Conditions: Non-alcoholic Steatohepatitis (NASH)
Keywords: LJN452 non-alcoholic steatohepatitis NASH phase 2 adaptive design randomized
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 350
Healthy volunteers: no

Brief summary:
The purpose of the study was to assess the effects of different doses of tropifexor (LJN452) with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH

Detailed description:
Part A In Part A, 77 subjects were randomized at baseline to receive tropifexor (10 μg, 30 μg, 60 μg or 90 μg) or placebo (Arms A, B, C, D and E) for 12 weeks. After ≥ 90% of the subjects from Part A completed 8 weeks of treatment, the first interim analysis of all Part A data was performed and the Data Monitoring Committee (DMC) recommended evaluation of 90 μg tropifexor (safe andefficacious) in Part B. The treatment arms of Part A were completed through Week 16 without adaptation.

Part B Randomization for Part B was started after the DMC recommendations on the dose to be used in Part B were implemented by the sponsor. As planned in the study protocol, since the first interim analysis selected one active dose (90 μg) to be tested in Part B, one of the other originally planned active treatment arms (60 μg) was included with a smaller sample size to confirm the earlier findings of this dose observed in Part A. Therefore, in Part B, 121 subjects, were randomized at baseline to receive tropifexor (90 μg and 60 μg) or placebo (Arms F, G and H) for 12 weeks.

Part C was introduced as a result of the DMC recommendation to pursue doses \> 90 μg. Randomization in Part C started once the Part B randomization was completed. In Part C, 152 subjects were randomized at baseline to receive 140 μg or 200 μg tropifexor or placebo (Arms I, J and K) for 48 weeks.

One patient was treated at 2 sites but is still only one patient. 350 total enrollment, and not 351.

Arms:
arm 1: Tropifexor (LJN452) Part A arm 2: Tropifexor (LJN452) Part A arm 3: Tropifezor (LJN452) Parts A + B arm 4: Tropifexor (LJN452) Parts A + B arm 5: Placebo Parts A + B arm 6: Tropifexor (LJN452) Part C arm 7: Tropifexor (LJN452) Part B arm 8: Placebo Part C

Interventions: intervention 1: Tropifexor (LJN452) intervention 2: Placebo
Intervention descriptions: intervention 1: Comparison of different doses of drug intervention 2: Comparator

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
LJN452
Clinical Trial Protocol CLJN452A2202 / NCT02855164
A randomized, double-blind, placebo controlled, 3- part, 
adaptive design, multicenter study to assess safety, 
tolerability and efficacy of tropifexor (LJN452) in patients 
with non-alcoholic steatohepatitis (NASH)
FLIGHT-FXR
Document type:
Clinical Trial Protocol
EUDRACT number:
2015-005215-33
Version number:
03 (Clean)
Clinical trial phase:
II
Release date:
05-Oct-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................12
Amendment 3 (05-Oct-2017) ............................................................................................13
Summary of previous amendments ...................................................................................16
Protocol summary..............................................................................................................20
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose ..................................................................................................................27
2
Study objectives and endpoints .........................................................................................27
2.1
Objectives and related endpoints...........................................................................30
3
Investigational plan ...........................................................................................................33
3.1
Study design...........................................................................................................33
3.2
Rationale for study design .....................................................................................38
3.3
Rationale for dose/regimen, route of administration and duration of treatment....39
3.3.1
Pre-Clinical Animal Studies..................................................................39
3.3.2
CLJN452X2101 – Healthy Volunteers .................................................41
3.3.3
Dose Selection.......................................................................................42
3.4
Rationale for choice of comparator .......................................................................43
3.5
Purpose and timing of interim analyses/design adaptations..................................43
3.6
Risks and benefits..................................................................................................45
4
Population..........................................................................................................................46
4.1
Inclusion criteria ....................................................................................................46
4.2
Exclusion criteria...................................................................................................47
5
Treatment...........................................................................................................................50
5.1
Study treatment......................................................................................................50
5.1.1
Investigational and control drugs..........................................................50
5.1.2
Additional treatment..............................................................................51
5.2
Treatment arms ......................................................................................................51
5.3
Treatment assignment and randomization.............................................................52
5.4
Treatment blinding.................................................................................................53
5.5
Treating the patient................................................................................................54
5.5.1
Patient numbering, ................................................................................54


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5.5.2
Dispensing the study drug.....................................................................55
5.5.3
Handling of study and additional treatment..........................................55
5.5.4
Instructions for prescribing and taking study treatment........................55
5.5.5
Permitted dose adjustments and interruptions of study treatment ........56
5.5.6
Rescue medication ................................................................................60
5.5.7
Concomitant medication .......................................................................60
5.5.8
Prohibited medication ...........................................................................61
5.5.9
Emergency breaking of assigned treatment code..................................62
5.6
Study completion and discontinuation...................................................................63
5.6.1
Study completion and post-study treatment..........................................63
5.6.2
Discontinuation of study treatment .......................................................63
5.6.3
Withdrawal of informed consent...........................................................64
5.6.4
Loss to follow-up ..................................................................................65
5.6.5
Early study termination by the sponsor.................................................65
6
Visit schedule and assessments .........................................................................................65
6.1
Information to be collected on screening failures..................................................81
6.2
Patient demographics/other baseline characteristics .............................................81
6.2.1
Demographic Information.....................................................................81
6.2.2
Medical history......................................................................................81
6.2.3
Alcohol history and assessments...........................................................82
6.2.4
Smoking history ....................................................................................82
6.2.5
Prior and concomitant medications.......................................................82
6.2.6
Liver evaluation ....................................................................................82
6.2.7
Other baseline characteristics................................................................83
6.2.8
Screening visit 2 – additional assessments............................................84
6.3
Treatment exposure and compliance .....................................................................84
6.4
Efficacy..................................................................................................................84
6.4.1
Magnetic Resonance Imaging...............................................................85
6.4.2
Liver Function Tests .............................................................................85
6.4.3
Coagulation tests ...................................................................................85
6.4.4
Markers of liver fibrosis........................................................................86
6.4.5
NAFLD fibrosis score...........................................................................86
6.4.6
Fasting Lipids........................................................................................86
86
86
6.4.9
Liver Biopsy..........................................................................................87


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6.4.10
Appropriateness of efficacy assessments..............................................87
6.5
Safety.....................................................................................................................88
6.5.1
Physical examination ............................................................................88
6.5.2
Vital signs..............................................................................................88
6.5.3
Anthropometric assessments.................................................................88
6.5.4
Laboratory evaluations..........................................................................89
6.5.5
Electrocardiogram (ECG) .....................................................................90
6.5.6
Pregnancy and assessments of fertility .................................................90
6.5.7
Appropriateness of safety measurements..............................................91
6.6
Other assessments..................................................................................................91
6.6.1
Clinical Outcome Assessments (COAs) ...............................................91
6.6.2
Resource utilization...............................................................................94
6.6.3
Pharmacokinetics ..................................................................................94
95
95
7
Safety monitoring ..............................................................................................................96
7.1
Adverse events.......................................................................................................96
7.2
Serious adverse events...........................................................................................97
7.2.1
Definition of SAE .................................................................................97
7.2.2
SAE reporting........................................................................................98
7.3
Liver safety monitoring .........................................................................................99
7.4
Renal safety monitoring.......................................................................................100
7.5
Reporting of study treatment errors including misuse/abuse ..............................100
7.6
Pregnancy reporting.............................................................................................101
7.7
Monitoring for clinically significant LDL-cholesterol increases ........................101
8
Data review and database management...........................................................................102
8.1
Site monitoring ....................................................................................................102
8.2
Data collection.....................................................................................................102
8.3
Database management and quality control..........................................................103
8.4
Data Monitoring Committee................................................................................104
8.5
Adjudication Committee......................................................................................104
9
Data analysis....................................................................................................................104
9.1
Analysis sets ........................................................................................................105
9.2
Patient demographics and other baseline characteristics.....................................105
9.3
Treatments ...........................................................................................................106
9.4
Analysis of the primary variable(s) .....................................................................106


