the DDI study (CLJC242A2101) the safety and tolerability of the combination treatment of
tropifexor + CVC were found to be comparable to those of each of the mono therapy treatment. 
No additional particular safety considerations are expected for the combination of tropifexor 
and cenicriviroc, beyond those previously observed for each of the individual monotherapies 
(see section 1.1 and section 3.6 for risks). As both drugs may increase liver transaminases, there 
is a potential for an additive effect, thus close liver monitoring is included.  Diarrhea has been 
identified as a non-serious adverse effect for cenicriviroc and is a possible (but unconfirmed) 
adverse effect of tropifexor from animal studies.
Tropifexor and cenicriviroc (combination) - rationale 
Due to the multifactorial etiology of NAFLD/NASH and limited monotherapy results so far, 
the combination therapy of compounds with different mechanisms of actions may provide more 
effective therapy for NASH patients. 
This study will combine the potent FXR agonist (anti-steatotic, anti-inflammatory and anti-
fibrotic) tropifexor and the CCR2/5 inhibitor (anti-inflammatory and anti-fibrotic) cenicriviroc.
The preclinical animal study STAM mouse models of diet induced NASH, shows that 
combination therapy of tropifexor and cenicriviroc have additive effects on steatosis, ballooning, 
and inflammation.
Both tropifexor and cenicriviroc as monotherapy are currently being evaluated in phase 2 and 
phase 3 clinical trials, respectively CLJN452A2202 (clinicalTrials.gov Identifier: 
NCT02855164) and AURORA (clinicalTrials.gov Identifier: NCT03028740), and to date have 
shown improvements on biomarkers and in case of cenicriviroc improvements in liver fibrosis 
in NASH patients. 
In summary, these two drugs have different mechanisms of action (FXR and CCR2/5 inhibitor), 
and this multi target approach may lead to greater efficacy than monotherapy alone. 


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1.2
Purpose
The purpose of this study is to assess the safety, tolerability, efficacy 
 of 
two regimens of tropifexor and cenicriviroc (CVC) (further described as tropifexor + CVC) 
compared to monotherapies tropifexor and CVC in patients with NASH and liver fibrosis. Data 
from this study will be used to evaluate whether further development of combination therapy 
with tropifexor + CVC in the treatment of patients with non-alcoholic steatohepatitis (NASH) 
and liver fibrosis is beneficial.
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 
To evaluate the safety and tolerability of  
tropifexor + CVC in patients with NASH and 
fibrosis (stage 2 or 3 as per NASH CRN 
histological score, F2/F3) by monitoring adverse 
events, vital signs and laboratory values during 
48 weeks of treatment as compared to 
monotherapy with each of tropifexor and CVC
Occurrence of adverse events, serious adverse 
events, adverse events resulting in 
discontinuation of study treatment, adverse 
events of special interest and changes in vital 
signs and laboratory values over 48 weeks of 
treatment
Secondary Objective(s)
Endpoint(s) for secondary objective(s)
To characterize the efficacy of tropifexor + CVC 
in patients with NASH with fibrosis stage F2/F3
as assessed by histological improvement  after 
48 weeks of treatment compared to 
monotherapies (tropifexor and CVC) compared 
to baseline biopsy
Proportion of patients who have at least a one 
point improvement in fibrosis 
Proportion of patients with resolution of 
steatohepatitis 


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3
Investigational plan
3.1
Study design
This study is a 48-weeks, randomized, double-blind, multicenter study that will consist of a 
screening period, a treatment period starting from randomization on Day 1 and running to Week 
48, and a follow up period of 4 weeks after the last dose of study treatment. The total study 
duration is up to 62 weeks.
The screening period starts from the time of the signing of informed consent and continues for 
up to 10 weeks when all inclusion/exclusion criteria have been evaluated and all baseline 
assessments have been performed. 
Patients are eligible to participate in the study if they have histological evidence of NASH and 
liver fibrosis stage 2 or 3 (NASH clinical research network (CRN) staging criteria) 




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3.2
Rationale for study design
A Novartis sponsored Phase 2 trial (CLJN452A2202) is ongoing, with the purpose to identify 
the appropriate doses of tropifexor in patients with NASH, the tropifexor doses selected for this 
study are based on the currently planned doses being utilized in that study (CLJN452A2202).
The availability of long term non-clinical toxicity data supports the treatment duration with 
tropifexor up to 48 weeks and the inclusion of a histological endpoint (GLP–toxicology studies 
of 13 weeks duration, and longer term GLP-toxicology of 26 weeks duration in rat and 39 weeks 
in dog studies (tropifexor IB). For tropifexor monotherapy a long term efficacy study 
(CLJN452A2202) is ongoing, with 48 week treatment period and safety follow-up to Week 52
which will provide the opportunity for evaluation of histological improvement by paired 
biopsies at Baseline and Week 48.
Paired liver biopsies at baseline and at Week 48 will be included for all patients in this study.  
Inclusion criteria will require histologic evidence consistent with NASH and fibrosis level, F2 
or F3 at baseline, based on liver biopsy (as determined by a central reader) obtained during the 
screening period or within 6 months before randomization.  
CVC at a dose of 150 mg once daily is currently in Phase 3 (AURORA) clinical development 
for the treatment of liver fibrosis in adults with NASH and in Phase 2 development in subjects 
with primary sclerosing cholangitis (PSC). Overall, over 1000 subjects have been exposed to 
CVC in both ongoing and completed studies (CVC IB).
In a 2-year placebo-controlled Phase 2b study (652-2-203-CENTAUR, Friedman et al 2017), 
289 adult patients with liver fibrosis and NASH were randomized. The recent data on CVC
reported significant antifibrotic benefit in subjects with NASH, in addition to decreasing 
markers of systemic inflammation.
All the available data for both compounds support the use of the tropifexor and CVC 
monotherapies and combination regimens for a total duration of 48 weeks. 
The current available reports of NASH monotherapy studies have been lacking significant 
efficacy. The expectation of a combined therapy is to improve efficacy based on the 
combination of different mechanisms of action. In this study we are combining a potent FXR 
(anti-steatotic, anti-inflammatory and anti-fibrotic) and a CCR2/5 inhibitor (anti-inflammatory
and anti-fibrotic).
The patient population will be described in more detail in Section 4 below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment 
Tropifexor is currently being studied in NASH as monotherapy in study CLJN452A2202. The 
initial range of doses of 10 µg to 90 µg tropifexor studied in CLJN452A2202 Part A were
chosen on the basis of safety and likely pharmacological activity, indicated by elevation of 
FGF19 up to 6 h after dosing in the First-in-Human study CLJN452X2101, and preclinical 
experience (tropifexor IB).
The DMC for study CLJN452A2202, upon review of CLJN452A2202 Part A data, 
recommended to investigate doses higher than 90 µg. The current non-clinical safety profile of 




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3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits
As well as the risks and potential risks described in the tropifexor and CVC (TBR-652) 
Investigators’ Brochures, there may be unknown risks to tropifexor and CVC which may be 
unforeseen.
Tropifexor
Based on the mechanism of action of tropifexor as a highly potent and specific agonist of the 
Farnesoid X Receptor (FXR) and data acquired in the First-in-Human study CLJN452X2101
and in nonclinical toxicology studies the risk-benefit assessment of tropifexor is as follows:
Transient and asymptomatic increases in ALT have been identified as an adverse reaction to 
tropifexor in healthy volunteers. Potential toxicities to be considered for tropifexor include more 
severe liver effects, gastrointestinal effects, coagulation effects, renal function abnormalities, 
and embryo-fetal toxicity. In addition it is anticipated that tropifexor
may have 
pharmacodynamic effects on drug metabolism and elimination. Guidelines for the evaluation 
and detection of these potential toxicities and for their management and for minimization of 
risk if they do arise are discussed in the tropifexor Investigator’s Brochure.
Tropifexor treatment may have the anticipated benefits on biliary metabolism (reduced 
synthesis and increased detoxification), lipid profile (lowering triglycerides) and anti-fibrotic 
activities (reduced hepatic fibrosis) may improve pathophysiology and patient outcomes over 
longer term treatment in longer-term development studies. 
In addition to usual study monitoring, patients’ liver tests will be followed closely, especially 
early in therapy, in conjunction with the Data Monitoring Committee (DMC), including 
frequent checks of a liver safety panel and drug dosage dose reduced or discontinued if 
necessary. 
Cenicriviroc
CVC is currently in Phase 3 clinical development for the treatment of liver fibrosis in adults 
with NASH and in Phase 2 development in subjects with primary sclerosing cholangitis (PSC). 
Overall, over 1000 subjects have been exposed to CVC in both ongoing and completed studies, 
with a maximum exposure available of ≥48 weeks of treatment in approximately 260 subjects. 
CVC doses ranged from 25 mg to 900 mg across all CVC studies. 
Study 652-2-203 (CENTAUR) is an ongoing 2-year placebo-controlled Phase 2b study in 289 
adult patients with liver fibrosis and NASH. CVC demonstrated significant antifibrotic benefits 
in adult subjects with NASH, in addition to decreasing markers of systemic inflammation after 
only one year of treatment (CVC IB).
Toxicology studies showed no target organ toxicity, thus no adverse liver findings, in mice or 
monkeys. In rats, the liver was the primary target organ identified in repeat dose studies, with 
biliary hyperplasia being the primary finding. Overall, the risk for hepatobiliary effects due to 
CVC appears to be low. The nonclinical data suggest that CVC will not adversely affect the 
liver at or near clinical exposures. Liver findings were present in only 1 of 3 species and when 




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4
Population
The study population will consist of approximately 200 adult male and female patients with 
histologic evidence of NASH and fibrosis (stage 2 or 3 as per NASH CRN histological score, 
F2/F3); see Inclusion and Exclusion criteria for details.
The study will be conducted in approximately 90 centers worldwide. Since a screening failure 
rate is expected to be around 66%, approximately 600 patients may be screened. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Male and female patients 18 years or older (at the time of the screening visit). Patients 
must weigh at least 50 kg (110 lb) and no more than 200 kg (440 lb) to participate in the 
study.
3. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4. Adequate liver biopsy sample for evaluation by a central reader.
5. Presence of NASH as demonstrated by histologic evidence based on liver biopsy - NASH 
with fibrosis stage F2/F3, demonstrated on liver biopsy with evaluation by central reading 
during the screening period. Alternatively, a historical biopsy can be used if performed 
within 6 months prior to screening and evaluated by central reader, if:

the patient has been receiving any of the therapies listed in Table 5-4, the dose must 
have been stable (since 1 month before the biopsy up to and including screening),

the patient’s weight has been stable (maximum weight loss of 10% since biopsy up to 
and including screening).
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days 
whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
3. Previous exposure to elafibranor, CVC, tropifexor, obeticholic acid (OCA), LMB763 or 
other FXR agonist.
4. Participated in a clinical trial and treated with any investigational product being evaluated 
for the treatment of liver fibrosis or NASH in the 6 months before screening (subjects 
documented to be assigned to placebo in such trials may be eligible immediately following 
completion of their participation in the previous trial).


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5. Patients taking medications prohibited by the protocol. An overview of prohibited 
medications is given in Table 5-2, and the summary of medications permitted only if on 
stable dose is in Table 5-4.
6. History of treated or untreated malignancy of any organ system, other than localized basal 
cell carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.
7. Pregnant or nursing (lactating) women.
8. 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 30 days after stopping of tropifexor and/or CVC medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
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 
investigational drug. 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 subjects on the study, 
the vasectomized male partner should be the sole partner for that subject.

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 investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) 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. 
Sexually active males must use a condom during intercourse while taking drug and for 30 days 
after stopping tropifexor and/or CVC 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. 
9. 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 more than 20 g/day in females and more than 30 g/day in males, on average) 
and/or a score on the modified AUDIT questionnaire ≥ 8


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10. Inability to reliably quantify alcohol consumption based upon local study physician 
judgment
11. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization. 
Marijuana use is not allowed if it is determined to be medically inappropriate by the 
investigator 
12. Prior or planned (during the study period) bariatric surgery (e.g. gastroplasty, roux-en-Y 
gastric bypass) 
13. Uncontrolled diabetes defined as HbA1c ≥ 9% at screening
14. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the 
presence of any of the following abnormalities (confirmed at screening visit 2):

Serum albumin <  3.2 g/dL

International Normalized Ratio (INR) > 1.3

Total bilirubin > 1.3 mg/dL (including Gilbert’s syndrome)

ALT or AST > 5× ULN 

Alkaline phosphatase > 300 IU/L

History of esophageal varices, ascites or hepatic encephalopathy

Splenomegaly 
15. Previous diagnosis of other forms of chronic liver disease:

Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) or hepatitis 
B core antibody (HBcAb) positive

Hepatitis C antibody (HCVAb) positive with the following 2 exceptions: 

Subjects previously treated for viral hepatitis C with at least a 3-year period since 
documented sustained virologic response at Week 12 (post-treatment) may be 
eligible if all other eligibility criteria are met

Subjects with presence of hepatitis C antibody but negative hepatitis C virus (HCV) 
ribonucleic acid (RNA) without treatment (i.e., spontaneous clearance) may be 
eligible if all other eligibility criteria are met

History of autoimmune liver disease:

Primary biliary cholangitis as defined by the presence of at least 2 of these criteria:

Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation

Presence of anti-mitochondrial antibodies (AMA)

Histologic evidence of nonsuppurative destructive cholangitis and destruction of 
interlobular bile ducts

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
History of Wilson's disease 

History of Alpha-1-antitrypsin (A1AT)  deficiency 

History of hemochromatosis or iron overload.