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9.4.1
Primary Variable(s).............................................................................106
9.4.2
Statistical model, hypothesis, and method of analysis........................106
9.4.3
Handling of missing values/censoring/discontinuations.....................107
9.4.4
Sensitivity analyses .............................................................................107
9.4.5
Supportive analyses of the primary variables .....................................108
9.5
Analysis of secondary variables ..........................................................................108
9.5.1
Efficacy variables................................................................................108
9.5.2
Safety variables ...................................................................................109
9.5.3
Resource utilization.............................................................................111
9.5.4
Pharmacokinetics ................................................................................111
111
9.5.6
Biomarkers ..........................................................................................112
9.5.7
PK/PD .................................................................................................112
112
9.7
Interim analyses ...................................................................................................113
9.8
Sample size calculation........................................................................................114
9.8.1
Power considerations with given sample size for safety assessment..115
9.8.2
Power considerations with given sample size for efficacy 
assessment...........................................................................................116
9.8.3
Power consideration for biopsy endpoints in Part C...........................118
10 Ethical considerations......................................................................................................119
10.1
Regulatory and ethical compliance......................................................................119
10.2
Informed consent procedures...............................................................................119
10.3
Responsibilities of the investigator and IRB/IEC................................................119
10.4
Publication of study protocol and results.............................................................120
10.5
Quality Control and Quality Assurance...............................................................120
11 Protocol adherence ..........................................................................................................120
11.1
Protocol amendments...........................................................................................120
12 References .......................................................................................................................122
13 Appendix 1: Clinically notable laboratory values and vital signs...................................124
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements...................................................................................................................125
15 Appendix 3: Specific Renal Alert Criteria and Actions ..................................................127
16 Appendix 4: Sampling schedules and sample logs..........................................................128
17 Appendix 5: The American Heart Association (AHA) Recommended Diet ..................131


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................30
Table 5-1
Overview of treatment - type and number of capsules taken per day...52
Table 5-2
Isolated ALT/AST Elevations...............................................................58
Table 5-3
Dose reduction ......................................................................................60
Table 5-4
Prohibited medication ...........................................................................61
Table 5-5
Medications permitted only if dose is stable (within 25 percent of 
baseline dose) for at least 1 month prior to randomization and 
expected to remain stable through the double-blind treatment 
period.....................................................................................................62
Table 6-1
Assessment schedule Parts A and B......................................................67
Table 6-2
Assessment schedule Part C..................................................................74
Table 6-3
NAS Components..................................................................................87
Table 6-4
Timing of PK samples...........................................................................94
Table 7-1
Treatment errors and appropriate actions............................................101
Table 9-1
Primary variables and methods of analysis.........................................106
Table 9-2
Secondary efficacy variables and analyses .........................................108
112
Table 9-4
Power for multiple contrast test for trend over placebo......................118
Table 13-1
Notable abnormalities in vital signs....................................................124
Table 14-1
Liver Event and Post Baseline Laboratory Trigger Definitions..........125
Table 14-2
Follow Up Requirements for Post-Baseline Liver Events and 
Laboratory Triggers ............................................................................125
Table 15-1
Specific Renal Alert Criteria and Actions for Post Baseline Values ..127
Table 16-1
Blood collection log for pharmacokinetics – Part A...........................128
Table 16-2
Blood collection log for pharmacokinetics – Part B ...........................128
128
Table 16-4
Blood collection log for biomarkers – Parts A and B.........................129
Table 16-5
Blood collection log for pharmacokinetics – Part C ...........................129
Table 16-6
Blood collection log for biomarkers – Part C .....................................130


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List of figures
Figure 1-1
Co-ordinated effects of FXR on metabolism ........................................25
Figure 3-1
Study design..........................................................................................37
Figure 3-2
NAS score (mouse NASH model) ........................................................40
Figure 9-1
Binomial probability to observe an event with given sample size......115
Figure 9-2
Predictions for probability of event based on observed number.........116
Figure 9-3
Potential dose-response curves ...........................................................117


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List of abbreviations
A1AT
Alpha-1-antitrypsin
ACR
Albumin-Creatinine ratio
AE
Adverse Event
AHA
American Heart Association
ALT
Alanine Aminotransferase
ALP
Alkaline Phosphatase
AMA
Anti-mitochondrial antibody
ANA
Anti-nuclear antibody
ANIT
Alpha-Naphtha Isothiocyanate 
ANCOVA
Analysis of Covariance
ANOVA  
Analysis of Variance
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
BMI   
Body Mass Index
BSEP
Bile Salt Export Pump
BSL
Baseline visit
BUN
Blood Urea Nitrogen
C4
7α-Hydroxy-4-cholesten-3-one
CDT
Carbohydrate Deficient Transferrin 
CFR
US Code of Federal Regulations 
CI
Confidence Interval
Cmax
Maximum drug concentration
COA
Clinical Outcome Assessment
CPO
Country Pharma Organization
CRA
Clinical Research Associate
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events version 4.03 (2010)
CYP3A4
Cytochrome P450 3A4
CYP7A1
Cytochrome P450 7A1
DAR  
Dose Administration Record
DMC
Data Monitoring Committee
  
DBP
Diastolic Blood Pressure
ECG
Electrocardiogram
EC50
Half Maximal Effect Concentration


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EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis
EMA
European Medicines Agency
   
EOS
End of Study
EOT
End of Treatment
FAS
Full analysis set
FGF19
Fibroblast Growth factor 19
FXR
Farsenoid X Nuclear Receptor
GCP
Good Clinical Practice
GGT
Gamma-glutamyl Transferase
GLP
Good Laboratory Practice
HA
Hyaluronic Acid
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B Surface Antigen
HCG
Human Chorionic Gonadotropin
HCP
Health Care Professional
HCV
Hepatitis C virus
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
IA    
Interim Analysis
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFG
Impaired Fasting Glucose
INR
International Normalized Ratio
  
IN
Investigator Notification
IU
International Unit
IQR  
Interquartile Range
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention To Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LDL
Low Density Lipoprotein
LFT
Liver Function Test 
LLOQ
Lower Limit of Quantification
MAR
Missing at random 
MCV
Mean Corpuscular Volume
MDRD
Modification of Diet in Renal Disease


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MedDRA
Medical dictionary for regulatory activities 
miRNA
Micro Ribonucleic acid
MMRM
Mixed-Effects Model Repeated Measures
MRI
Magnetic Resonance Imaging
NAFLD
Non-alcoholic fatty liver disease
NAS
NAFLD Activity Score
NASH
Non-alcoholic Steatohepatitis
NOAEL
No Observed Adverse Effect Level
NSAIDS
Nonsteroidal Anti-Inflammatory Drugs
OCA
Obeticholic Acid
OC/RDC
Oracle Clinical/Remote Data Capture 
PBC
Primary Biliary Cirrhosis / Primary Biliary Cholangitis
PCR  
Protein-Creatinine ratio
PD
Pharmacodynamics
PIIINP
Propeptide of Procollagen Type III
PK
Pharmacokinetic
PNPLA3
Patatin-like phospholipase domain-containing protein 3
PRO
Patient Reported Outcome
PSW
Premature Study Withdrawal
PT
Prothrombin Time
PUFA
Polyunsaturated Fatty Acids
QTcF
Corrected QT interval (Fridericia method) 
RAN
Randomized set
RBC
Red Blood Cell
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SAF
Safety Set
SBP
Systolic Blood Pressure
sCr
Serum Creatinine
SCR
Screened set
SHP
Small Heterodimer Partner
SOC
System Organ Class
SPP
Safety Profiling Plan
SULT2A1
Sulfotransferase Family 2A Member 1
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBC
To Be Confirmed
TBL
Total Bilirubin
TD
Study Treatment Discontinuation
TIMP-1
Tissue Inhibitors of Metalloproteinases
Tmax
Time post-dose when Cmax occurs
TNF-α
Tumor Necrosis Factor α
TT
Thrombin Time
UGT1A1
UDP Glucuronosyltransferase 1 Family, Polypeptide A1
UGT1A3
UDP Glucuronosyltransferase 1 Family, Polypeptide A3
UGT2B4
UDP Glucuronosyltransferase 2 Family, Polypeptide B4


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ULN
Upper Limit Normal
VAS
Visual Analogue Scale
WBC
White Blood Cell
WHO
World Health Organization 
WHR
Waist-to-Hip ratio
WTH
Waist-to-Hip 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients fulfilling certain criteria
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 twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from 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)
Epoch
A portion of the study which serves a specific purpose. Typical epochs are: 
screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US 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 ID 
A unique number assigned to each patient upon signing the informed consent 
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 consent (WoC)
Withdrawal of consent from the study is defined as when a patient does not 
want to participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further study related contact, and 
does not allow analysis of already obtained biologic material


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Amendment 3 (05-Oct-2017)
Amendment Rationale
The purpose of this amendment is to add Part C to the protocol to explore doses of tropifexor 
(LJN452) > 90 µg. Part C will enroll 150 patients to be treated for 48 weeks with 140 μg
tropifexor, 200 μg tropifexor, or placebo once daily in a 1:1:1 randomization.
Use of the 90 µg dose in Part B, and subsequent use of tropifexor doses > 90 µg, were 
recommendations from the Data Monitoring Committee (DMC) upon review of the Part A 
interim analysis data. The DMC review revealed no safety concerns at the doses up to 90 µg 
studied in Part A. PK/PD modeling and simulation of the Part A data at the time of the DMC 
interim analysis suggested that exposures of AUC > 40 ng*h/mL should be explored to better 
define the maximum response for the ALT, AST, FGF-19 and GGT biomarkers evaluated.
Modeling of the Part A PK data indicates that exposure at the doses explored in Parts A and B 
were approximately 40 ng*h/mL at the 90 μg dose, 25 ng*h/mL at the 60 μg dose, 15 
ng*h/mL at the 30 μg dose and 5 ng*h/mL at the 10 μg dose. Extrapolation of the modeled 
PK Part A data shows that for doses of 140 μg and 200 μg approximately 80% and 95% of 
patients, respectively, will achieve an AUC > 40 ng*h/mL, and these doses will approximate
AUC values of 60 and 80 ng*h/mL respectively.  Therefore the 140 μg and 200 μg doses were 
selected for use in Part C to complete the broad dose finding approach in this study.
Initial non-clinical oral gavage toxicology studies conducted in rats and dogs for up to 13-
weeks limited the upper systemic exposures to tropifexor in patients to 70 ng*h/mL and 12 
weeks of treatment in previous versions of this protocol (v00 – v02). Non-clinical toxicity 
studies exploring higher doses for longer duration have been ongoing.  Newly available 
results from 26-week rat and 39-week dog toxicity studies indicate that greater FXR 
activation is possible (both in vitro and in vivo) at higher exposure levels than those currently 
used in Parts A and B of this trial.  These chronic toxicology studies support a higher NOAEL.  
The higher systemic exposure to tropifexor achieved at the NOAEL in these toxicity studies is 
AUC0-24h > 274 ng*h/mL in dogs which is more than 3 x greater than the predicted exposure 
at 200 µg (AUC = 80 ng*h/mL) in NASH patients.
Due to the longer term toxicity data now available, study duration will be increased to 48 
weeks. Longer term treatment provides the opportunity for inclusion of biopsies in this trial.  
Paired liver biopsies at baseline and at Week 48 will be included for all patients in Part C of 
this study.  Inclusion criteria for Part C 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, AND 
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females).  The phenotypic diagnosis of NASH will not 
confer eligibility in Part C.
Changes to the protocol
The main modifications to the protocol are:
1. Tropifexor, the newly assigned INN, replaces LJN452 throughout the protocol.


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2. Sample Size - Overall sample size for the study is 345 patients.  
Part B: As a result of the DMC selection of one Part A dose (90 µg) for Part B, the sample 
size is 120 patients as specified in previous versions of the protocol and outlined in 
Section 3.1, Study Design.  This is not a change to the original study design options.  The 
Part B sample size has been updated in the following Sections:

Protocol summary

Figure 3-1

Section 4 - Population
Part C will include 150 patients.  Details were added throughout the protocol.  These 
include

Requirement for liver biopsy for eligibility

48 weeks duration

Doses of 140 and 200 µg
3. Use of doses 140 and 200 µg in Part C - Section 5.2 and throughout.
4. Study Design - Section 3.1 was updated to include Part C
5. Diagnosis of NASH was modified to include the requirement for liver biopsies in Part C
in the following sections:

Protocol Summary

4.1 Inclusion Criteria
Diagnosis of NASH:

Parts A & B:  Presence of NASH as demonstrated by ONE of the following: 

Histologic evidence of NASH based on liver biopsy obtained 2 years or less 
before randomization with a diagnosis consistent with NASH, fibrosis level F1, 
F2 or F3, (i.e. fibrosis in the absence of established cirrhosis) no diagnosis of 
alternative chronic liver diseases 

Part C (All patients): Adequate liver biopsy sample for evaluation by Central 
Reader to confirm Histologic evidence of NASH based on liver biopsy obtained 
during the Screening period or within 6 months before randomization with a 
diagnosis consistent with NASH, fibrosis level F2 or F3, and no diagnosis of 
alternative chronic liver diseases.  Permitted therapies must be stable as outlined in 
Table 5-5 (from 1 month prior to biopsy up to and including screening)
AND (all Parts)
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
OR (for Parts A and B only)

Phenotypic diagnosis of NASH based on presence of ALL THREE of the 
following:
o
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND


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o
BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian)  or 
≥23 kg/m2 (in patients with a self-identified Asian race) AND
o
Diagnosis of Type 2 diabetes mellitus by having either:
-
HbA1C ≥ 6.5% or
-
Drug therapy for Type 2 diabetes mellitus
6. Liver biopsies required for eligibility and at End of Treatment at Week 48 in Part C. In 
sections 6.2.6, 6.4.9 and throughout.
 