Drug-induced liver disease as defined on the basis of typical exposure and history

Known bile duct obstruction

Suspected or proven liver cancer

Any other type of liver disease other than NASH 
16. Calculated eGFR less than 60 mL/min/1.73m2 (using the MDRD formula)
17. History of biliary diversion 
18. History of liver transplantation or planned liver transplant
19. Known positivity for Human Immunodeficiency Virus (HIV) infection
20. Any other condition which, in the opinion of the investigator, would impede compliance or 
hinder completion of the study
21. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

QTcF interval of greater than 450 ms at screening

History of familial long QT syndrome or known family history of Torsades de Pointes
22. History of inflammatory bowel disease 
23. Patients who are not candidates for liver biopsy
24. Presence of cirrhosis on liver biopsy (F4 by NASH CRN System) or medical history 
25. Patients with an abnormal platelet count (see reference ranges in central laboratory manual) 
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Tropifexor:
Dosage form: 10 μg, 30 μg, 90 μg and 100 μg hard gelatin capsules.
Presentation: Bottles


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Tropifexor Placebo:
Dosage form: hard gelatin capsules
Presentation: Bottles
CVC:
Dosage form: 150 mg coated tablet
Presentation: Bottles
CVC Placebo:
Dosage form: coated tablet
Presentation: Bottles
Novartis will provide sufficient supplies of tropifexor and CVC to last each patient between 
visits (or more).
5.1.2
Additional treatment
No additional treatment beyond investigational drug and placebo is provided in this trial.
5.2
Treatment arms
Patients (n = 200) will be assigned at baseline visit to one of the following 4 treatment arms in 
a ratio of 1:1:1:1 in a blinded manner. Placebo capsules/tablets will be given in each treatment 
arm where necessary to maintain blinding.
Arm A: tropifexor 140 μg, once-daily
Arm B: CVC 150 mg, once-daily
Arm C: tropifexor 140 μg + CVC 150 mg, once-daily
Arm D: tropifexor 90 μg + CVC 150 mg, once-daily
In order to maintain the blind, placebo capsules matching tropifexor 10, 30, 90 and 100 µg 
capsules and placebo tablets matching CVC 150 mg will be given to patients as indicated in
Table 5-1, so that all patients will receive 3 capsules and 1 tablet per day. One capsule/tablet 
from each of the 4 bottles dispensed should be taken with food (e.g. immediately following a 
meal) and at about the same time each day. 
5.3
Treatment assignment and randomization
At baseline visit, all eligible patients/subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the caller.




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If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the appropriate 
eCRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to a certain treatment. Investigator staff will identify the 
study drug package(s) to dispense to the patient by contacting the IRT and obtaining the 
medication number(s). Immediately before dispensing the package to the patient, investigator 
staff will detach the outer part of the label from the packaging and affix it to the source 
document (Drug Label Form) for that patient’s unique subject number. 
For patients who are unable to come to the study site for their end-of-treatment visit (week-48)
and the liver biopsy visit as scheduled per study protocol due to the COVID-19 pandemic:- the
investigator may consider to extend the study treatment to allow the visit (including liver biopsy) 
to be performed later. This can be done using the following stepwise approach:

The study medication dispensed at week 40 should have about 2 weeks’ excess 
medication. The liver biopsy visit can be delayed until the medication runs out. 

If this is not sufficient, an unscheduled visit can be performed (by phone if necessary) 
and an additional 4-week supply of study medication requested via  IRT and send the 
medication to patient’s home address (if considered safe and appropriate). If feasible, 
central or local lab assessments (Liver tests, Serum BUN & Creatinine) should be 
performed every 8 weeks to monitor the patient’s safety.

If that is still not sufficient, a second 4-week supply of study medication can be 
requested via IRT. 
The Investigator should ensure that this study treatment extension is discussed with the 
impacted patients thoroughly, including the possible risks and benefits of longer treatment 
duration. The discussion and the patient’s willingness to extend the study treatment duration 
should be recorded in the source documents.
5.5.3
Handling of study and additional treatment 
5.5.3.1
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. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.


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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits and at the completion of the trial. Patients/subjects will be asked to 
return all unused study treatment and packaging at each visit or at the time of discontinuation 
of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment 
Patients should be instructed to take the dose of study medication daily, in the morning, with 
food (e.g. immediately after a meal) at approximately the same time each day except the days 
with a morning visit. On the days where there are study visits, if the visit is in the morning time, 
the patients should take their doses at the clinic following a meal. From the baseline day
onwards, patients will be instructed to take 1 tablet and 3 capsules each day during the duration 
of the study.
The patient will be dispensed 4 bottles for each 4 weeks period and should take one tablet from 
one bottle and 3 capsules (one from each of the other 3 bottles).
Table 5-1
Overview of treatment - type and number of capsules and tablets 
taken per day
Treatment 
arm
CVC 150 
mg tablet
CVC 
placebo
Tropifexor 
10µg 
capsule
Tropifexor
30µg 
capsule
Tropifexor 
90µg 
capsule
Tropifexor 
100µg 
capsule
Tropifexor 
placebo
A
0
1
1
1
0
1
0
B
1
0
0
0
0
0
3
C
1
0
1
1
0
1
0
D
1
0
0
0
1
0
2
Dosing recommendations:

Patients should take the medications in the morning with food (e.g. immediately after a 
meal) and at about the same time each day.

Patients should be instructed to swallow the capsules whole and not to chew them.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose.

Missed doses should not be made up.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 


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validity of the study. It should be emphasized to the patient that the study medication bottles 
are not identical; the patient must take one tablet or capsule from each bottle each day. The 
patient must also be instructed to contact the investigator if he/she is unable for any reason to 
take the study treatment as prescribed.
5.5.4.1
Dietary restrictions 
No alcohol consumption is allowed for 8 hours before each dose of study medication. Alcohol 
should also not be consumed for 8 hours before each study visit.
To keep the fat intake as constant as possible, patients participating in this study will be 
instructed to carefully adhere to American Heart Association (AHA) diet or local equivalent if 
there is a country specific recommended diet (Appendix 5). Patients will be asked about dietary 
compliance to the AHA diet (or local equivalent) as outlined in Table 6-1. Patients should also 
be counseled regarding appropriate exercise as per local standards, and will be asked about their 
exercise as outlined in Table 6-1.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
For potential drug-related adverse events, temporary interruptions are permitted up to 28 
consecutive days. Study drugs can be reintroduced under careful monitoring if the investigator 
feels it is in the best interest of the patient. Interruption of study drug for more than 28 
consecutive days should lead to permanent discontinuation of the patient from study drug with 
the respective follow-up visits. 
Investigational treatment dose adjustments are not permitted.
These changes must be recorded on the appropriate eCRF.
5.5.6
Rescue medication
Use of rescue medication is not allowed in this study.
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the appropriate eCRF.
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 patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Use of the treatments displayed in the below table (Table 5-2) is NOT allowed after the start of 
investigational drug. 


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Table 5-2
Prohibited medications
Medication
Guidance
Inhibitors, inducers and sensitive substrates of drug metabolizing enzymes
Specific UGT1A1 inhibitors:
atazanavir, gemfibrozil, indinavir, itraconazole, ketoconazole, 
manidipine, and zafirlukast
Prohibited from first drug 
intake to end-of-study visit
Herbal remedies inhibiting UGT1A1: 
Silybum marianum (sylamarin, milk thistle) and Valeriana 
officinalis (valerian)
Prohibited from first drug 
intake to end-of-study visit
Non-selective UGT inhibitors: 
diclofenac, probenecid, valproic acid 
Prohibited  from first drug 
intake to end-of-study visit
Strong CYP3A4 inhibitors:
VIEKIRA PAK2, indinavir/ritonavir, tipranavir/ritonavir, ritonavir, 
cobicistat (GS-9350), indinavir, ketoconazole, troleandomycin, 
telaprevir, danoprevir/ritonavir, elvitegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, 
voriconazole,mibefradil, LCL161, clarithromycin, posaconazole, 
telithromycin, grapefruit juice, conivaptan, nefazodone, 
nelfinavir, saquinavir, idelalisib, boceprevir, darunavir/ritonavir.
Prohibited use from first drug 
intake to end-of-study visit
Strong CYP3A4 inducers:
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort
(Hypericum perforatum), rifabutin, phenobarbital, mitotane, 
enzalutamide.
Prohibited from first drug 
intake to end-of-study visit
Strong CYP2C8 inhibitors:
gemfibrozil, clopidrogrel.
Prohibited from first drug 
intake to end-of-study visit
Sensitive CYP3A4 substrates with narrow therapeutic index (i.e. 
drugs that should not be co-administered with weak CYP3A4 
inhibitors):
astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergonovine, ergotamine, ergotamine, methylergonovine, 
pimozide, quinidine, sirolimus, tacrolimus, terfanadine, 
thioridazine. 
Prohibited from first drug 
intake to end-of-study visit
Sensitive CYP3A4 substrates exceptions: 
midazolam, triazolam
Use only allowed for sedation 
on the day of the liver biopsy 
or for surgical outpatient 
procedures. If given after 
intake of study drug, the first 
dose should be reduced by 
50% of the recommended 
dose and titrated according to 
the desired clinical response.
Sensitive CYP3A4 substrates exceptions: 
intravenous alfentanil or fentanyl
Use is allowed for sedation on 
the day of screening biopsy 
but is not allowed for any 
procedure after intake of 
study drug.
Sulfasalazine and methotrexate
Prohibited from first drug 
intake to end-of-study visit


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Medication
Guidance
Vitamin E
Prohibited at doses 
> 400 IU/day 
5.5.8.1
Drugs to be used with restrictions
If required, the medications specified on Table 5-3 should be used with caution, at the lowest 
dose possible and for the shortest duration possible considering individual subject risk-benefit 
considerations. Clinical monitoring and dose titration are recommended to achieve the desired 
clinical response. Other medications of a similar class should be considered if possible. Consult 
the individual medication prescribing information for additional guidance. 
Table 5-3
Drugs that are allowed but must be taken with caution
Medication
Guidance
Acid-reducing agents 
(H2 receptor 
antagonists, proton-
pump inhibitors)
Acid reducing agents should be administered at least 2 hours after study 
drug administration. When possible, use of an H2 receptor antagonists 
(except cimetidine) or antiacids is preferred over a proton-pump 
inhibitor. It is recommended to start with the lowest dose of these agents 
and titrate according to clinical response.
H2 receptor antagonists (e.g. famotidine or ranitidine) should preferably 
be given from 2 to 12 hours after administration of study drug at a dose 
that does not exceed doses comparable to famotidine 40 mg daily.
Antiacids (e.g. aluminium hydroxide, calcium carbonate, magnesium 
carbonate, magnesium hydroxide or bismuth subsalicylate) should 
preferably be given at least 4 hours after administration of study 
PPIs (e.g., omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole, or delansoprazole) should preferably be given 
approximately 3 hours after administration of study drug at a dose that 
does not exceed doses comparable to omeprazole 20 mg daily. 
Lipid lowering agents
The maximum recommended daily doses  of atorvastatin, simvastatin,
lovastatin (CYP3A4 substrates), pravastatin (CYP3A4 substrate and 
weak CYP2C8 inhibitor) and rosuvastatin (BCRP substrate) are
restricted as follows: atorvastatin 40 mg, simvastatin 10 mg, lovastatin 
40 mg, pravastatin 40 mg, and rosuvastatin 10 mg; pitavastatin use is 
allowed without dose restriction.
CVC may increase the exposure of rosuvastatin and simvastatin and 
patients taking these drugs concomitantly could be at increased risk for 
adverse effects. Monitor patients closely for symptoms of myopathy or 
liver injury.
PDE5 inhibitors
The recommended starting doses for these CYP3A4 substrates are as 
follows: sildenafil 25 mg, tadalafil 2.5 mg and vardeafil 2.5 mg.
Patients on medications specified in Table 5-4 can be included if the dose has been stable for at 
least 1 month before the baseline biopsy (historical or performed during screening). 
A stable dose is defined as a dose within 25% of the baseline dose. 
No new use of the medications in Table 5-4 is allowed between 1 month before the baseline 
biopsy and until Study Completion.


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Table 5-4
Medications permitted only if dose is stable within 25 percent of 
baseline dose
Medication
Oral anti-diabetic medications such as pioglitazone, metformin and/or sulfonylureas
GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide  
Fibrates,  niacin 
Vitamin E 
Pentoxifylline
5.5.9
Emergency breaking of assigned treatment code 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
Study treatment must be discontinued after emergency unblinding. The appropriate personnel 
from the study site and Novartis will assess whether study treatment should be discontinued for 
any patient whose treatment code has been broken inadvertently for any reason.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Continuing care should be provided by investigator and/or referring physician based on patient 
availability for follow-up. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
This continuing care for patients who complete 48 weeks of treatment may include enrollment 
in an extension study, if any, to allow for therapy beyond 48 weeks.
For all patients who discontinue treatment early or who complete treatment and do not rollover 
to an extension study (if available), a safety follow-up visit (visit EOS) should be conducted 4 
weeks after last treatment (EOT, Week 48). The information to be collected at this follow up 
visit includes concomitant medications, adverse events, and laboratory samples, as detailed on
Table 6-1.


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5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. The 
investigator must discontinue study treatment for a given patient if, on balance, he/she believes 
that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances: 

Patient wish

Pregnancy (Ref. protocol Section 6.5.6 and Section 7.6)

Use of prohibited treatment as per recommendations (Section 5.5.8)

Any situation in which study participation might result in a safety risk to the patient

Emergence of the following adverse events:

Hypersensitivity reaction to tropifexor or CVC

For ALT, AST, total bilirubin and/or alkaline phosphatase elevations mandating study 
treatment discontinuations (Section 7.3 and Table 14-1 for further instructions and 
monitoring).

Specified renal events (Section 7.4 and Table 15-1 for further instructions and 
monitoring).

Other SAE that are related to study drug.

Other life-threatening SAE regardless of attribution to study drug.

Any other adverse events, abnormal laboratory values or abnormal test result that 
indicate a safety risk to the patient.

Decompensated cirrhosis as defined by ascites, bleeding esophageal varices, hepatic 
encephalopathy, jaundice or any other liver decompensation related symptom.
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently for 
any reason. Study treatment must be discontinued after emergency unblinding. If 
discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after discontinuation 
of study drug, for a study treatment discontinuation visit. Treatment discontinuation visit 
assessments detailed in the treatment discontinuation visit (TD) in Table 6-1 should be 
completed and recorded in the appropriate eCRF. The investigator must determine the primary 
reason for the patient’s premature discontinuation of study treatment and record this 
information on the appropriate eCRF. The investigator must also contact the IRT to register the 
patient’s discontinuation from study treatment.
During the Treatment discontinuation visit (TD), at least the following data should be collected:

new/concomitant treatments

adverse events/Serious Adverse Events
For patients who discontinue study treatment prematurely before the end of the treatment period 
for any reason other than withdrawal of informed consent, the TD visit (EOT) and Week 52 
(EOS) visits must be performed.