8. Assessment Schedule for Part C added in Table 6-2 to include visits through week 48.
9. Secondary 
 endpoints added to assess histologic changes by biopsy for 
Part C patients in Sections 2, 9, and throughout.  Primary endpoint remains unchanged at 
Week 12 for all study Parts.
10. Editorial Changes throughout.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
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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Summary of previous amendments
Amendment 2 (07-Mar-2017)
Amendment rationale 
The purpose of Amendment 2 is to ensure that the protocol text clearly outlines that a second 
interim analysis of Part A, to include data collected up to Week 16, will be conducted.  
Additionally, the eligibility criteria are updated based on the accumulating experience from
ongoing Part A, other NASH studies, input from study investigators, and review of recent
literature.  Additional clarifications and corrections of small errors are made at this time.
At the time of amendment 2, Part A enrollment is ongoing. More than 154 patients have been 
screened and 39 patients have been randomized to double-blind treatment.
Changes to the protocol
The main modifications to the protocol are:

Section 4.1 Inclusion Criteria:
3: Update on the cut-off for ALT elevation to ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females).  
Although ‘elevated’ ALT is part of the robust formula for determining NASH in diabetic
patients, the accumulating experience indicates that there is a wide overlap of ALT values
between patients with biopsy proven NASH (81+60) and those with simple fatty liver (52+34) 
(Bazick et al., 2015). Although ALT values vary little between laboratories based on technical 
issues, the laboratory ‘normal’ ALT is often not associated with true normal values which 
vary between genders. This is highlighted by an extensive review of this subject (Liu et al., 
2014) in which the upper limits of normal for ALT are 38 IU/L in males and 28 IU/L in 
females. Similar and somewhat more conservative of these values, 43 IU/L in males and 28 
IU/L in females, have been now chosen to define ALT cutoff for eligibility in this amendment.  
The consensus around lower values of ‘normal’ ALT is further reflected by the recently issued 
ACG Clinical Guideline on the Evaluation of Abnormal Liver Chemistries (Kwo et al 2017)
which declares that ALT levels greater than the true “healthy normal ALT” cutoff values 29 
to 33 IU/L for males and 19 to 25 IU/L for females should be further evaluated. The updated 
cut-off values adapted in this protocol, 43 IU/L (males) and 28 IU/L (females) are 1.5 times 
the values of 29 and 19 in the ACG Guideline.  

Section 4.2 Exclusion Criteria:
18: Hepatitis C virus exclusion clarified to reflect the original intent to exclude patients with 
active HCV (positive HCV RNA by PCR) and not previous infection as reflected in HCV 
antibody.
20: Cholecystectomy was removed as an exclusion.  LJN452 is a non-bile acid FXR agonist
without significant enterohepatic recirculation.  Therefore the absence of the gall-bladder 
should have little or no effect on the activity of LJN452.
26: GLP-1 agonist exclusion modified to exclude GLP-1 agonists if not on a stable dose for 3 
months prior to screening.  Phenotypic definition of NASH includes type 2 diabetes.  GLP -1 


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agonists are frequently prescribed for this patient population.  If patients are on a stable dose 
of GLP-1 agonists for 3 months prior to screening, meet eligibility criteria, and remain on the 
same dose throughout the study, the effect on change from baseline on protocol assessments is 
expected to be minimal. This is similar to how the protocol approaches other interventions 
with some suggestion of anti-NASH activity such as vitamin E.

Various Sections:  Primary objective(s)
The Key secondary endpoint ‘To determine the dose-response relationship of LJN452 on liver 
fat content by changes in quantitative MRI determined fat’ has been included in the primary 
objective.   

To determine safety and tolerability of different doses of LJN452

To determine the dose-response relationship of LJN452 on markers of hepatic 
inflammation in NASH (ALT and AST) 

To determine the dose-response relationship of LJN452 on liver fat content by changes in 
quantitative MRI determined fat 
Hepatic fat is a key component of NASH. MRI determination of hepatic fat fraction is 
considered by many to be the best measure of hepatic fat due to its precision and ability to 
average fat content over several areas of the liver.  Elevation of hepatic fat reduction to a n 
additional, independent primary end-point is due to recognition that reduction of hepatic fat 
content has been demonstrated in studies of similar length (12 weeks) and that the sensitivity 
of the ALT response signal is somewhat diminished by modification of the ALT entry criteria. 
LJN452 has been demonstrated to have multi-modal actions in animal models including the 
reduction of hepatic fat in the fa/fa rat.

Various Sections:  Second interim analysis of Part A Week 16 data clarified.

Section 5.5.8:  Prohibited medication section was simplified and requirements for stable 
doses of concomitant medications were clarified. 

Tables 6-2, 16-1 and 16-2: Week 6, 4 hour post-dose PK sample was added to 
complement the PD sample collected at this timepoint.
 

Section 10.5:  New Novartis template language for ‘Quality’ section was added.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes herein do not affect the Informed Consent. 
Amendment 1
Amendment rationale 
Amendment 1 is being issued to implement recommendations from the US FDA to modify 
certain details of study CLJN452A2202. Additional clarifications and corrections of small 
errors are made at this time.
At the time of the amendment, the study has not started and no patients were enrolled. 


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Changes to the protocol
The major modifications to the protocol are:

Title page and protocol summary: added the new acronym for the study

Section 4 and Section 6: Revision of Exclusion criterion 19 into “eGFR less than 60 
mL/min” and increase in the frequency of monitoring serum creatinine, as well as increase 
in blood urea nitrogen (BUN). 

Several sections: Updates to define baseline levels of AST, ALT, GGT and bilirubin as 
mean of screening and baseline values.

Section 5: Inclusion of additional discontinuation criteria for patients who develop an AE 
of Common Terminology Criteria for Adverse Events (CTCAE) of grade 3 related to the 
study drug, or for patients who develop an AE of CTCAE of grade 4 or higher regardless 
of attribution to study drug. 

Section 5.5.4.1: Removal of grapefruit juice restriction in the dietary restriction section

Section 5.5.8: Updated list of prohibited UGT inhibitors.
 

Table 6-1 (Section 6.1) and Section 6.2.7: Added condition for hepatitis serology testing

Section 7: Updates to include the use of the CTCAE grading system for adverse events 
(AEs). 

Several sections: Updates to outline that the DMC will be alerted if more than 3 patients 
develop an AE of CTCAE of grade 3 or higher in the same system organ class. 

Several sections: Updates to reflect that patients with an elevation of ALT or AST > 2x 
baseline will have liver function retest re-assessed within 48-72 hours, and repeated in 
similar time frames until levels stabilize or decrease.

Several sections: Updates to include that patients who develop medically important 
laboratory abnormalities or medically important AEs that are related to study drug will be 
followed until these events have resolved or stabilized (change in follow up period 2). The 
following will be considered as medically important: 
i) severe AEs (CTCAE grade ≥3),
ii) serious AEs,
iii) hepatic and renal AEs, 
iv) elevated liver enzymes (ALT, AST or alkaline phosphatase >2x ULN and >1.5x 
baseline)

Several sections: Updates to include that there will be reporting of PK data for interim 
analysis evaluation by DMC at Week 8. 

Editorial changes throughout the document
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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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
LJN452A2202
Full Title
A randomized, double-blind, placebo controlled, 3- part, adaptive design, 
multicenter 12-week study to assess safety, tolerability and efficacy of 
tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH): 
FLIGHT-FXR
Brief title
Study of safety and efficacy of tropifexor in patients with non-alcoholic 
steatohepatitis (NASH) 
Sponsor and Clinical 
Phase
Novartis 
Phase 2
Investigation type
Drug
Study type
Interventional
Purpose and rationale
To assess the safety and tolerability profile of tropifexor and to determine 
the early hepatic response to different doses of tropifexor in patients with 
phenotypic or histologic (in Part C) non-alcoholic steatohepatitis (NASH). 
Data from this study will be used to support further development of 
tropifexor in the treatment of patients with NASH
Primary Objective(s) 
The primary objective of the study is to determine safety and tolerability of 
different doses of tropifexor by monitoring adverse events 
Moreover, the study will determine the dose-response relationship of 
tropifexor on markers of hepatic inflammation in NASH by changes in ALT 
and AST from baseline to Week 12.  
The study will also determine the dose-response relationship of tropifexor
on liver fat content by changes from baseline to Week 12 in quantitative 
MRI determined fat
Secondary Objectives
To determine the effect of different doses of tropifexor on anthropometric 
assessments (weight, BMI, waist-to-hip (WTH) ratio) over time
To determine the dose-response relationship of tropifexor on FGF19 over 
time, a marker of FXR target engagement in the gut, and C4, a marker of 
hepatic target engagement
To determine the dose-response relationship of tropifexor on markers of 
liver fibrosis commonly available such as Fibroscan® (in a subset of 
patients), enhanced liver fibrosis panel (ELF), and fibrosis biomarker test 
(originally known as Fibrotest®/ FibroSure®)
To determine the dose-response relationship of tropifexor on GGT, a 
marker of cholestasis
To determine the effect of tropifexor on fasting lipid profile
To determine the pharmacokinetics (PK) of tropifexor
To determine the effect of tropifexor compared to placebo with respect to 
occurrence of potential itch based on a visual analog scale (VAS) rating 
scale 
To determine effects of tropifexor on primary endpoints in the subset of 
patients who have historical biopsy data, both overall and by subsets 
defined by fibrosis score and/or NAS score as feasible (based on the extent 
of available data)
Additional Secondary Endpoints for Part C Only: 