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If study drug discontinuation occurs because treatment code has been broken, refer to protocol 
Section 5.5.9.
5.6.3
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:
•Does not want to participate in the study anymore, and
•Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in Table 6-
1.
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
5.6.4
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her planned end of study visit has passed.
5.6.5
Early study termination by the sponsor
The study can be 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, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 


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adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
An ‘S’ indicates the data for that assessment are in the source documents at the site.
Patients who have been screened and have a screening visit recorded in the IRT system at the 
time that the planned enrollment number is met will be allowed to enter the trial and to be 
randomized if they are eligible.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit 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 reconciled on the appropriate eCRF.
For patients who are unable to come to the study site for their scheduled visit due to COVID-
19 pandemic and related measures, consider to conduct patient study visits on schedule as a 
remote consultation (except the Week 48, End Of Treatment visit) and send the medication to 
patient’s home adress (if considered safe and appropriate). At these visits, the occurence of AEs 
or SAEs, change in co-medications, study drug compliance, alcohol and AHA diet compliance  
should be determined. Patients with child bearing potential  must be reminded to perform urine 
pregnacy test at home every 4 weeks.
Any unplanned assessments for: Vital signs, ECG, Hepatitis serology, Liver tests, Serum BUN 
and Creatinine, Coagulation panel, 
 
 Clinical chemistry panel, HbA1c, Urinalysis and Serum pregnancy test must be 
recorded in the unplanned eCRF.
For patients who discontinue study treatment prematurely before the end of the treatment period 
for any reason other than withdrawal of informed consent, the Week 48, planned End of 
Treatment (EOT) and Week 52 End of Study (EOS) visits must be performed.
If a patient refuses to return for these assessments or is unable to do so, every effort should be 
made to contact them, or a knowledgeable informant, by telephone or by sending appropriate 
correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g. potential 
occurrence of AEs or SAEs) and the primary reason for the patient’s premature withdrawal 
should be determined. Documentation of attempts to contact the patient should be recorded in 
the patient source documents.
Refer to Section 5.6 for additional details regarding procedures for patients who discontinue 
study treatment or prematurely withdraw. 
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment. 


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Patients who develop medically important laboratory abnormalities or medically important 
adverse events (AE) that are considered related to study drug will be followed beyond the End 
of Study visit until these events have resolved or stabilized.
The following will be considered as medically important:
i.
severe AEs,
ii.
serious AEs,
iii.
hepatic and renal AEs,
iv.
elevated liver enzymes (ALT, AST or alkaline phosphatase >2x ULN and >1.5x 
baseline).


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Table 6-1
Assessment schedule
Periods
Screening
Treatment Period 
Post 
Treatment 
Follow Up
Notes
Week
-10 
to    
-2
-21
(no 
later 
than)2
BSL
2
4
8
12
16
24
32
40
4816
TD/EOT
52
EOS
Screening
Informed consent
X
Pharmacogenetic 
informed consent
X
Inclusion / Exclusion 
criteria
X
X
X
Demography
X
Medical history/ current 
medical conditions
X
Protocol solicited medical 
history
X
Assessments
Physical examination3
S
S
S
S
S
S
S
S
S
S
S
S
Prior and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Surgical and medical 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol history / 
compliance with protocol
X 
X 
X
X
X
X
X
X
X
X
X
X
X
Smoking history
X


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Periods
Screening
Treatment Period 
Post 
Treatment 
Follow Up
Notes
Week
-10 
to    
-2
-21
(no 
later 
than)2
BSL
2
4
8
12
16
24
32
40
4816
TD/EOT
52
EOS
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG4
X
X
X
Liver Biopsy14
X
X
Biopsy to be 
performed no later 
than 2 weeks prior 
randomization
Adverse Events  / Serious 
AE
X
X
X
X
X
X
X
X
X
X
X
X
X


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Periods
Screening
Treatment Period 
Post 
Treatment 
Follow Up
Notes
Week
-10 
to    
-2
-21
(no 
later 
than)2
BSL
2
4
8
12
16
24
32
40
4816
TD/EOT
52
EOS
Modified AUDIT 
questionnaire15
X
X
X
X
X
X
X
X
X
X
X
X
Randomization via IRT
S
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
S
S
S
S
S
S
S
S
Drug administration record
X
X
X
X
X
X
X
X
X
Drug compliance
S
S
S
S
S
S
S
S
AHA Diet Review
S
S
S
S
S
S
S
S
S
Diet Compliance
X
X
X
X
X
Exercise assessment
S
S
S
S
S
Blood collection
Hepatitis serology5
X
Liver tests
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum BUN and 
Creatinine
X
X
X
X
X
X
X
X
X
X
X
Coagulation panel
X
X
X
X
X
X
Only INR at screening 
visit 2


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Periods
Screening
Treatment Period 
Post 
Treatment 
Follow Up
Notes
Week
-10 
to    
-2
-21
(no 
later 
than)2
BSL
2
4
8
12
16
24
32
40
4816
TD/EOT
52
EOS
Hematology
X
X
X
X
X
X
X
Clinical chemistry panel7
X
X
X
X
X
X
X
HbA1c
X


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Periods
Screening
Treatment Period 
Post 
Treatment 
Follow Up
Notes
Week
-10 
to    
-2
-21
(no 
later 
than)2
BSL
2
4
8
12
16
24
32
40
4816
TD/EOT
52
EOS
Urine
Dipstick / routine 
Urinalysis with Reflex 
Micro
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test12
X
Urine pregnancy test12
S
S
S
S
S
S
S
S
S
S
S
S
The urine pregnancy 
test should be 
performed every 4 
weeks up to the follow 
up visit, including at 
week 20, 28, 36 and 
44, and during any
treatment extension 
period.
Drug screen
X
X
Study Completion Form
X






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6.1
Information to be collected on screening failures 
All patients who have signed informed consent and discontinue before randomization into the 
study at Baseline Visit are considered screening failures. If a patient discontinues before 
entering the treatment epoch, IRT must be notified within 2 days and the reason for not entering 
the study will be recorded on the appropriate eCRF. In addition, the following eCRFs should 
be completed: Visit Date, Informed Consent, Demography, Inclusion/Exclusion Criteria, 
Subject Re-Screening (if applicable), Disposition, Withdrawal of Consent (if applicable) and 
AE should be completed for any SAEs that occurred during the screening epoch. Adverse events 
that are not SAEs will be followed by the investigator and collected only in the source data.
If a patient is a screening failure, but is rescreened and subsequently enrolled, the reason for the 
original screening failure must be documented in the source documents. A new subject ID will 
be assigned to the patient.  
If for any reason the patient is a screen failure, the patient may be rescreened. There is no 
restriction on the number of times a potential patient may be rescreened or on how much time 
must pass from the date of screen failure and the date of rescreening.
If a patient rescreens for the study, THEN the patient must sign a new ICF and be issued a new 
patient number prior to any screening assessment being conducted for the patient under the new 
screening patient number. For all patients, the investigator/qualified site staff will record if the 
patient was rescreened on the rescreening eCRF and any applicable screening numbers the 
patient was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the Informed Consent eCRF 
to correspond to the new screening patient number. Informed Consent for a rescreened patient 
must be obtained prior to performing any study-related assessment or collecting any data for 
the new Screening Visit. For rescreening, all screening assessments must be performed as per 
protocol.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
6.1.1
Pre-screening
Prior to screening visit 1 optional pre-screening assessments may be carried out, including 
 assessments and/or local laboratory tests (HbA1c, platelets, INR, total bilirubin, ALT, 
AST, Alkaline phosphatase and serum albumin as applicable) to assess patient eligibility for 
inclusion. Prior to any assessments being carried out the pre-screening informed consent form 
must be signed by the patient.
Only data related to SAE’s 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.


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6.2
Patient demographics/other baseline characteristics
All baseline assessments should be performed prior to first study treatment administration. 
These may be in the screening period (e.g. demographics) or at the Randomization Visit (e.g. 
PROs), depending on the assessment. 
6.2.1
Demographic Information
Patient demographic data to be collected at screening on all patients include: age, gender, race, 
ethnicity and child-bearing potential (for females only).
6.2.2
Medical history
Any relevant medical history including surgical/medical procedures, protocol solicited medical 
history, and/or current medical conditions before obtaining informed consent will be recorded 
in the Medical History eCRF. Significant findings that are observed after the patient has signed 
the informed consent form and that meet the definition of an AE must also be recorded in the 
AE eCRF (see Section 7.1 for the timeframe to record AEs during the screening period). 
Whenever possible, diagnoses and not symptoms will be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2.3
Alcohol history and assessments
Any history of alcohol use will be recorded in the eCRF. Further, the Alcohol Use Disorders 
Identification Test (AUDIT) will be administered to the patients at the screening visit 2 and as 
indicated in Table 6-1. At screening visit 2 the 10-item questionnaire will be used, whereas at 
the following visits, the shortened version (AUDIT-C), a 3-item questionnaire will be used.
6.2.4
Smoking history
The current and/or previous use of tobacco products will be recorded, as well as the estimated 
number of pack-years based on the approximate consumption per year. Non-smokers will be 
advised not to start smoking during the study.
6.2.5
Prior and concomitant medications 
Concomitant medications and prior medications taken over the 6 months preceding study 
enrollment will be captured at the screening visit, and updated at the baseline visit. 
6.2.6
Liver evaluation 
6.2.6.1
Liver biopsy 
Patients must have histologic evidence of NASH and liver fibrosis stage 2 or 3 (NASH clinical 
research network (CRN) staging criteria) demonstrated on liver biopsy during the Screening 
period. Alternatively, a historical biopsy can be used if performed within 6 months prior to 
screening, if:




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6.2.8
Screening visit 2 – additional assessments
The second screening visit should only be conducted if eligibility is confirmed at screening visit 
1. Assessments for this visit include: Liver biopsy,
 
and other non-lab assessments as indicated in Table 6-1.
The period between screening visit 1 and the anticipated randomization / baseline visit is a
maximum of 10 weeks. Screening visit 2 should be done at least two weeks prior baseline visit 
to allow sufficient time for liver biopsy central reading.
A repeat of the liver test, INR as well as the serum pregnancy test (if applicable). Both repeat 
tests should be in compliance with protocol requirements before randomization of the patient. 
6.3
Treatment exposure and compliance
All doses of study treatment administration will be recorded on the appropriate CRF page. 
Compliance will be assessed by means of site and subject-specific drug accountability by
Novartis study personnel during the site monitoring visits using medication pack numbers,
Drug Label Form information and information collected by IRT.
6.4
Efficacy
All efficacy assessments should be performed prior to the administration of study treatment. 
The recommended order for the efficacy assessments is described below. 
All remaining study visits procedures (e.g. laboratory samples collection, vital signs 
measurement, 
 etc.) must be completed prior to administration of study treatment. 


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6.4.2
Liver tests
ALT, AST, GGT, total alkaline phosphatase (and isoenzymes if total alkaline phosphatase 
is > ULN, and 5’nucleotidase if either GGT or total alkaline phosphatase is > ULN during study 
participation), total bilirubin, direct bilirubin and albumin will be assessed as indicated in Table 
6-1.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reactive bilirubin will be quantified. The methods for assessment and recording are 
specified in the laboratory manual. Some of the liver tests may be completed as part of the blood 
chemistry panel.
6.4.3
Coagulation tests
Coagulation parameters including APTT, PT, INR and TT will be assessed as indicated in Table 
6-1.
The methods for assessment and recording are specified in the laboratory manual.


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6.4.9
Liver biopsy
Patients will have paired liver biopsies (Baseline and EOT, after 48 weeks of treatment).  
Fibrosis staging and scores of steatohepatitis markers (steatosis,
 
) 
 will be determined by a Central Reader. Five (5) to eight 
(8) unstained liver biopsy sections, must be prepared and submitted to the central 
histopathologist who will confirm eligibility prior to randomization.  If a suitable historical 
biopsy sample from which slides can be prepared is not available, the liver biopsy can be 
performed any time during the 10 week screening period, and should only be performed in 
subjects who fulfill Screening visit 1 inclusion criteria.  
 
  Additional details regarding liver biopsy requirements can be found in 
the accompanying central biopsy manual. 


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6.4.10
Appropriateness of efficacy assessments
The secondary 
 for this protocol include direct markers of NASH as 
measured by liver histology. The secondary efficacy variables selected for this protocol are to 
detect clinically meaningful changes in liver fat, liver enzymes and indirect markers of NASH. 
Improvement in steatosis and fibrosis as determined by liver histology is recommended as a 
valid endpoint by regulators (Sanyal et al 2016).
.
6.5
Safety
Standard safety parameters and measures will be collected including adverse events and serious 
adverse events according to definitions and process detailed in the protocol.
6.5.1
Physical examination 
A physical examination of the patient will be performed on patients according to the schedule 
defined in Table 6-1.
A complete physical examination will include the examination of general appearance, hydration 
status, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular and neurological systems. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
Information for physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing the Informed Consent Form must 
be included in the Medical History screen on the patient’s CRF. Significant findings that occur 
after signing the Informed Consent Form which meet the definition of an AE must be recorded 
in the Adverse Event screen of the patient’s CRF (Section 7).




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One sample of serum will be frozen and stored. This sample will be used to repeat study lab 
tests when needed. It may also be used for additional testing. 
6.5.4.1
Hematology
Red blood cell (RBC) count, hemoglobin (Hb), hematocrit, mean corpuscular volume (MCV), 
white blood cell (WBC) count, absolute differential WBC count, and platelet count will be 
measured as indicated in Table 6-1.
6.5.4.2
Clinical chemistry
The following will be measured as indicated in Table 6-1:
Clinical chemistry:  sodium, potassium, chloride, bicarbonate, calcium, phosphate, blood urea 
nitrogen (BUN)/urea, serum creatinine, uric acid, creatine kinase, total protein, 
 
haptoglobin and HbA1c. The estimated glomerular filtration rate (eGFR) will be calculated 
using the MDRD formula based on the patient’s age at the time of measurement, gender and 
race. 
At screening visit 1, the following assessments will be included: HbA1c, ferritin, transferrin 
saturation, iron, and if not historically available also ANA, ASMA, and AMA.
Optional: If the investigator requires additional data to evaluate the current alcohol use of the 
patient at the screening visit, the carbohydrate deficient transferrin (CDT) test can be assessed 
using the central lab.
Liver tests: see Section 6.4.2
Coagulation: see Section 6.4.3
6.5.4.3
Urinalysis
A clean-catch midstream urine sample (approx. 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments, as indicated 
in Table 6-1.
Parameters to be evaluated by urine dipstick test will include specific gravity, pH, glucose, 
protein, bilirubin, ketones, nitrite, leukocytes and blood. Standard microscopic evaluation of 
urinary sediments will be performed if the urine dipstick test shows abnormalities.
Spot urine for calculation of protein to creatinine ratio can be aliquoted from the clean-catch 
urine specimen.
6.5.5
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions.