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To determine safety and tolerability of different doses of tropifexor by 
monitoring adverse events up to the end of the study. 
To determine the dose-response relationship of tropifexor on markers of 
hepatic inflammation in NASH by changes in ALT and AST from baseline to 
Week 48.  
To determine the dose-response relationship of tropifexor on liver fat 
content by changes from baseline to Week 48 in quantitative MRI 
determined fat 
To characterize the efficacy of tropifexor in patients with NASH and F2/F3 
fibrosis as assessed by histological (biopsy based) improvement  after 48 
weeks of treatment relative to baseline compared to placebo 
Study design
This is a randomized, double-blind, placebo-controlled, multicenter, 
parallel-group, dose finding, 3-part, adaptive, study to assess the safety, 
tolerability and efficacy of six doses of tropifexor as compared to placebo in 
patients with non-alcoholic steatohepatitis (NASH).
Population
Adult male and female patients with EITHER histologic evidence of NASH 
on liver biopsy within 2 years prior to randomization and elevated ALT, OR 
phenotypic diagnosis of NASH based on elevated ALT, Type 2 diabetes 
mellitus or elevated HbA1c and increased BMI, in both cases accompanied 
by liver fat >10% on centrally-read MRI.
The study will include a total of approximately 345 patients of which 
approximately 75 patients will enroll in Part A, approximately 120 patients 
in Part B and 150 in Part C.
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)

Diagnosis of NASH:

Parts A & B:  Presence of NASH as demonstrated by ONE of the 
following: 

Histologic evidence of NASH based on liver biopsy obtained 2 years 
or less before randomization with a diagnosis consistent with NASH, 
fibrosis level F1, F2 or F3, (i.e. fibrosis in the absence of established 
cirrhosis) no diagnosis of alternative chronic liver diseases 

Part C (All patients):  Adequate liver biopsy sample for evaluation by 
Central Reader to confirm Histologic evidence of NASH based on liver 
biopsy obtained during the Screening period or within 6 months before 
randomization with a diagnosis consistent with NASH, fibrosis level F2 
or F3, and no diagnosis of alternative chronic liver diseases.  Permitted 
therapy must be stable as outlined in Table 5-5 (from 1 month prior to 
biopsy up to and including screening)

AND (all Parts)
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
OR (for Parts A and B only)

Phenotypic diagnosis of NASH based on presence of ALL THREE 
of the following:
o
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND
o
BMI ≥ 27 kg/m2 (in patients with a self-identified race other than 
Asian)  or ≥23 kg/m2 (in patients with a self-identified Asian 
race) AND


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o
Diagnosis of Type 2 diabetes mellitus by having either:
-
HbA1C ≥ 6.5% or
-
Drug therapy for Type 2 diabetes mellitus

Liver fat ≥ 10% at screening as determined by the central MRI 
laboratory

Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 
lb) to participate in the study
Key Exclusion criteria

Previous exposure to an FXR agonist including tropifexor

Patients taking medications prohibited by the protocol 

Pregnant or nursing (lactating) women

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 AUDIT 
questionnaire ≥8

Uncontrolled diabetes defined as HbA1c ≥ 9.5% within 60 days prior to 
enrollment

Presence of cirrhosis on liver biopsy or clinical diagnosis

Clinical evidence of hepatic decompensation or severe liver impairment 

Previous diagnosis of other forms of chronic liver disease

Patients with contraindications to MRI imaging
Study treatment
Tropifexor 10 µg, 30 µg, 60 µg, 90 µg, 140 µg or 200 µg
Matching placebo
Efficacy assessments

MRI for hepatic fat fraction

Liver Function Test

Liver histology

Coagulation test

Markers of liver fibrosis

NAFLD Fibrosis score

Fasting lipids 
Key safety 
assessments

Adverse events monitoring

Monitoring of laboratory markers in blood and urine

ECG

Vital signs

Physical examinations
Other assessments
Pharmacokinetics
Biomarkers
VAS scale on itching 
 


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Data analysis
No formal hypothesis tests will be performed. The analysis of efficacy 
variables will be based on descriptive statistics and repeated measures 
ANCOVA and supported by graphical displays. A general dose-response 
relationship (trend versus placebo) will be examined using a multiple 
contrast test with optimal contrasts for different dose-response models on 
ALT and AST. Safety variables will be analyzed using summary statistics, 
including exposure adjusted incidence rates to account for different lengths 
of exposure across study parts. Specific safety and efficacy criteria for 
selection of the doses for Part B will be defined in the DMC charter. In Part 
C, biopsy based endpoints will be analyzed using descriptive statistics and 
logistic regression.
Key words
Tropifexor, LJN452, non-alcoholic steatohepatitis, NASH, phase 2, 
adaptive design, randomized


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1
Introduction
1.1
Background 
NASH
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
in the Western world (Ratziu et al 2010, Szczepniak et al 2005, Browning et al 2004). The 
clinical-histologic phenotype of the disease extends from nonalcoholic fatty liver to 
nonalcoholic steatohepatitis (NASH). NASH includes not only fat in the liver but also 
inflammation which over time can lead to increasing fibrosis, cirrhosis and end stage liver 
disease. Estimates of the worldwide prevalence of NAFLD range from 6.3% to 33% with a 
median of 20% in the general population, based on a variety of assessment methods. The 
estimated prevalence of NASH is lower, ranging from 3 to 5% (Vernon et al 2011, Chalasani 
et al 2012). NASH is a worldwide problem with growing prevalence over the last few decades. 
One salient observation which relates to the increasing morbidity associated with NASH is 
that over the last decade it has risen from uncommon to the #2 indication for liver 
transplantation in the US (Wong et al 2015).
NASH is a condition characterized by increased fat accumulation in the liver and attendant 
inflammation. In addition to the histologic diagnosis of NASH, there is now a NAS (non-
alcoholic steatohepatitis) activity score which assigns points for 3 key elements: steatosis, 
ballooning degeneration and lobular inflammation. NASH is highly associated with the 
metabolic syndrome and Type 2 diabetes mellitus and a NASH phenotype can be desc ribed 
using combinations of several features of metabolic syndrome (obesity, Type 2 diabetes 
mellitus) along with elevated ALT/AST and fatty infiltration of the liver. Some would broadly 
consider NASH to be the liver component of metabolic syndrome. NASH is a cause of 
progressive fibrosis, and is a leading cause of cirrhosis (Ekstedt et al 2006). Cirrhosis due to 
NASH increases the risk of hepatocellular carcinoma and NASH contributes substantially to 
the population burden of hepatocellular cancer (Starley et al 2010). NASH is also associated 
with an increased risk of cardiovascular mortality and type 2 diabetes mellitus (Targher et al 
2010, Targher et al 2005). The role of the “NASH liver” in contributing to non-liver 
morbidity and mortality is not well understood.
There are no globally approved effective treatments for NASH. Several studies have been 
conducted with Vitamin E and thiazolidinediones, but no long term benefits have been 
demonstrated. There are a number of agents currently in various stages of testing for the 
treatment of NASH but no approved therapies to date.
Pharmacological activation of the farnesoid X nuclear receptor (FXR) has been proposed as a 
target for the treatment of NASH (Cariou 2008, Porez et al 2012). 
FXR
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 


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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).  
Figure 1-1
Co-ordinated effects of FXR on metabolism
FXR regulates bile acid metabolism through multiple mechanisms in the liver and intestine. The 
processes regulated by FXR are shown in rectangular boxes. Genes are shown with up or down 
arrows to indicate the direction of regulation by FXR agonists. Arrows are used to show the flow of bile 
acids in the enterohepatic circulation or the movement of FGF15 (rodents) or FGF19 (human) from the 
enterocyte to the hepatocyte. In normal physiology, FXR detects increased levels of bile acids and 
responds by decreasing bile acid synthesis and bile acid uptake while increasing bile acid modification 
and secretion in the liver. In the intestine, FXR d etects increased bile acid levels and decreases bile 
acid absorption and increases secretion of FGF15 or FGF19. The net result is a decrease in the 
overall levels of bile acids (Figure adapted from Calkin and Tontonoz 2012).
Clinical validation of a FXR agonist for the treatment of NASH has been shown in clinical 
trials with obeticholic acid (OCA), a semi-synthetic variant of the natural bile acid 
chenodeoxycholic acid. In a small study in patients with N AFLD and type 2 diabetes mellitus 


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in which OCA was given for 6 weeks, it was shown that OCA improved insulin sensitivity 
and reduced circulating alanine aminotransferase (ALT) concentrations (Mudaliar et al 2013). 
In a larger trial, it was shown that 45% of NASH patients receiving 25 mg OCA once daily 
for 72 weeks had improved liver histology compared to 23% of NASH patients receiving 
placebo in the same period (Neuschwander-Tetri et al 2015). 
Tropifexor
Tropifexor is a highly potent, specific and orally available non-bile acid agonist of the bile 
acid receptor FXR and is currently being evaluated in early phase healthy subject and patient 
studies. The Investigator’s Brochure (IB) provides a detailed review of the pre-clinical and 
clinical information on tropifexor available to date. 
In vitro pharmacology studies demonstrate that tropifexor is a potent human FXR agonist with 
an EC50 of 0.2 nM and 0.3 nM in a cell-based FXR reporter gene assay and in a biochemical 
co-activator interaction assay, respectively, with >30,000 fold selectivity over other nuclear 
receptors (ERα, GR, LXRα, PPARγ, RXR and PXR). Single and repeat oral dosing lead to 
dose dependent increases in FXR target genes (e.g., liver BSEP and SHP, ileum SHP and 
FGF15). Moreover, tropifexor protects rats from ANIT-induced cholestasis in a chronic 
setting.
Human safety and tolerability, pharmacokinetic and pharmacodynamic data are available from 
the First-in-Human study CLJN452X2101 (see also Section 3.3). In healthy volunteers 
administered tropifexor once daily for up to 14 days the treatment was generally well tolerated 
but isolated asymptomatic and reversible elevations in ALT were observed at higher doses. 
No significant findings in physical exam, vital signs or ECGs have been related to tropifexor; 
no adverse events related to itch, a common adverse event for bile acid-derived FXR agonists, 
were observed in CLJN452X2101. Pharmacokinetic data were consistent with once daily 
dosing (see also Section 3.3). Human pharmacodynamic data show that after single doses in 
healthy volunteers, there were dose-dependent increases in FGF19 from 10 µg to 3000 µg 
tropifexor. After multiple doses, a maximal mean serum FGF19 of 592 pg/ml (range 462- 847 
pg/ml) was observed at 6 hours after administration of 60 µg tropifexor consistent with likely 
pharmacological effect. In healthy volunteers administered tropifexor once daily for up to 14 
days the treatment was generally well tolerated but isolated asymptomatic and reversible 
elevations in ALT were observed at higher doses. At the 60 µg dose 2/6 patients had isolated 
ALT/AST elevations; one at 2X ULN and one just above the ULN. The ALT/AST peaked on 
Day 7 and fully resolved with uninterrupted dosing of tropifexor. At the 100 µg dose one 
patient had an isolated ALT/AST elevation of 5X ULN: one patient had an elevation slightly 
greater than 3X ULN. These elevations were noted by Day 7 and resolved quickly after 
discontinuation of therapy. No significant findings in physical exam, vital signs or ECGs have 
been related to tropifexor; no adverse events related to itch, a common adverse event for bile 
acid-derived FXR agonists, have been observed in CLJN452X2101 to date. 
Currently patients are receiving tropifexor in ongoing studies CLJN452X2201 (Primary 
Biliary Cholangitis (PBC)) and CLJN452X2202 (primary Bile Acid Diarrhea (pBAD)). 


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This study is the first study of tropifexor in patients with phenotypic or biopsy-confirmed 
NASH (see Section 4.1), and it aims to assess safety and tolerability as well as efficacy after 
daily dosing for 12 weeks in Parts A and B and for 48 weeks in Part C.
1.2
Purpose
The purpose of this study is to assess the safety and tolerability profile of tropifexor and to 
determine the early hepatic response to different doses of tropifexor in patients with 
phenotypic non-alcoholic steatohepatitis (NASH). Data from this study will be used to 
support further development of tropifexor in the treatment of patients with NASH.
2
Study objectives and endpoints
Primary objective(s)
To determine safety and tolerability of different doses of tropifexor
To determine the dose-response relationship of tropifexor on markers of hepatic inflammation 
in NASH (ALT and AST)
To determine the dose-response relationship of tropifexor on liver fat content by changes in 
quantitative MRI determined fat 
Secondary objective(s)
To determine the effect of different doses of tropifexor on anthropometric assessments 
(weight, BMI, waist-to-hip (WTH) ratio) after 12 weeks of treatment 
To determine the dose-response relationship of tropifexor on FGF19 over time, a marker of 
FXR target engagement in the gut, and C4, a marker of hepatic target engagement
To determine the dose-response relationship of tropifexor on markers of liver fibrosis 
commonly available such as Fibroscan® (in a subset of patients), enhanced liver fibrosis panel 
(ELF), and fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)
To determine the dose-response relationship of tropifexor on GGT, a marker of cholestasis
To determine the effect of tropifexor on fasting lipid profile
To determine the pharmacokinetics (PK) of tropifexor
To determine the effect of tropifexor compared to placebo with respect to occurrence of 
potential itch based on a visual analog scale (VAS) rating scale
To determine effects of tropifexor on primary endpoints in the subset of patients who have 
historical biopsy data, both overall and by subsets defined by fibrosis score and/or NAS score 
as feasible (based on the extent of available data)
Additional Secondary Objectives in Part C only: 
To demonstrate the efficacy of tropifexor in patients with NASH and F2/F3 fibrosis as 
assessed by histological improvement from baseline after 48 weeks of treatment compared to 
placebo


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To determine safety and tolerability of different doses of tropifexor by monitoring adverse 
events up to the end of the study. 
To determine the dose-response relationship of tropifexor on markers of hepatic inflammation 
in NASH by changes in ALT and AST from baseline to Week 48.  
To determine the dose-response relationship of tropifexor on liver fat content by changes from 
baseline to Week 48 in quantitative MRI determined fat 