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Single 12 lead ECGs are collected. The original ECGs on non-heat sensitive paper, 
appropriately signed, must be collected and archived at the study site. The original trace will be 
sent electronically for central review directly from the ECG machine.
A standard 12-lead ECG will be recorded at the visits indicated in Table 6-1. 
All ECGs must be performed on the ECG machines provided for the study.
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual.
12-lead ECG parameters (RR [Heart Rate], PR, QRS, and QT) are to be assessed.
Each ECG tracing must be labeled with study number, subject initials, subject number, date and 
time, and filed in the study site source documents. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), the ECG is repeated to confirm the 
diagnosis and both ECGs sent to the core laboratory for expedited review if applicable.
Clinically significant abnormalities must be recorded on the relevant section of the appropriate 
CRFs capturing medical history/Current medical conditions/AE as appropriate.
6.5.6
Pregnancy and assessments of fertility 
A positive test at Screening Visit and/or Baseline Visit is an exclusion criterion for participating 
in the study. The urine pregnancy test will be repeated every four weeks up to the follow up 
visit (see Table 6-1) including at weeks 20, 28, 36,44 and during any treatment extension period . 
The tests will be performed at the clinical center or at patient’s home. In case of home pregnancy 
test, the patients will be provided with urine pregnancy test kits. The result must be provided to 
the investigator at next scheduled visit, in case of positive test the patient must contact 
investigator immediately. A positive urine pregnancy test after start of study drug requires 
immediate interruption of study drug until serum hCG is performed and found to be negative. 
If positive, the patient will enter the post-treatment follow up period. See also Section 5.6.2.
Additional pregnancy testing might be performed if requested by local requirements.
6.5.7
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population and have 
been used in previous trials in this indication or deemed appropriate based on non-clinical and 
early clinical experience. Patients are seen frequently during treatment and will be assessed for 
safety parameters
6.6
Other assessments
No additional tests will be performed on patients/subjects entered into this study.


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6.6.1
Clinical Outcome Assessments
6.6.1.1
Patient Reported Outcomes (PRO)


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Trial feedback questionnaire
This trial will include an anonymized questionnaire, ‘Trial Feedback Questionnaire’ for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses would be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or adverse events 


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and therefore would not be trial data. Should any spontaneous information be collected about 
AEs, this would be transferred to the safety database.
6.6.2
Resource utilization
Not applicable.


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7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [possibly including abnormal laboratory findings - see below], symptom or 
disease) in a subject or clinical investigation subject after providing written informed consent 
for participation in the study until the end of study visit. Therefore, an AE may or may not be 
temporally or causally associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.


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The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the appropriate CRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information:

the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment 

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met

action taken regarding [investigational] treatment

its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown)
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

[investigational] treatment interrupted/withdrawn

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 


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any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product 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 has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE 
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:

is fatal or life-threatening 

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:

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

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 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 (Annex IV, ICH-E12D Guideline).


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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 patient or might 
require intervention to prevent one of the other outcomes listed above. 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 (Annex IV, ICH-E12D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 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. 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 with study procedures 
(i.e. blood sampling).
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 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
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. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert and 
is thought to be related to the study treatment a Patient Safety 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 




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
Rule out acute viral hepatitis Types A, B, C, D, and alcoholic hepatitis; hypoxic/ischemic 
hepatopathy; autoimmune hepatitis and biliary tract disease

Obtain a history of exposure to environmental chemical agents
These investigations can include serology tests, liver biopsy, imaging and pathology 
assessments, hepatologist’s consultancy, based on investigator’s discretion. 
Any cases of possible drug-related liver injury will be blindly adjudicated by a hepatologist 
with expertise in drug-related liver injury and as necessary reviewed by the DMC which 
includes additional hepatologists.
Subjects 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 subject is asymptomatic. All follow-up information, and the procedures 
performed must be recorded on the appropriate CRFs.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria;

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in
Appendix 3. 
7.5
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, patient or 
consumer (European Medicines Agency definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
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 collected in 
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.


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Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in CRF 
(Yes/No)
Document in  eCRF 
capturing AE
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
7.6
Pregnancy reporting
To ensure patient safety, any pregnancy occurring in a study subject or their partner 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Patient Safety 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 SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner.
8
Data review and database management 
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (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 patient records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, 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 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 






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9
Data analysis
The final (end-of study) analysis will be conducted on all patient data collected up to the Week 
52 visit.
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
9.1
Analysis sets 

Screened set (SCR) – All patients who signed the informed consent.

Randomized set (RAN) – All patients who received a randomization number, regardless of 
receiving trial medication.

Full analysis set (FAS) – All patients to whom study treatment has been assigned*. 
Following the intent-to-treat (ITT) principle, patients are analyzed according to the 
treatment they have been assigned to at randomization.

Safety set (SAF) - All patients who received at least one dose of study drug and have at least 
one post-baseline safety assessment. Of note, the statement that a patient had no adverse 
events also constitutes a safety assessment. Patients will be analyzed according to the 
treatment received. 
*excluding patients who were mis-randomized and did not take investigational drug. Mis-
randomized patients are those who were not qualified for randomization, but were inadvertently 
randomized into the study.
The number of patients in each analysis set will be presented by treatment group and overall for 
the screened set.
9.2
Patient demographics and other baseline characteristics
Demographic variables and other baseline characteristics will be summarized for the FAS. 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
presented for continuous variables for each treatment group and for all patients (total). The 
number and percentage of patients in each category will be presented for categorical variables 
for each treatment group and all patients (total). In addition, all relevant medical history, and 
protocol solicited medical history will be summarized by treatment group.
9.3
Treatments
The duration of investigational treatment exposure (days) will be summarized by treatment 
group for the SAF, both descriptively (i.e. mean, standard deviation, median, quartiles, 
minimum and maximum) and by duration category (e.g. weeks).
The proportion of patients with dose reduction will be presented by treatment group.
Medications will be identified using the WHO dictionary including ATC code and presented 
for the SAF. Prior medications are defined as any medications taken prior to the randomization 
visit (regardless of whether they are stopped or continued after randomization).  Concomitant 
medications and significant non-drug therapies are defined as those used during the double-


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blind period. Prior and concomitant medications will be summarized by treatment group in 
separate tables. Medications will be presented in alphabetical order, by ATC codes and grouped 
by anatomical main group (the first level of the ATC code). Tables will also show the overall 
number and percentage of subjects receiving at least one drug of a particular ATC code and at 
least one drug in a particular anatomical main group.
Concomitant medications that were prohibited as per protocol and given during the conduct of 
the study as well as significant non-drug therapies will be provided in separate tables.
9.4
Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
Safety (to be assessed in SAF):

Occurrence of adverse events

Occurrence of serious adverse events

Occurrence of adverse events resulting in permanent discontinuation

Occurrence of adverse events of special interest

Changes in Vital signs

Changes in Laboratory data
9.4.2
Statistical model, hypothesis, and method of analysis
There are no pre-specified hypotheses and statistical models in this study. The methods to 
analyze the primary safety variables are outlined in Table 9-1.
Table 9-1
Primary variables and methods of analysis
Variable
Method of analysis
Occurrence of  adverse events
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of  serious adverse events
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of adverse events resulting in 
discontinuation or dose reduction of study 
treatment
Summary table of absolute and relative 
frequency, overall and by preferred term
Occurrence of adverse events of special interest
Summary table of absolute and relative 
frequency, overall and by type of AE as the 
risks are described for both tropifexor and CVC 
(risk definition for tropifexor are those that 
appear  in in tropifexor and CVC IB)
Changes in vital signs
Descriptive statistics by visit 
Changes in Laboratory data
Descriptive statistics by visit
9.4.3
Handling of missing values/censoring/discontinuations
Imputation of incomplete adverse events start and end dates will follow standard conventions 
and will be described in detail in the statistical analysis plan.


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9.4.4
Sensitivity analyses
No sensitivity analyses are planned for the assessment of the primary variables.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
An overview of the secondary efficacy variables and planned analysis is given in Table 9-2.
Table 9-2
Secondary efficacy variables and analyses
Variable
Analysis
At least a one point improvement of fibrosis 
Cochran-Mantel-Haenszel test controlling for 
baseline fibrosis stage for each tropifexor + CVC 
combination vs. each monotherapy treatment, 
with supporting information from risk differences, 
odds ratios with 95% confidence intervals
Resolution of steatohepatitis (as determined by 
central pathologist)
Cochran-Mantel-Haenszel controlling for baseline 
fibrosis stage for each tropifexor + CVC 
combination vs. each monotherapy treatment, 
with supporting information from risk differences, 
odds ratios with 95% confidence intervals
There is a single secondary objective in this study which is to characterize the efficacy of 
tropifexor + CVC in patients with NASH with fibrosis stage F2/F3 as assessed by histological 
improvement  after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) 
relative to baseline biopsy.  There are two estimands that will be used to evaluate this objective.
The first estimand is the difference on the proportion of patients on the different 
tropifexor + CVC regimens who achieve at least a one point improvement in fibrosis at Week 
48 compared to tropifexor and CVC monotherapy patients.  It is assumed that anyone who does 
not have a Week 48 liver biopsy or does not remain on their randomized study treatment for at 
least 24 weeks (even if a Week 48 biopsy was obtained) will have their outcome imputed by 
multiple imputation (MI). For subjects who remain on their randomized study treatment for at 
least 24 weeks, but discontinue study treatment prior to Week 48, available Week 48 biopsy 
results will be used as observed.  This is a hypothetical strategy addressing the question “what 
would be the outcome if subjects had stayed at least 24 weeks on treatment and a Week 48 
biopsy had been obtained”. Treatment differences between tropifexor + CVC combination 
therapy and monotherapy with tropifexor or CVC will be evaluated using a Cochran-Mantel-
Haenszel test controlling for baseline fibrosis stage (F2/F3). The estimand will be evaluated in 
the FAS population.  
The second estimand is the difference in the proportion of patients on the different 
tropifexor + CVC regimens who achieve resolution of steatohepatitis at Week 48 relative to 
baseline compared to tropifexor and CVC monotherapy patients.  It is assumed that anyone who 
does not have a Week 48 liver biopsy result or does not remain on their randomized study 
treatment for at least 24 weeks will have their outcome imputed by multiple imputation (MI). 
The handling of intercurrent events (discontinuation of assigned treatment) is equivalent to the 
first estimand as described above Treatment differences between tropifexor + CVC combination 
therapy and monotherapy with tropifexor or CVC will be evaluated using a Cochran-Mantel-


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Haenszel test controlling for baseline fibrosis stage (F2/F3). The estimand will be evaluated in 
the FAS population. 
Due to COVID-19 pandemic, it may not be possible for patients to return on time for Week 48
visit to perform liver biopsy and according to drug dispensing plan in Section 5.5.2, the Week 
48 liver biopsy can be delayed by approximately 10 weeks. Since the purpose of the secondary 
efficacy analysis is to evaluate the potential histological benefit of study treatment, all biopsies 
obtained, including those from eligible patients after week 48, will be included in the analysis. 
Sensitivity analyses:
Sensitivity analyses will be conducted to account for delayed Week 48 biopsies due to extended 
treatment under COVID-19 pandemic. Further details are to be described in the statistcal 
analysis plan (SAP).
9.5.2
Safety variables
All safety variables (i.e. adverse events, laboratory data, vital signs, and ECG) will be 
summarized by treatment for all patients of the safety set. Safety variables which are part of the 
primary variables are listed in Table 9-1 as well. Analyses of the safety variables will be 
performed in the Safety Set.
9.5.2.1
Adverse events
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term) will be summarized. AEs will be summarized by presenting, for each treatment 
group, the number and percentage of patients having experienced

Any adverse event (AE),

Any serious adverse event (SAE),

Any adverse event by primary system organ class (SOC),

Any adverse event by preferred term,

Any adverse by severity,

Any adverse event possibly related to study treatment (investigator assessment),

Any adverse event resulting in discontinuation of study treatment,

Any adverse events of special interest for tropifexor or CVC treatment.
Exposure adjusted tabulations of adverse events and tabulations of appropriate adverse events 
according to defined intervals will be provided as well. If a patient reported more than one 
adverse event with the same preferred term, the adverse event with the greatest severity will be 
presented. If a patient reported more than one adverse event within the same primary system 
organ class, the patient will be counted only once with the greatest severity at the system organ 
class level, where applicable. A separate summary will be provided for deaths, if they occur 
during the course of the study.


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9.5.2.2
Laboratory data
The summary of safety laboratory evaluations will be presented for the groups of laboratory 
tests (e.g. hematology, clinical chemistry). Descriptive summary statistics for the change from 
baseline to each study visit will be presented. These descriptive summaries will be presented 
by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for patients with both baseline and post baseline values. Relative and absolute 
frequencies of patients with liver events as defined in Appendix 2 will also be provided, as well 
as shift tables based on the normal laboratory ranges. For the shift tables, the normal laboratory 
ranges will be used to evaluate whether a particular laboratory test value was normal, low, or 
high for each visit value relative to whether or not the baseline value was normal, low, or high. 
These summaries will be presented by laboratory test category and treatment group.
The number and percentage of patients with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory results, for those parameters where ranges are 
available. Only patients with laboratory results within the normal reference range from the 
central laboratory at baseline will be included in the tabulations. 
Safety laboratory parameters which are also part of the efficacy analyses will be included in the 
safety tables as well (e.g. liver enzymes, lipids).
9.5.2.3
Baseline definition
Generally,  baseline  is  defined  as  the  last  assessment  before  date  and  time  of  first 
administration of study drug; if only the date is available, the last assessment before or at the 
date of first administration of study drug will be used. For transaminases (ALT, AST, GGT)
and bilirubin, the baseline value will be calculated as the mean of the last two assessments 
before first administration of the study drug, which are usually those taken at the Screening 2 
and Baseline visit (if a test was performed).
9.5.2.4
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for patients 
with both baseline and post-baseline values. Patients with notable vital signs as defined in 
Appendix 1 will be listed.
9.5.2.5
ECG
ECG data will be summarized by treatment and visit (post-baseline ECGs are performed at 
Week 24 and Week 48). 
The Fridericia QT correction formula (QTcF) will be used for clinical decisions and for analyses.
Notable QTcF values and changes from baseline will be summarized at Week 24 and Week 48. 
A notable value is defined as a QTcF interval of greater than 450 ms. The categories used for 
the change (increase) in QTcF are: ≤30 ms, > 30 to ≤60 ms and > 60 ms.


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9.5.3
Resource utilization 
Data relating to resource utilization will be used for the purpose of economic evaluation which 
will be carried out and reported as a separate activity.


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9.7
Interim analyses
No interim analysis is planned for the study.
9.8
Sample size calculation
The primary objective of the study is to determine if there is a safe combination between one 
of the chosen doses of tropifexor and 150 mg of cenicriviroc. However, the assessment will be 
made based on the whole safety profile and not on quantitatively formulated hypotheses for 
distinct parameters.  Therefore the sample size is based on the feasibility with respect to 
expected speed of enrollment and duration of the study, not on formal statistical criteria.
9.8.1
Power considerations with given sample size for safety assessment
Events with a true incidence of 30% and above are likely to be observed (almost 100% 
probability) in a group of 50 patients (size of each treatment group). Events with true incidences 
below 10% down to 3% are still very likely to be observed, while events are observed with less 


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than 50% probability only if the true incidence is less than about 2.5% (Figure 9-1). It is 
noteworthy, however, that a single patient constitutes 2% in a sample of 50.
Figure 9-1
Binomial probability to observe an event with given sample size
Probabilities of the incidence being below a certain threshold are plotted in Figure 9-2 for a 
sample size of 50 patients when the event is observed in 0, 1, 2, ...,10 patients (assuming a beta 
distribution with prior shape parameters 0.33, 0.33).


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Figure 9-2
Predictions for probability of event based on observed number
For example, if 0 events are observed, the probability (Prob) that the incidence is ≤ 5% would 
be 98.7%. If an event is observed in one patient, the probability that the incidence is ≤ 5% would 
be 86.6%. Similarly, if an event is observed in 10 patients (one fifth), the probability that the 
incidence is ≤ 20% would be approximately 50% (calculated using R function pbeta).
9.8.2
Power considerations with given sample size for efficacy assessment
To evaluate the effectiveness of tropifexor + CVC with respect to the proportion of patients 
who have at least a one point improvement in fibrosis at Week 48 compared to baseline (i.e, 
the response rate), one needs to consider the effect size that one is able to detect with respect 
to both tropifexor and CVC as monotherapy.  

For CVC, based on information from the CENTAUR Phase 2b study, Friedman 2017), it 
can be assumed that the monotherapy response rate at Week 48  in F2/F3 patients would 
be approximately 35%

For tropifexor, a response rate of 42% is assumed  (best-case scenario) based on the 
interpolation of expected Week 72 response rate and assuming linear improvement over 
time

For the combined effect of tropifexor + CVC it will be assumed that 75% of the efficacy 
for CVC will be added to the effect of tropifexor (i.e. a response rate of 69%)
For comparisons between tropifexor + CVC and CVC monotherapy a 2-group continuity 
corrected χ2 test of proportions with type error 0.10 (2-sided, no adjustment for multiple 
comparisons), a sample size of 50 per group results in a power of 95% (nQuery Advisor 7.0). 


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For comparisons between tropifexor + CVC and tropifexor monotherapy a 2-group continuity 
corrected χ2 test of proportions with type error 0.10 (2-sided, no adjustment for multiple 
comparisons), a sample size of 50 per group results in a power of 81% (nQuery Advisor 7.0).
Further scenarios assuming different response rates for tropifexor and the magnitude of effect 
added to tropifexor by CVC are described in Table 9-4.
Table 9-4
Power for detecting a treatment difference between tropifexor + CVC 
and tropifexor and CVC monotherapy
Assumed
tropifexor response 
rate
Assumed response 
rate of tropifexor +
CVC
Power
N = 50/arm vs. 
tropifexor 
monotherapy
Power N =
50/arm vs. 
CVC 
monotherapy
Current target
42% response rate at 
Week 48 (50% 
improvement over 
OCA)
½ effect of CVC added 
to tropifexor ((60%)
48%
75%
¾ effect of CVC added 
to tropifexor (69%)
81%
95%
Full effect of CVC 
added to tropifexor 
(77%)
96%
99%
Response rate between 
target and OCA at 
Week 48 (35%)
½ effect of CVC added 
to tropifexor (53%)
48%
48%
¾ effect of CVC added 
to tropifexor (62%)
81%
81%
Full effect of CVC 
added to tropifexor 
(70%)
96%
96%
Worst case: tropifexor 
same effect as OCA 
28% at Week 48
½ effect of CVC added 
to tropifexor (46%)
50%
23%
¾ effect of CVC added 
to tropifexor (55%)
82%
56%
Full effect of CVC 
added to tropifexor 
(63%)
96%
81%
*Power calculated assuming a two-sided Type I error rate of 0.10
10
Ethical considerations
10.1
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 Japanese 




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10.4
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group 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 Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes.
11
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 patients/subjects 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, 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. 
11.1
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. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the 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 patient included in this 


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study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References
References are available upon request
Abdelmalek (2017) Favorable safety and tolerability of the dual CCR2/5 antagonist cenicriviroc 
in over 1000 subjects treated to date. Hepatology, 66(S1), 1177A.
Angulo P, Kleiner D, Dam-Larsen S, et al (2015). Liver Fibrosis, but No Other Histologic 
Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver 
Disease. Gastroenterology, 149(2), 389-397.e10.
Beste LA, Leipertz SL, Green PK, et al (2015). Trends in Burden of Cirrhosis and 
Hepatocellular Carcinoma by Underlying Liver Disease in US Veterans, 2001–2013. 
Gastroenterology, 149(6), 1471-1482.e5.
Burke LB, Kennedy DL, Miskala PH et al (2008). The use of patient-reported outcome 
measures in the evaluation of medical products for regulatory approval. Clin Pharmacol Ther; 
84:281-283.
Calkin A, and Tontonoz P (2012). Transcriptional integration of metabolism by the nuclear 
sterol-activated receptors LXR and FXR. Nature Reviews Molecular Cell Biology, 13(4), 213-
24.
Cariou B, and Cariou B (2008). The farnesoid X receptor (FXR) as a new target in non-alcoholic 
steatohepatitis. Diabetes & Metabolism, 34(6), 685-691.
Cella D, Hahn EA, Dineen K (2002). Meaningful change in cancer- specific quality of life 
scores: Differences between improvement and worsening. Qual Life Res; 11(3):207-221.
Cohen JC, Horton JD, & Hobbs HH. (2011). Human Fatty Liver Disease: Old Questions and 
New Insights. Science, 332(6037), 1519-1523.
Ekstedt M, Hasgtrom H, Nasr P, et al (2015). Fibrosis Stage is the Strongest Predictor for 
Disease-Specific Mortality in NAFLD After Up to 33 Years of Follow-Up. Hepatology; 
61:1547-1554.
Flaishon L, Becker-Herman S, Hart G, et al (2004). Expression of the chemokine receptor 
CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration. 
Blood First Edition Paper, May 4, 2004; DOI 10.1182/blood-2003-11-4013.
Foster T, Chalasani N, Harrison J, & Budoff M (2012). 935 Light Alcohol Consumption is 
Associated With Lower Prevalence of NAFLD: The Multi Ethnic Study of Atherosclerosis 
(MESA). Gastroenterology, 142(5), S-937
Friedman S, Ratziu V, Harrison S, et al (2017). A Randomized, Placebo-Controlled Trial of 
Cenicriviroc for Treatment of Nonalcoholic Steatohepatitis with Fibrosis. Hepatology
2018;67:1754-1767 
Friedman S, Sanyal A, Goodman Z, et al . (2016). Efficacy and safety study of cenicriviroc for 
the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR 
Phase 2b study design. Contemporary Clinical Trials, 47, 356-365.


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Goodwin B, Jones S, Price R, et al (2000). A Regulatory Cascade of the Nuclear Receptors 
FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis. Molecular Cell, 6(3), 517-526.
ICH Guideline E2D; Post-approval safety data management: definitions and standards for 
expedited reporting (2004).
Kabbany MN, Selvakumar P, Watt K, et al (2017). Prevalence of Nonalcoholic Steatohepatitis-
Associated Cirrhosis in the United States: An Analysis of National Health and Nutrition 
Examination Survey Data. Am J Gastroenterol 2017; 112:581–587.
Laffitte B, Vig P, Mueller P, et al (2017). LJN452/CVC combination therapy shows additive 
effects on NAS vs. monotherapies in mice. AASLD 2017, poster # P-2052
Lefebvre E, Gottwald M, Lasseter K, et al (2016). Pharmacokinetics, Safety, and CCR2/CCR5 
Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment. 
Clinical and Translational Science, 9(3), 139-148.
Lefebvre E. (2014). Pharmacokinetics and safety of multiple-dose cenicriviroc, a novel, oral, 
once-daily CCR2 and CCR5 antagonist, in adults with mild or moderate hepatic impairment. 
Hepatology, 60(6), 1275A.
Mossanen J, Krenkel O, Ergen C, et al (2016). Chemokine (C-C motif) receptor 2-positive 
monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology, 
64(5), 1667-1682.
Mudaliar S Henry R, Sanyal A, 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), 574-582.
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):956-965.
Neuschwander-Tetri BA, & Neuschwander-Tetri B. (2003). Nonalcoholic steatohepatitis: 
Summary of an AASLD Single Topic Conference. Hepatology, 37(5), 1202-1219.
Patrick DL, Burke LB, Powers JH, et al (2007). Patient-reported outcomes to support medical 
product labeling claims: FDA perspective. Value in Health; 10 (Suppl 2):S125-S137.
Pattni SS, Brydon WG, Dew T, et al (2012). Fibroblast Growth Factor 19 and 7a-hydroxy-4-
cholesten-3-one in the diagnosis of patients with possible bile acid diarrhea. Clin Trans 
Gastroenterol; 3: e18.
Porez G, Prawitt G, Gross B, et al (2012). Bile acid receptors as targets for the treatment of 
dyslipidemia and cardiovascular disease. Journal of Lipid Research, 53(9), 1723-1737.
PuengelT, Krenkel O, Mossanen J, et al (2016). The Dual Ccr2/Ccr5 Antagonist Cenicriviroc 
Ameliorates Steatohepatitis and Fibrosis in Vivo by Inhibiting the Infiltration of Inflammatory 
Monocytes into Injured Liver. Journal of Hepatology, 64(2), S160.
Ratziu. (2015). Novel therapies for NASH: What is on the horizon? Journal of Viral Hepatitis, 
22, 10.




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13
Appendix 1: Clinically notable laboratory values and vital 
signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. Any clinically significant abnormal 
laboratory value should be evaluated and followed-up by the investigator until normal or a cause 
for the abnormality is determined.
SEE APPENDIX 2 FOR SPECIFIC LIVER EVENT AND LABORATORY TEST 
TRIGGER DEFINITIONS AND FOLLOW-UP REQUIREMENTS.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of > 450 msec for
males or > 460 msec for females, all such ECGs will be flagged by the Central CRO and require 
assessment for clinical relevance and continuance of the patient by the Investigator.
For vital signs, please see Table 13-1 for notable abnormalities.
Table 13-1
Notable abnormalities in vital signs
Vital signs
Notable abnormalities
Absolute
Relative to baseline
Pulse rate (beats/min)
> 130
< 40 
> 120 and increase from baseline ≥ 15
≤ 50 and decrease from baseline ≥ 15
Blood pressure (mmHg)
Systolic
> 200
< 75
≥ 180 and increase from baseline ≥ 20
≤ 90 and decrease from baseline ≥ 20
Diastolic
> 115
< 40
≥ 105 and increase from baseline ≥ 15
≤ 50 and decrease from baseline ≥ 15
Note: these notable ranges should not be used as reference ranges to establish a clinical diagnosis


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14
Appendix 2: Liver Monitoring and Follow-up Requirements
For transaminases (ALT, AST, GGT) and bilirubin, the baseline value will be calculated as the mean of the last two assessments before first 
administration of the study drug, which are usually those taken at the Screening 2 and Baseline visit.
Table 14-1
Management of Subjects 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, 
Interrupt dosinge
ALT and/or AST
> 3 × ULN but ≤5 × baseline 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, 
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, 
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, 
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
Interrupt dosinge


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Baseline
Treatment-Emergent (Confirmeda)
Liver-Related 
Clinical 
Symptomsb
Action taken
Monitoringc
Study Drug
ALT and/or AST
> 3 × baseline 
With or without 
liver-related clinical 
symptoms
Comprehensive clinical evaluation and 
laboratory monitoring, as well as causality 
evaluationd, 
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, 
Interrupt dosinge
ALP
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, 
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, 
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, 
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, 
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, 
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, 
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
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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Baseline
Treatment-Emergent (Confirmeda)
Liver-Related 
Clinical 
Symptomsb
Action taken
Monitoringc
Study Drug
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic case report form; INR = international normalized ratio; 
; ULN = upper limit of normal
a The required confirmatory measurement should be obtained within 48 to 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 symptoms of abdominal pain, 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 subjects 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 subjects should be closely monitored until resolution of clinical symptoms/stabilization of liver biochemistries to baseline levels or baseline grade of abnormality. 
In subjects 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, which are usually those taken at the screening 2 and baseline visit) 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 28 days (see Section 5.5.5). If significant liver abnormalities recur at any time after 
restarting study drug, then study drug must be permanently discontinued.
f In subjects with 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 poss ble, study drug should be interrupted and subject followed for laboratory monitoring and causality evaluation.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or > 15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the eCRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio stabilization at 
a new level with ± 50% variability over last 6 months.