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2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective
Endpoint
Unit of measure
Time Frame
Stat Analysis 
Section
Primary
To determine safety and tolerability of different 
doses of tropifexor
Occurrence of SAE, AE resulting in 
discontinuation of study treatment 
and/or dose reductions, and AE of 
special interest
Adverse events 
monitoring
up to End of 
Study
Section 9.4
To determine the dose-response relationship 
of tropifexor on markers of hepatic 
inflammation in NASH (ALT and AST)
Change from baseline to Week 12
Clinical chemistry
up to Week 12
Section 9.4
To determine the dose response relationship 
of tropifexor on liver fat content by changes in 
quantitative MRI determined fat
Relative change from baseline to Week 
12 in % of fat in the liver assessed using 
MRI
% of fat
baseline, 
Week 12
Section 9.4
Secondary
To determine the effect of different doses of 
tropifexor on anthropometric assessments 
(weight, BMI, waist-to-hip (WTH) ratio) after 12 
weeks of treatment
Changes from baseline to Week 12
kg, kg/m2
up to Week 12
Section 9.5
To determine the dose-response relationship 
of tropifexor on FGF19 over time, a marker of 
FXR target engagement in the gut, and C4, a 
marker of hepatic target engagement
Changes from baseline to Week 12
Lab variables
up to Week 12
Section 9.5
To determine the dose-response relationship 
of tropifexor on markers of liver fibrosis 
commonly available such as Fibroscan®, 
enhanced liver fibrosis panel (ELF), and 
Changes from baseline to Week 12
kPa, Clinical 
chemistry
up to Week 12
Section 9.5


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Objective
Endpoint
Unit of measure
Time Frame
Stat Analysis 
Section
fibrosis biomarker test (originally known as 
Fibrotest®/ FibroSure®)
To determine the dose-response relationship 
of tropifexor on GGT, a marker of cholestasis
Changes from baseline to Week 12
Clinical chemistry
up to Week 12
Section 9.5
To determine the effect of tropifexor on fasting 
lipid profile
Changes from baseline to Week 12
Fasted clinical 
chemistry
up to Week 12
Section 9.5
To determine the pharmacokinetics (PK) of 
tropifexor
Ctrough, C2h
ng/mL
up to Week 12
Section 9.5
To determine the effect of tropifexor compared 
to placebo with respect to occurrence of 
potential itch based on a visual analog scale 
(VAS) rating scale
The score (distance from left) on the 
VAS will be recorded by the patient 
marking with a line. The distance 
marked will be converted to a score 
between 0 and 10
VAS score 
between 0-10
up to Week 12
Section 9.5
To determine effects of tropifexor on primary 
endpoints in the subset of patients who have 
historical biopsy data, both overall and by 
fibrosis score and/or NAS score subsets as 
feasible (based on the extent of available 
data)
Subgroup analysis with respect to: 
occurrence of SAE, AE resulting in 
discontinuation of study treatment 
and/or dose reductions, and AE of 
special interest, relative change from 
baseline to Week 12 in % of fat in the 
liver assessed using MRI, and change 
from baseline to Week 12 of ALT and 
AST and GGT
Adverse events 
monitoring
% of fat 
Clinical chemistry
up to Week 12
Section 9.5
Additional Secondary Endpoints for Part C:
To demonstrate the efficacy of tropifexor in 
patients with NASH and F2/F3 fibrosis as 
assessed by histological improvement  
from baseline after 48 weeks of treatment 
compared to placebo
Proportion of patients who have at least 
a one point improvement in fibrosis 
without worsening of steatohepatitis at 
Week 48 compared to baseline
Proportion of patients with resolution of 
steatohepatitis without worsening of 
fibrosis at Week 48 compared to 
baseline
NAS, NASH
CRN scoring 
system and 
NAFLD fibrosis 
score
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Objective
Endpoint
Unit of measure
Time Frame
Stat Analysis 
Section
To determine the effect of tropifexor on 
markers of hepatic inflammation in NASH 
(ALT and AST) in Part C
Change from baseline to Week 48 
Clinical chemistry
up to Week 48
Section 9.5
To determine the effect of tropifexor on 
liver fat content by changes in quantitative 
MRI determined fat in Part C
Relative change from baseline to Week 
48 in % of fat in the liver assessed using 
MRI
% of fat
baseline, 
Week 48
Section 9.5
To determine safety and tolerability of 
different doses of tropifexor, adjusted for 
length of exposure
Exposure adjusted incidence of SAE, 
AE resulting in discontinuation of study 
treatment and/or dose reductions, AE of 
special interest and other AE
Adverse events 
monitoring
up to Week 52
Section 9.5


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3
Investigational plan
3.1
Study design
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose 
finding, 3-part, adaptive, study to assess the safety, tolerability and efficacy of six doses of 
tropifexor as compared to placebo in patients with non-alcoholic steatohepatitis (NASH). 
Patients can be included if they have either histologic evidence of NASH or phenotypic 
diagnosis of NASH (In Parts A & B), as further specified in Section 4.1. Histologic evidence 
of NASH (with fibrosis stage 2 or 3), per central read, during the Screening period or within 6 
months of randomization is required for all patients in Part C.  The composite criterion for 
phenotypic diagnosis has been shown to be nearly as precise as locally read liver biopsy 
which can be frequently re-read as ‘non-NASH’ (Neuschwander-Tetri et al 2015).  
The study will start with screening and enrolling patients for Part A. Screening will continue 
without pause, even after all patients for Part A have been enrolled, but randomization for Part 
B will not start until after the first interim analysis in Part A. When ≥ 90% of the patients in 
Part A have completed 8 weeks of treatment, an interim analysis will be performed using all 
available data to allow for the DMC to recommend dose selection for the arms in Part B (see 
Section 3.5 and Section 9.7). The treatment arms of Part A are planned to be completed 
without adaptation. In addition, a second interim analysis of Part A data collected up to Week 
16 will be performed. 
Randomization for Part B will only be started after the DMC recommendations on the dose(s) 
to be used in Part B are implemented by the Sponsor.   
Part C was introduced as a result of the DMC recommendation to pursue doses > 90 µg after 
the planned interim analysis and DMC review of the Part A data, as well as the preclinical and 
pharmacokinetic data described in Section 3.3. Randomization into Part C will commence 
after Part B randomization is complete.  
Each patient will be randomized into only one Part of the study.  Patients may be screened for 
more than one study Part as appropriate and randomized into the Part for which all eligibility 
criteria are met.
Study Periods 
The total planned duration of the study for each patient in either Part A or Part B is up to 16 
weeks from randomization to the last follow up visit (Figure 3-1); study treatment is taken for 
12 weeks. 
In Part C, the total planned duration for each patient is 52 weeks from 
randomization: 48 weeks of treatment and a 4 week follow up period.  
Screening period:
PART A
The duration of the screening period will be 14 to 35 days during which study eligibility will 
be confirmed. Screening will consist of two consecutive visits. During the first screening visit 