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17
Appendix 5: The American Heart Association (AHA) 
Recommended Diet
Optimization of diet can result in a marked triglyceride-lowering effect that ranges between 20% 
and 50%. Good practices include weight loss, reducing simple carbohydrates at the expense of 
increasing dietary fiber, eliminating industrial-produced trans fatty acids, restricting fructose 
and saturated fatty acids, implementing a Mediterranean-style diet, and consuming marine-
derived omega-3 PUFA. 
AHA recommends the following:
Eat a variety of fruit and vegetable servings every day. Dark green, deep orange, or yellow fruits 
and vegetables are especially nutritious. Examples include spinach, carrots, peaches, and berries. 
Eat a variety of grain products every day. Include whole-grain foods that have lots of fiber and 
nutrients. Examples of whole grains include oats, whole wheat bread, and brown rice. Eat fish 
at least 2 times each week. Oily fish, which contain omega-3 fatty acids, are best for your heart. 
These fish include tuna, salmon, mackerel, lake trout, herring, and sardines. Stay at a healthy 
weight by balancing the amount of calories you eat with the activity you do every day. If you 
want to lose weight, increase your activity level to burn more calories than you eat. 
Eat foods low in saturated fat and cholesterol. Try to choose the following foods:

Lean meats and meat alternatives like beans or tofu

Fish, vegetables, beans, and nuts

Nonfat and low-fat dairy products

Polyunsaturated or monounsaturated fats, like canola and olive oils, to replace saturated 
fats, such as butter 
Read food labels and limit the amount of Trans fat you eat. Trans fat is found in many processed 
foods made with shortening or with partially hydrogenated or hydrogenated vegetable oils. 
These foods include cookies, crackers, chips, and many snack foods. 
Limit sodium intake to less than 2,300 mg of sodium a day (about one teaspoon). Choose and 
prepare foods with little or no salt.  
Limit alcohol intake to 2 drinks a day for men and 1 drink a day for women. 
Limit drinks and foods with added sugar.

SAP_001.pdf: 
Clinical Development
LJC242
CLJC242A2201J / NCT03517540
A randomized, double-blind, multicenter study to assess 
the safety, tolerability, and efficacy of a combination 
treatment of tropifexor (LJN452) and cenicriviroc (CVC) in 
adult patients with nonalcoholic steatohepatitis (NASH) 
and liver fibrosis (TANDEM)
Statistical Analysis Plan (SAP)
Author:
Document type:
SAP Documentation
Document status:
Final 2.0
Release date:
November 11, 2020
Number of pages:
33
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
20 August 
2018
Prior to 
DB lock
Creation of 
final version
N/A – first version
N/A – first 
version
10 July 
2020
Prior to 
DB lock
Creation of 
Amendment 
1
Added several supportive analyses for 
the secondary efficacy for the impact 
of COVID-19.
Added AE summary by the onset time 
of COVID-19 pandemic in different 
countries and regions.
Section 2.7.3, 
2.7.4
Section 2.8.1
Added treatment extension and 
corresponding actions taken for 
analyses. 
Section 1.1, 
2.4.1
11 
November 
2020
Prior to 
DB lock
Creation of 
Amendment 
2
Added several supportive analyses for 
the secondary efficacy.
Section 2.7
Added analyses based on paired 
biopsy for secondary efficacy 
endpoints 
 
Section 2.7, 
2.13


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.2
Analysis sets ..........................................................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Prior, concomitant, and post therapies..................................................13
2.5
Analysis of the primary objective..........................................................................13
2.5.1
Primary endpoint...................................................................................13
2.5.2
Statistical hypothesis, model, and method of analysis..........................14
2.5.3
Handling of missing values/censoring/discontinuations.......................14
2.5.4
Supportive analyses...............................................................................14
2.6
Analysis of the key secondary objective ...............................................................14
2.7
Analysis of secondary efficacy objective(s)..........................................................15
2.7.1
Secondary endpoints .............................................................................15
2.7.2
Statistical hypothesis, model, and method of analysis..........................15
2.7.3
Handling of missing values/censoring/discontinuations.......................16
2.7.4
Supportive Analyses..............................................................................16
2.8
Safety analyses.......................................................................................................17
2.8.1
Adverse events (AEs)............................................................................17
2.8.2
Deaths....................................................................................................18
2.8.3
Laboratory data .....................................................................................19
2.8.4
Other safety data ...................................................................................19
19
.20
20
20
20
2.14
Interim analysis......................................................................................................22
3
Sample size calculation .....................................................................................................22


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3.1
Power considerations with given sample size for safety assessment ....................22
3.2
Power considerations with given sample size for efficacy assessment .................24
4
Change to protocol specified analyses ..............................................................................26
5
Appendix ...........................................................................................................................26
5.1
Imputation rules.....................................................................................................26
5.1.1
Study drug.............................................................................................26
5.1.2
AE date imputation ...............................................................................26
5.1.3
Concomitant medication date imputation .............................................27
5.1.4
Other imputations..................................................................................29
5.2
AEs coding/grading ...............................................................................................29
5.3
Laboratory parameters derivations ........................................................................29
5.3.1
Laboratory parameters ..........................................................................29
30
30
30
5.3.5
Derived baseline characteristics............................................................31
31
5.4
Statistical models...................................................................................................31
5.4.1
Primary analysis....................................................................................31
5.4.2
Key secondary analysis.........................................................................31
5.5
Not applicable. Rule of exclusion criteria of analysis sets....................................31
5.6
Other statistical aspects..........................................................................................32
6
Reference...........................................................................................................................33


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List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
APTT
Activated partial thromboplastin time
AST
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical classification
CI
Confidence interval
CRN
Clinical Research Network
CSR
Clinical Study report
CV
Coefficient of variation
CVC
Cenicriviroc
DMC
Data Monitoring Committee 
eGFR
Estimated glomerular filtration rate
EOS
End of study
EOT
End of treatment
FAS
Full analysis Set
GGT
Gamma glutamyl transferase
INR
International Normalized Ratio
ITT
Intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
OCA
Obeticholic acid
PRO
Patient-reported Outcomes


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PT
Preferred term / Prothrombin time
RAN
Randomized set
SAE
Serious adverse event
SAF
Safety set
SAP
Statistical Analysis Plan
SCR
Screened set
SD
Standard deviation
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TFLS
Tables, Figures and Listings Shells
ULN
Upper limit of normal range
WHO
World Health Organization


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1
Introduction
The purpose of Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol. It addresses the analyses intended for the final 
clinical study report.
Reference documents: Clinical Trial Protocol version 03, 7 May 2020. 
1.1
Study design
This study is a 48-week, randomized, double-blind, multicenter study that consists of a 
screening period, a treatment period starting from randomization on Day 1 and running to Week 
48, and a follow up period of 4 weeks after the last dose of study treatment. The total study 
duration is up to 60 weeks.
The study population are adult male and female patients with histologic evidence of NASH and 
fibrosis (stage 2 or 3 as per NASH CRN histological score, F2/F3); see Inclusion and Exclusion 
criteria in the protocol for details.
At baseline, approximately 200 patients whose eligibility is confirmed will be randomized in a 
1:1:1:1 ratio, resulting in approximately 50 patients randomized in each of the four arms:
Arm A: tropifexor 140 µg, once-daily
Arm B: CVC 150 mg, once-daily
Arm C: tropifexor 140 µg + CVC 150 mg, once-daily
Arm D: tropifexor 90 µg + CVC 150 mg, once-daily.
 
The primary analysis will be performed when all randomized patients have completed or 
discontinued the trial participation. No interim analyses are planned. 
Due to the COVID-19 pandemic, it may not be possible for patients to return in time for the 
Week-48 visit to perform scheduled assessments including biopsies, and according to drug 
dispensing plan in Section 5.5.2 of the protocol, the Week-48 visit and associated assessments 
can be delayed up to approximately 12 weeks. Since the primary objective of the study is to 
determine if there is a safe combination between one of the chosen doses of tropifexor and 150 
mg of cenicriviroc, all assessment results obtained, including those from eligible patients after 
Week 48, will be included in analyses as they are with no special plan to account for the 
treatment extension.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 


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Objective(s)
Endpoint(s)
To evaluate the safety and tolerability of  
tropifexor + CVC in patients with NASH and 
fibrosis (stage 2 or 3 as per NASH CRN 
histological score, F2/F3) by monitoring adverse 
events, vital signs and laboratory values during 
48 weeks of treatment as compared to 
monotherapy with each of tropifexor and CVC
Occurrence of adverse events, serious adverse 
events, adverse events resulting in 
discontinuation of study treatment, adverse 
events of special interest and changes in vital 
signs and laboratory values over 48 weeks of 
treatment
Secondary Objective(s)
Endpoint(s) for secondary objective(s)
To characterize the efficacy of tropifexor + CVC 
in patients with NASH with fibrosis stage F2/F3 
as assessed by histological improvement  after 
48 weeks of treatment compared to 
monotherapies (tropifexor and CVC) compared 
to baseline biopsy
Proportion of patients who have at least a one-
point improvement in fibrosis 
Proportion of patients with resolution of 
steatohepatitis 


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Objective(s)
Endpoint(s)


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Objective(s)
Endpoint(s)
2
Statistical methods
2.1
Data analysis general information
Analyses for the CSR will be performed by Novartis using SAS 9.4 or newer. Other statistical 
software and programming languages, such as R, may be used as well, in the newest version 
available in the validated environment. Data exploration will be aided by specific tools focusing 
on interactive visualization, e.g. an R Shiny App.
 
 Unless mentioned otherwise in the 
respective section of this SAP and the TFLS document, formal tables, figures and listings will 
therefore be specified ad hoc for these.
Summary tables will be presented by treatment group and analysis visit (as applicable) using 
descriptive statistics. These include absolute and relative frequencies for categorical variables. 
Continuous variables will be summarized by arithmetic mean, standard deviation, minimum, 
maximum, median and first and third quartile per default. Where indicated, geometric mean and 
coefficient of variation will also be displayed, and the ratio instead of percentage change.
The data analysis for the CSR will be performed after the clinical database lock, when all 
patients have completed or discontinued the study, and will therefore include all collected data.
Data cutoffs for safety DMC analyses will occur approximately every 6 months after start of 
randomization.
Centers, which are expected to be small in this study, will be pooled for all analyses. No 
analyses by center and no stratification by center are planned upfront. In case of some 
unexpectedly large centers (>15 randomized subjects), effects in these centers will be explored 
ad hoc (e.g., using a ShinyApp). The randomization stratification factor 
 
will not be used as a covariate in statistical analyses, because it represents an optional 
assessment and not a subject baseline characteristic.


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General definitions 
The term “Study treatment” refers to the treatment assigned to or received by the study subject, 
which is either tropifexor 140 µg (once-daily), CVC 150 mg (once-daily), tropifexor 140 µg + 
CVC 150 mg (once-daily), or tropifexor 90 µg + CVC 150 mg (once-daily).
The term “Study drug” refers to tropifexor, CVC, or placebo.  
Date of first administration of study treatment: Date of first administration as recorded in the 
CRF (Drug Administration Record page) 
Date of last administration of study treatment: Date of last administration as recorded in the 
CRF (Drug Administration Record page) 
Study day: Study day is calculated from the date of first administration of study treatment, 
which is defined as Day 1.
Baseline: Generally, baseline is defined as the last assessment before date and time of first 
administration of study treatment; if only the date is available, the last assessment before or at 
the date of first administration of study drug will be used. For transaminases (ALT, AST, and
GGT) and bilirubin, the baseline value will be calculated as the mean of the last two assessments 
before first administration of the study drug, which are usually those taken at the Screening 1 
and Baseline visits (Screening 2 and Baseline if a test was performed during Screening 2 visit).
Last contact: Date of last data point entered in the database.
Treatment period: Period from Baseline visit to End-of-treatment visit (included).
Follow-up period: Period from End-of-treatment visit (not included) to End-of-Study visit 
(included). 
2.2
Analysis sets

Screened set (SCR) – All patients who signed the informed consent.

Randomized set (RAN) – All patients who received a randomization number, regardless of 
receiving trial medication.

Full analysis set (FAS) – All patients to whom study treatment has been assigned*. 
Following the intent-to-treat (ITT) principle, patients are analyzed according to the 
treatment they have been assigned to at randomization.

Safety set (SAF) - All patients who received at least one dose of study treatment and have 
at least one post-baseline safety assessment. Of note, the statement that a patient had no 
adverse events also constitutes a safety assessment. Patients will be analyzed according to 
the treatment received.
 
 
 


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* Excluding patients who were mis-randomized and did not take any study drug. Mis-
randomized patients are those who were not qualified for randomization, but were inadvertently 
randomized into the study.
The number of patients in each analysis set will be presented by treatment group and overall for 
the screened set.
Subgroup of interest
No subgroups of particular interest are defined in the protocol. Due to the relatively small 
sample size per group, subgroup analyses will only be performed within the data exploration 
framework. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Demographic variables and other baseline characteristics will be summarized for the FAS. 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be 
presented for continuous variables for each treatment group and for all patients (total). The 
number and percentage of patients in each category will be presented for categorical variables 
for each treatment group and all patients (total). In addition, all relevant medical history and 
protocol solicited medical history will be summarized by treatment group.
Patient disposition
The number of subjects in each analysis set will be presented overall for the screened set and 
by treatment group for the randomized set.
The number and percentage of subjects in the randomized set who completed or discontinued 
each study period (screening, treatment, and follow-up), and the reason for discontinuation will 
be presented for each treatment group and all subjects.
The frequency (%) of subjects with CSR reportable protocol deviations as well as the criteria 
leading to exclusion from analysis sets will be presented in separate tables for the randomized 
set.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Overall duration (in weeks) for the double-blind investigational treatment will be computed for 
each randomized patient as follows:
(date of last administration of study treatment – date of first administration of study 
treatment + 1) / 7
If a patient was randomized, but did not receive any dose of randomized double-blind study 
treatment (protocol deviation) then the exposure is set to 0. 


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The duration of exposure to study treatment (in weeks) will be summarized for the SAF using
descriptive statistics and additionally by duration category in steps of “week” (+/- one-day time 
window included):

≥0 week- < 12 weeks

≥12 week- < 24 weeks

≥ 24 weeks - < 36 weeks

≥ 36 weeks - < 48 weeks

≥ 48 weeks - < 52 weeks

≥52 weeks - < 56 weeks

≥ 56 weeks
The cutoff of 52 weeks and 56 weeks is to account for the extended treatment for patients who 
are unable to perform the Week-48 visit as scheduled.
2.4.2
Prior, concomitant, and post therapies
Medications will be identified using the WHO dictionary including ATC code and presented 
for the SAF. Prior medications are defined as any medications taken prior to the first 
administration of study drug (regardless of whether they are stopped or continued after 
randomization). Concomitant medications and significant non-drug therapies are defined as 
those used during the double-blind period. Prior and concomitant medications will be 
summarized by treatment group in separate tables. Medications will be presented in alphabetical 
order, by ATC codes and grouped by anatomical main group (the 1st level of the ATC code,
e.g. “Cardiovascular system”, C), and by the first subgroup, e.g. “Lipid modifying agents” 
(C10). Tables will also show the overall number and percentage of subjects receiving at least 
one drug of a particular ATC code and at least one drug in a particular anatomical main group 
and first subgroup.
Concomitant medications that were prohibited as per protocol and given between start and end 
of treatment period as well as significant non-drug therapies, and medications that are permitted 
only if the dose is stable within 25 percent of the baseline dose (Table 5-4 in the protocol) will 
be provided in separate tables.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary study objective is to evaluate the safety and tolerability of tropifexor + CVC in 
patients with NASH and fibrosis (stage 2 or 3 as per NASH CRN histological score, F2/F3) by 
monitoring adverse events, vital signs and laboratory values during treatment as compared to 
monotherapy with each of tropifexor and CVC. The related endpoints are (over treatment):

occurrence of adverse events,

occurrence of serious adverse events,

occurrence of adverse events resulting in discontinuation of study treatment,


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
occurrence of adverse events of special interest,

changes in vital signs and laboratory values.
Only treatment emergent adverse events will be considered for the analysis, which are defined 
as those starting on or after first day of application of study treatment and before EOS visit or 
30 days after EOT visit, whichever comes earlier. 
2.5.2
Statistical hypothesis, model, and method of analysis
There are no pre-specified hypotheses and statistical models in this study. The methods to 
analyze the primary safety variables are outlined in Table 2-1.
Table 2-1
Primary variables and methods of analysis
Variable
Method of analysis
Occurrence of adverse events
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of serious adverse events
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of adverse events resulting in 
discontinuation or dose reduction of study 
treatment
Summary table of absolute and relative 
frequency, overall and by preferred term
Occurrence of adverse events of special interest
Summary table of absolute and relative 
frequency, by type of AE as the risks are 
described for both tropifexor and CVC (risk 
definition for tropifexor are those that appear  
in the tropifexor IB or CVC IB, DSPP and 
eCRS) together with any other events 
identified during the course of this or other 
studies
Changes in vital signs
Descriptive statistics by visit 
Changes in laboratory data
Descriptive statistics by visit
The statistical analysis of these variables is described in Section 2.8, along with the analysis of 
other safety variables.
2.5.3
Handling of missing values/censoring/discontinuations
Imputation of incomplete adverse events start and end dates follow standard conventions and 
are described in detail in Section 5.1.2.
Missing follow-up assessments for laboratory and vital signs will not be imputed. 
2.5.4
Supportive analyses
Supportive analyses are added for evaluation of the impact of COVID-19 on study results. See 
Section 2.8.1.
2.6
Analysis of the key secondary objective
There is no key secondary objective defined in the protocol.


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2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
There is a single secondary objective in this study which is to characterize the efficacy of 
tropifexor + CVC in patients with NASH with fibrosis stage F2/F3 as assessed by histological 
improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) 
relative to baseline biopsy.  There are two endpoints that will be used to evaluate this objective:

Proportion of patients who have at least a one-point improvement in fibrosis 

Proportion of patients with resolution of steatohepatitis 
The determination of fibrosis improvement will be based on NASH CRN staging (see Table 2-
2). Only main stages (0, 1, 2, 3, and 4) will be considered. For example, a change from 1c to 1b 
or 1a will not be counted as a one-point change.
Table 2-2
Fibrosis score according to NASH CRN
Fibrosis score
Histopathology
0
none
1a
mild perisinusoidal fibrosis
1b
moderate perisinusoidal fibrosis
1c
portal/periportal fibrosis only
2
perisinusoidal and periportal fibrosis
3
bridging fibrosis
4
cirrhosis
Results of the paired biopsy readings will be used for all biopsy-based outputs, yet not 
retrospectively for re-evaluation of patient eligibility at screening, which is performed based on 
real-time biopsy reading.
Resolution of steatohepatitis will be determined as diagnostic category “not NAFLD” or 
“NAFLD, not NASH” as provided in the central biopsy report. 
2.7.2
Statistical hypothesis, model, and method of analysis
The two secondary endpoints are incorporated in two estimands.
The first estimand is defined as below:

Treatment: The randomized treatment (tropifexor 140 µg once-daily, CVC 150 mg once-
daily, tropifexor 140 µg + CVC 150 mg once-daily, and tropifexor 90 µg + CVC 150 mg 
once-daily) taken for 48 weeks, further defined in Section 5.2 in the protocol.

Population: Full analysis set.

Endpoint: Proportion of patients who have at least a one-point improvement in fibrosis.

Summary measure: Difference in the proportion of patients on the different tropifexor + 
CVC regimens who achieve at least a one-point improvement in fibrosis at Week 48 biopsy 
compared to tropifexor and CVC monotherapy patients.
The second estimand is the same as the first one except

Endpoint: Proportion of patients with resolution of steatohepatitis


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
Summary measure: Difference in the proportion of patients on the different tropifexor +
CVC regimens who achieve resolution of steatohepatitis at Week 48 relative to baseline 
compared to tropifexor and CVC monotherapy patients.  
Both estimands will be evaluated using a Cochran-Mantel-Haenszel test controlling for baseline 
fibrosis stage (F2/F3). Risk differences and odds ratios with 95% confidence intervals will 
provide supporting information for both estimands. 
2.7.3
Handling of missing values/censoring/discontinuations
Missing baseline data (if applicable) for the secondary endpoints will not be imputed.
Missing follow-up data for the secondary endpoints will be handled as follows:
If a patient stayed on randomized study treatment for less than 24 weeks, missing data will not 
be imputed, and if data are available (which is not expected as per protocol) they will not be 
included in the analysis. 
If a patient stayed on randomized study treatment for at least 24 weeks, but follow-up data are 
not available, data will be imputed by multiple inputation (see Section 5.1.4).
If a patient stayed on randomized study treatment for at least 24 weeks, and follow-up data are 
available, data will be used as observed, even if treatment was discontinued prior to Week 48.
Due to the COVID-19 pandemic, it was not possible for some patients to return in time for the 
Week-48 visit to perform a liver biopsy. Instead, it was possible for additional treatment to be 
dispensed (see drug dispensing plan in Section 5.5.2 in the protocol), and the Week-48 liver 
biopsy could be delayed up to approximately 12 weeks. Since the purpose of the secondary 
efficacy analysis is to evaluate the potential histological benefit of study treatment, all biopsies 
obtained, including those from eligible patients after Week 48, will be included in the analysis
as Week-48 biopsies.
2.7.4
Supportive Analyses
Since that some Week-48 biopsies may not be obtained as originally scheduled, the same 
endpoints as in Section 2.7.2 will be re-evaluated. Summary tables will be provided for 
corresponding summary measures by treatment group and by whether the patients received 
extended treatment.
In addition, the same endpoints as in Section 2.7.2 will be re-evaluated for patients with at least 
10% weight loss at Week 48 compared to Baseline. Summary tables will be provided for 
corresponding summary measures by treatment group and by population with or without at least 
10% weight loss at Week 48 compared to Baseline.
 
 
 


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Analyses of proportion of patients who have at least one-point improvement in fibrosis 
described in Section 2.7.2 and corresponding supportive analyses described in Section 2.7.4 
will be repeated based on modified ISHAK scoring system.
Analyses of both secondary efficacy endpoints described in Section 2.7.2 and corresponding 
supportive analyses described in Section 2.7.4 will be repeated based on real-time biopsy 
reading. 
Qualitative results of comparison between biopsies obtained during Screening and Week 48 
based on paired biopsy readings will be summarized by treatment group into three categories 
(better, same, 
) for following parameters: steatosis, 
 
 NASH CRN fibrosis, and modified ISHAK score.
2.8
Safety analyses
The analysis of safety parameters will be performed in the Safety Analysis Set.
2.8.1
Adverse events (AEs)
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term, until EOS visit or 30 days after EOT visit, whichever comes earlier) will be 
summarized. AEs will be summarized by presenting, for each treatment group, the number and 
percentage of patients having experienced

Any adverse event (AE),

Any serious adverse event (SAE),

Any adverse event by primary system organ class (SOC),

Any adverse event by preferred term (PT),

Any adverse event by severity,

Any adverse event possibly related to study treatment (investigator assessment),

Any adverse event resulting in discontinuation of study treatment,

Any adverse events of special interest for tropifexor or CVC treatment,

Any adverse events by onset time before and after the start date of COVID-19 pandemic 
by country/region,

Any serious adverse events by onset time before and after the start date of COVID-19 
pandemic by country/region.
If a patient reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a patient reported more than one adverse 
event within the same primary system organ class, the patient will be counted only once with 
the greatest severity at the system organ class level, where applicable. 
The start date of COVID-19 for different countries or regions is defined in Table 5-1 of 
“COVID-19 (Coronavirus) Guidance - Start and End Dates by Region for Sensitivity Analyses” 
Version 1.0 released on May 19, 2020. As of the time of finalization of this SAP, the start (and 
end) dates are listed below:


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Table 2-3
Defined Dates
Region/Country
Start Date
End Date
Italy
23-Feb-2020
End date has not yet been defined
Rest of the World
01-Mar-2020
End date has not yet been defined
Tabulations of adverse events, SAE, and adverse events of special interest broken down by time 
of onset according to the following intervals will be provided as well:

Starting within 4 weeks after first administration of study treatment,

Starting between 4 weeks and 12 weeks after first administration of study treatment, 

Starting more than 12 weeks after first administration of study treatment. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than or equal to 5% in any treatment group and on treatment emergent serious adverse 
events and SAE suspected to be related to study treatment will be provided by system organ 
class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end 
date of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE’s in a ≤1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Adverse events of special interest / grouping of AEs
Adverse events of special interest are the risks as described for both tropifexor and CVC (those 
that appear in tropifexor Development Safety Profiling Plan or CVC Investigator’s Brochure, 
respectively). These will be summarized with absolute and relative frequency overall and by 
type of risk / AE.
Relative and absolute frequencies of patients with liver and renal events (see protocol Appendix 
2 and 3, respectivley) will also be provided.
2.8.2
Deaths
A separate summary and listing will be provided for deaths, if they occur during the course of 
the study.


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2.8.3
Laboratory data
The summary of safety laboratory evaluations will be presented for the groups of laboratory 
tests (e.g., hematology, clinical chemistry). Descriptive summary statistics for the change from 
baseline to each study visit will be presented. These descriptive summaries will be presented 
by test group, laboratory test, and treatment group. Change from baseline will only be 
summarized for patients with both baseline and post baseline values. Shift tables based on the 
normal laboratory ranges will be provided. For the shift tables, the normal laboratory ranges 
will be used to evaluate whether a particular laboratory test value was normal, low, or high for 
each visit value relative to whether or not the baseline value was normal, low, or high. These 
summaries will be presented by laboratory test category and treatment group.
The number and percentage of patients with new clinically notable laboratory results after 
baseline will be presented. Clinically notable laboratory results are listed in Section 5.3.1, for 
those parameters where ranges are available.
Safety laboratory parameters which are at the same time part of the efficacy analyses will be 
included in the safety tables as well.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
ECG data will be summarized by treatment and visit (post-baseline ECGs are performed at 
Week 24 and Week 48). 
The Fridericia QT correction formula (QTcF) will be used for clinical decisions and for analyses.
Notable QTcF values and changes from baseline will be summarized at Week 24 and Week 48. 
A notable value is defined as a QTcF interval of greater than 450 ms for both male and female. 
Those with QTcF interval greater than 500 ms will also be presented. The categories used for 
the change (increase) in QTcF are: ≤0 ms, > 0 and ≤30 ms, > 30 to ≤ 60 ms and > 60 ms.
2.8.4.2
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign parameter and treatment group. 
 
.
Change from baseline will only be summarized for patients with both baseline and post-baseline 
values. Patients with notable vital signs as defined in protocol Appendix 1 will be listed.


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2.14
Interim analysis
No interim analysis is planned for the study.
3
Sample size calculation
The primary objective of the study is to determine if there is a safe combination between one 
of the chosen doses of tropifexor and 150 mg of cenicriviroc. However, the assessment will be 
made based on the whole safety profile and not on quantitatively formulated hypotheses for 
distinct parameters.  Therefore, the sample size is based on the feasibility with respect to 
expected speed of enrollment and duration of the study, not on formal statistical criteria.
3.1
Power considerations with given sample size for safety 
assessment
Events with a true incidence of 30% and above are likely to be observed (almost 100% 
probability) in a group of 50 patients (size of each treatment group). Events with true incidences 
below 10% down to 3% are still very likely to be observed, while events are observed with less 
than 50% probability only if the true incidence is less than about 2.5% (Figure 3-1). It is 
noteworthy, however, that a single patient constitutes 2% in a sample of 50.


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Figure 3-1
Binomial probability to observe an event with given sample size
Probabilities of the incidence being below a certain threshold are plotted in Figure 3-2 for a 
sample size of 50 patients when the event is observed in 0, 1, 2, ...,10 patients (assuming a beta 
distribution with prior shape parameters 0.33, 0.33).


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Figure 3-2
Predictions for probability of event based on observed number
occurring in a group of 50 subjects
For example, if 0 events are observed, the probability (Prob) that the incidence is ≤ 5% would 
be 98.7%. If an event is observed in one patient, the probability that the incidence is ≤ 5% would 
be 86.6%. Similarly, if an event is observed in 10 patients (one fifth), the probability that the 
incidence is ≤ 20% would be approximately 50% (calculated using R function pbeta).
3.2
Power considerations with given sample size for efficacy 
assessment
To evaluate the effectiveness of tropifexor + CVC with respect to the proportion of patients 
who have at least a one point improvement in fibrosis at Week 48 compared to baseline (i.e, the 
response rate), one needs to consider the effect size that one is able to detect with respect to 
both tropifexor and CVC as monotherapy.  

For CVC, based on information from the CENTAUR Phase 2b study, Friedman (2017), it 
can be assumed that the monotherapy response rate at Week 48  in F2/F3 patients would be 
approximately 35%

For tropifexor, a response rate of 42% is assumed (best-case scenario) based on the 
interpolation of expected Week 72 response rate and assuming linear improvement over 
time

For the combined effect of tropifexor + CVC it will be assumed that 75% of the efficacy for 
CVC will be added to the effect of tropifexor (i.e. a response rate of 42 + 0.75*35 = 69%)


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For comparisons between tropifexor + CVC and CVC monotherapy a 2-group continuity 
corrected χ2 test of proportions with type I error rate of 0.10 (2-sided, no adjustment for multiple 
comparisons), a sample size of 50 per group results in a power of 95% (nQuery Advisor 7.0). 
For comparisons between tropifexor + CVC and tropifexor monotherapy a 2-group continuity 
corrected χ2 test of proportions with type I error rate of 0.10 (2-sided, no adjustment for multiple 
comparisons), a sample size of 50 per group results in a power of 81% (nQuery Advisor 7.0).
Further scenarios assuming different response rates for tropifexor and the magnitude of effect 
added to tropifexor by CVC are described in Table 3-1.
Table 3-1
Power for detecting a treatment difference between tropifexor + CVC 
and tropifexor and CVC monotherapy
Assumed
tropifexor response 
rate
Assumed response 
rate of tropifexor + 
CVC
Power
N = 50/arm vs. 
tropifexor 
monotherapy
Power N = 
50/arm vs.
CVC 
monotherapy
Current target
42% response rate at 
Week 48 (50% 
improvement over 
OCA)
½ effect of CVC added 
to tropifexor ((60%)
48%
75%
¾ effect of CVC added 
to tropifexor (69%)
81%
95%
Full effect of CVC 
added to tropifexor 
(77%)
96%
99%
Response rate between 
target and OCA at 
Week 48 (35%)
½ effect of CVC added 
to tropifexor (53%)
48%
48%
¾ effect of CVC added 
to tropifexor (62%)
81%
81%
Full effect of CVC 
added to tropifexor 
(70%)
96%
96%
Worst case: tropifexor 
same effect as OCA 
28% at Week 48
½ effect of CVC added 
to tropifexor (46%)
50%
23%
¾ effect of CVC added 
to tropifexor (55%)
82%
56%
Full effect of CVC 
added to tropifexor 
(63%)
96%
81%
*Power calculated assuming a two-sided Type I error rate of 0.10


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4
Change to protocol specified analyses

AE and SAE summary by the onset time with respect to COVID-19 pandemic in different 
countries and regions are added.

Paired-biopsy reading will be used for all biopsy-based outputs.

NAS-based definition of resolution of steatohepatitis is added in the supportive analyses 
for secondary efficacy endpoint 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The date of the end-of-treatment visit (EOT, Week 48) will be used if the date of last 
administration  of study treatment is missing and the date of randomization will be used if the 
date of first administration is missing.
5.1.2
AE date imputation
Adverse Event Start Date Imputation (#IMPUTAEV)
This algorithm is expressed in the Variable Source Derivation column as #IMPUTAEV(event)
where event is the partial start date of the adverse event.
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
YYYY < TRTY
( D )
Before Treatment 
Start
( C )
Before Treatment 
Start
( C )
Before Treatment 
Start
( C )
Before Treatment 
Start
YYYY = TRTY
(B)
Uncertain
( C )
Before Treatment 
Start
(B)
Uncertain
(A)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(A)
After Treatment Start
(A)
After Treatment Start
(A)
After Treatment Start
The following table is the legend to the logic matrix.
If AE end date is complete and AE end date < Treatment start date then AE start reference = 
min (informed consent date, earliest visit date from SV)


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Else if AE end date is partial or AE is ongoing then AE start reference = treatment start date
Relationship                               Date Imputation
Before AE Start  reference
Partial date indicates AE start date prior to AE start reference
After AE  Start reference
Partial date indicates AE start date after AE start reference
Uncertain
Partial date insufficient to determine relationship of AE start date to AE start reference
Imputation Calculation
NC / Blank
No convention
(A)
01MONYYYY
(B)
Treatment start date+1
(C)
max(15MONYYYY, the start date of the screening period +1 day)
(D)
max(01JULYYYY, the start date of the screening period +1 day)
(E)
01JANYYYY
Complete date
No date imputation
Adverse Event End Date Imputation
Imputed date = date part of original date, if complete date
If a patient is not randomized, then the AE end date is the date of completion of pre-
randomization period.
If a patient is randomized:
If AE end date, month, and year are missing or just month is missing, then the AE end 
date is set to the study completion/discontinuation visit date.
If AE day is missing, then it is set to minimum of (treatment end day, last day of the 
month).
If imputed AE end date is less than the AE start date, use the AE start date as the imputed AE 
end date.
Impute Date Flag: 
If year of the imputed date <> YYYY then date flag = Y
else if  month of the imputed date <> MON then date flag = M
else if day of the imputed date <> day of original date then date_flag = D
else date flag = null
5.1.3
Concomitant medication date imputation
This algorithm is used when event is the partial start date of the concomitant medication or non-
drug therapy/procedure.
The following table explains the notation used in the logic matrix. Please note that completely
missing start dates will not be imputed. Also note that imputation of a start date must not result 
in a date later than the end date. In such case, start date will be max(01-MMM-YYYY, 
Treatment start date) if only the day is missing and max(01-JAN-YYYY, Treatment start date) 
if day and month are missing. 


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Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(C2)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
YYYY < TRTY
(D)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
YYYY = TRTY
(C2)
Uncertain
(A)
Before Treatment Start
(C2)
Uncertain
(B)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
The following table is the legend to the logic matrix.
Relationship                            Date Imputation
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment Start Date
After Treatment Start 
Partial date indicates CMD start date after Treatment Start Date
Uncertain
Partial date insufficient to determine relationship of CMD start date relative to Treatment 
Start Date
Imputation Calculation
(A)
15MONYYYY
(B)
01MONYYYY
(C1 or C2)
IF relative reference start = before THEN Treatment Start Date -1 day
ELSE IF relative reference start  = ‘ ’ THEN Treatment Start Date +1 day
(D)
01JULYYYY
(E)
01JANYYYY
Concomitant Medication End Date Imputation: 
If not ongoing then 
Imputed date  = date part of CMENDTC,  if complete date
Imputed date = min(reference end date,  DEC 31) , if month is missing, (C2, D, E)
Imputed date = min(reference end date,  last day of the Month) , if day is missing. (A, B, 
C1)
Concomitant Medication Date Flag: 
If not a complete date then
Y - If year of the imputed date <> YYYY  else
M – If month of the imputed date <> MON else 
D 


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5.1.3.1
Prior therapies date imputation
Same as concomitant medication date imputation (as applicable).
5.1.3.2
Post therapies date imputation
Not applicable.
5.1.4
Other imputations
A multiple imputation approach will be applied to missing follow-up biopsies.
For subjects who do not have a Week 48 liver biopsy or not remain on their randomized study 
treatment for at least 24 weeks (even if a Week 48 biopsy was obtained), the biopsy based 
outcomes will be imputed by multiple imputation (MI). It is assumed that biopsy results are 
missing at random (MAR). Available results for subjects who discontinue treatment before 24 
weeks are set to missing for this analysis. Imputation will be based on available results from 
subjects who did not discontinue study treatment, thus addressing the question what the results 
would have been if subjects had not discontinued. The imputation model will take into account 
the treatment group, the baseline fibrosis stage (categorical),
, the baseline ALT, 
and change in ALT, 
from baseline to Week 12 and to Week 24 (continuous). As there is only 
one post-baseline biopsy assessment, an arbitrary missing pattern is assumed and a fully 
conditional specification (FCS) method with logistic regression is applied. The randomization 
seed is 4572201 and the number of imputations will be set to 50.
5.2
AEs coding/grading
AEs are coded using the MedDRA dictionary, and severity is graded mild/moderate/severe.
5.3
Laboratory parameters derivations
5.3.1
Laboratory parameters
Liver laboratory events will be classified in two ways:

Events as defined in Appendix 2 of the protocol (Table 14-1). Only the laboratory results 
criteria will be considered. Confirmation of the results is not taken into account. For Table 
14-1, criteria of ALT and AST are evaluated as either-or relationship, while those of 
baseline and treatment-emergent assessments as both-and relationship.

Events as defined in the internal Novartis “Analysis plan for liver safety data”, Table 6-1.
Renal laboratory events will be classified in two ways:

Events as defined in Appendix 3 of the protocol (Table 15-1). Only the laboratory results 
criteria will be considered. Confirmation of the results is not taken into account.

Events as defined in the internal Novartis “Analysis plan for renal safety data”,
Criteria for other laboratory parameters:


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Table 5-1
Notable criteria for other laboratory parameters 
Parameter
Threshold value
Unit
Albumin
<32
g/L
Hemoglobin
<70 
g/L
Hemoglobin
>200
g/L
White blood cell count
<2.0
109/L 
White blood cell count
>35.0
109/L 
Platelets
<50
109/L
Platelets
>1000
109/L
Prothrombin Time INR
>4.0
PT
>40.0
sec
APTT
>80.0
sec
Sodium
<120
mmol/L
Sodium
>160
mmol/L
Potassium
<3.0
mmol/L
Potassium
>6.0
mmol/L
Glucose
<2.2
mmol/L
Glucose
>27.8
mmol/L
Calcium
<1.50
mmol/L
Calcium
>3.00
mmol/L
Phosphate
<0.29
mmol/L
Creatinine
>177
µmol/L
Calculated eGFR
<60
mL/min


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5.3.5
Derived baseline characteristics
Use of lipid reducing drugs (e.g. statins)
Concomitant use of statins is determined as follows:
If drug belonging to ATC code C10 was used either starting prior to randomization and ongoing 
at randomization, or starting during the treatment epoch, concomitant use of statins is 
considered Yes, otherwise No.   
5.4
Statistical models
5.4.1
Primary analysis
Not applicable.
5.4.2
Key secondary analysis
5.5
Not applicable. Rule of exclusion criteria of analysis sets 
Table 5-2
Criteria for exclusion from analysis sets 
Deviation ID
Description of Deviation
Exclusion from
OTH10
Patient was rescreened but did not sign a new ICF
All analysis sets
TRT05
No drug taken after randomization
SAF
INCL01
ICF not signed
All analysis sets


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5.6
Other statistical aspects
Secondary efficacy endpoints
Multiple imputation is adopted to impute missing Week 48 biopsy results for eligible patients. 
See Section 5.1.4 for more details.
CMH test is adopted for inference controlled for the baseline fibrosis stage (F2/F3). In order to 
pool results from multile imputation, test statistic of CMH test is transformed using Wilson-
Hilferty transformation
ST_	
() =
CMH()/

−(1 −
2
9 ∗)
2/(9 ∗)

,
Where CMH() is the CMH test statistic computed from the -th imputed dataset,  is the 
degrees of freedom accosiated with the test statsitic, and ST_	
() follows approximately 
standard normal distribution. Consequently, the test results obtained from muliple imputation
datasets can be combined by specifying the model effects and standard error in PROC 
MIANALYZE in SAS and the final one-side p-value for CMH test can be obtained.
Odds ratio and relative risk obtained from PROC FREQ also need to be transformed to normal 
distribution before pooling. Both statistics are log-normally distributed and hence a simple log 
transformation would transform them to normal and similar procedure to the above can be 
followed to obtain the pooled results. Finally, exponential tranformation is implemented to 
tranform the statistics and their CI back to the original scale.
Repeated measurements
For inference of repeated measurements, PROC MIXED with REML option is employed for 
MMRM model. The model will include treatment group, visit, interaction between treatment 
group and visit, and baseline value of the variable of interest and its interaction with visit. The 
model will adopt unstructured covariance matrix and the degrees-of-freedom method of 
Kenward and Roger. The difference in the variable of interest between treatment groups and its 
CI will be calculated using LSMEANS statement.
Crude incidence and related risk estimates
For n patients each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of patients with the event.
Odds ratio and  !!( −")% confidence interval
For an investigational drug group with $% patients at risk, independent from placebo with $&
patients at risk, of whom '%and '& experience a certain event with probability π1 and π0
respectively, the odds ratio is estimated as
()/(%*())
(+/(%*(+) with ,% = '%/$% and ,& = '&/$&. A 
conditional exact 100(1 −.)% confidence interval will be obtained by using the SAS 
procedure PROC FREQ with statement EXACT OR or EXACT COMOR. In case that exact 
method fails to produce valid results, asymptotic approach should be adopted. EXACT 


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statement is not to be used in combination with multiple imputation, in which case asymptotic 
approach is adopted.
Risk difference and  !!( −")% confidence interval
For an investigational drug group with $% patients at risk, independent from placebo with $&
patients at risk, of whom '%and '& experience a certain event, the risk difference is estimated 
as ,% −,& with ,% = '%/$% and ,& = '&/$&. Exact unconditional confidence limits for the risk 
difference will be obtained with SAS procedure PROC FREQ and option RISKDIFF in the 
TABLES statement, specifying the RISKDIFF option also in the EXACT statement. In case 
that exact method fails to produce valid results, asymptotic approach should be adopted. 
EXACT statement is not to be used in combination with multiple imputation, in which case 
asymptotic approach is adopted.
Geometric mean and coefficient of variation
The geometric mean (where applicable) will be presented for the baseline values, absolute post-
dose values and for the ratio to baseline (or pre-dose, respectively) values. The geometric mean 
of the ratio to baseline will be presented in terms of % change from baseline and will be 
calculated as follows: (exp (mean of the log-transformed ratio to baseline values) -1)*100.
The Coefficient of Variation (CV) will be calculated for the baseline values, the absolute post-
dose values and the ratio to baseline (or pre-dose, respectively) values.
6
Reference
 
van Ginkel, Joost R., and Pieter M. Kroonenberg. "Analysis of variance of multiply imputed 
data." Multivariate behavioral research 49.1 (2014): 78-91.