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(maximum -5 weeks prior to baseline/randomization), patients will be assessed for eligibility 
to participate in the trial. Patients’ potential entry into the study will be determined when the 
majority of screening procedures including inclusion and exclusion criteria are assessed.  
Laboratory assessments required for eligibility during the screening period should not be 
repeated unless the sample is compromised rendering testing impossible or is otherwise 
reasonably suspected of being inaccurate (e.g. a nonsensical value). If liver biopsy results are 
available prior to randomization, the results will be reviewed prior to MRI (to be done at 2nd
screening visit) to confirm they are consistent with NASH and without the diagnosis of other 
chronic liver diseases. If potential eligibility is confirmed, patients will proceed to the second 
screening visit (-2 weeks prior to baseline/randomization) at which a qualifying quantitative 
MRI will be performed to assess their liver fat percentage for entry into the study.
MRI 
should only be scheduled to occur within 2 weeks of the expected date of randomization. The 
MRI assessment will be forwarded to a central MRI laboratory for evaluation. Patients with 
liver fat ≥ 10% as determined by the central MRI laboratory will be eligible for randomization 
into the study. The investigator will be notified whether the patient qualifies for the study and 
will be informed of any other safety findings that would influence the participation of the 
patient in the study; however he/she will be blinded to the actual liver fat percentage until 
after the study is completed. 
PART B 
There may be a variable duration of screening (5 weeks to approximately 8 months) during 
which study eligibility will be confirmed; screening will consist of two visits. During the first 
screening visit (visit duration will be dependent on time needed for the first interim analysis 
and dosing recommendations from Part A), patients will be assessed for eligibility to 
participate in the trial. Patients’ potential entry into the study will be determined when the 
majority of the screening procedures including inclusion and exclusion criteria are assessed.  
If liver biopsy results are available prior to randomization, the results will be reviewed prior to 
MRI (to be done at 2nd screening visit) to confirm they are consistent with NASH without 
cirrhosis and without the diagnosis of other chronic liver diseases. Laboratory assessments 
required for eligibility during the screening period should not be repeated unless the sample is 
compromised rendering testing impossible or is otherwise reasonably suspected of being 
inaccurate (e.g. a nonsensical value). If the period between the first screening visit and the 
expected date of randomization for a subject in Part B is greater than 2 months, certain 
assessments of screening visit 1 will be repeated at screening visit 2 (see Table 6-1 and 
Section 6.2.8). If randomization into Part B can occur within 2 months after screening visit 1, 
the repeat of these assessments is not needed. In either case, potentially eligible patients will 
proceed to screening visit 2 (-2 weeks prior to baseline/ randomization) at which a qualifying 
quantitative MRI will be completed to assess their liver fat percentage for entry into the study 
and repetition of selected screen 1 assessments, when applicable (Table 6-1 and Section 6.2.8). 
MRI should only be scheduled to occur within 2 weeks of the expected date of randomization. 
The MRI assessment will be forwarded to a central MRI laboratory for evaluation. Patients 
with liver fat ≥ 10% as determined by the central MRI laboratory will be eligible for 
randomization into the study. The investigator will be notified whether the patient qualifies 
for the study and will be informed of any other safety findings that would influence the 


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participation of the patient in the study; however he/she will be blinded to the actual liver fat 
percentage until after the study is completed.  
PART C
The duration of the screening period will be 14 to 70 days during which study eligibility will 
be confirmed. Screening will consist of two consecutive visits. During the first screening visit 
(10 weeks prior to baseline/randomization), patients will be assessed for eligibility to 
participate in the trial. Patients’ potential entry into the study will be determined when the 
majority of screening procedures including inclusion and exclusion criteria performed at 
Screening Visit 1 are assessed. Laboratory assessments required for eligibility during the 
screening period should not be repeated unless the sample is compromised rendering testing 
impossible or is otherwise reasonably suspected of being inaccurate (e.g. a nonsensical value). 
If potential eligibility is confirmed, patients will proceed to the second screening visit (-2 
weeks prior to baseline/randomization) for histology and hepatic fat assessments. If liver 
biopsy was performed within 6 months of planned randomization, slides must be prepared as 
required by, and sent to, the central reader to confirm eligibility.  If tissue from a liver biopsy 
within 6 months of randomization is not available, a liver biopsy must be performed during 
the Screening Period (and may be performed prior to SV2 to allow sufficient time for central 
review and site notification prior to baseline) after other eligibility is confirmed. Patients 
whose biopsy results are consistent with NASH (with Fibrosis scoring F2 or F3), as 
determined by the Central Reader will be eligible for Randomization into the study. A
qualifying quantitative MRI will also be performed at Screening Visit 2 to assess liver fat 
percentage for entry into the study.  MRI should be scheduled to occur within 2 weeks prior to 
the expected date of randomization.  The MRI assessment will be forwarded to a central MRI 
laboratory for evaluation. Patients with liver fat ≥ 10% as determined by the central MRI 
laboratory will be eligible for randomization into the study. The investigator will be notified 
whether the patient’s liver biopsy and MRI qualify for the study and will be informed of any 
other safety findings that would influence the participation of the patient in the study.  
However investigators will remain blinded to the actual histology findings and liver fat 
percentage until after the study is completed.  
Treatment period
PART A (12 weeks)
In Part A, approximately 75 patients whose eligibility is confirmed will be randomized at the 
baseline visit (BSL) to tropifexor (10 µg, 30 µg, 60 µg or 90 µg) or placebo in a 1:1:1:1:1 
ratio (Arms A, B, C, D and E). Tropifexor or matching placebo will be administered once 
daily for 12 weeks in a blinded manner. 
After ≥90% of the patients from Part A have completed 8 weeks of treatment, the first interim 
analysis for all Part A patients will be done and all available data will be evaluated by a Data 
Monitoring Committee who will recommend the treatment arms to be used in Part B. 
PART B (12 weeks)
In Part B, approximately 120 patients, whose eligibility is confirmed, will be randomized at 
baseline to tropifexor (anticipated 2 doses as recommended by the DMC) or placebo in a 


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15:4:5 ratio (Arms F, G and H). Tropifexor or matching placebo will be administered once 
daily for 12 weeks in a blinded manner. 
In August 2017, the DMC recommended one tropifexor dose, 90 µg (safe and efficacious) to 
be evaluated in 75 patients in Part B.  Therefore, per protocol, one of the other originally 
planned active treatment arms, 60 µg (next highest dose), will continue with a smaller sample 
size (20 patients) to confirm the earlier findings of this dose observed in Part A. In this 
scenario, 90 µg will be tested in approximately 90 patients, 60 µg in 35 patients, and placebo 
in 40 patients in the combined Parts A and B. If only one arm was deemed safe, the DMC 
may have recommended only one active dose to be pursued in Part B, along with matched 
placebo.
PART C (48 weeks) 
In Part C approximately 150 patients, whose eligibility is confirmed, will be randomized at 
baseline to 140 µg or 200 µg tropifexor or placebo in a 1:1:1 ratio (Arms I, J and K).  
Tropifexor or matching placebo will be administered once daily for 48 weeks in a blinded 
manner. Part C dose selection is detailed in Section 3.3.
Post treatment follow-up period (4 weeks) – Follow up 1 period
All patients in all parts will be followed up for 4 weeks after the last dose of study treatment 
(Follow up 1 period).
Post treatment follow-up period (flexible period) – Follow up 2 period
Patients who develop medically important laboratory abnormalities or medically important 
AEs that are considered related to study drug and which are not resolved or stabilized at the 
Follow up 1 visit (Visit 299) will be followed, beyond the planned post treatment follow-up 
period, until these events have resolved or stabilized. 
The following will be considered as medically important:  
i.
severe AEs CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3,
ii.
serious AEs,
iii.
hepatic and renal AEs, 
iv.
elevated liver enzymes (ALT, AST or alkaline phosphatase >2x ULN and >1.5x 
baseline) (see Section 9.5.2.5 for definition of baseline levels)
These patients will be monitored frequently by the investigator and have unscheduled visits to 
collect safety and/or laboratory data. It is advised that the first follow up of these patients with 
such events will be scheduled approximately 4 weeks after the completion of the Follow up 1 
period, or sooner based on investigators discretion; if events are not resolved or stabilized at 
this time point, further follow up will be scheduled at the investigators discretion and 
unscheduled visits will be used to collect safety and/or laboratory data. As soon as the event is 
resolved and/or stabilized, and as long as there are no additional medically important events 
from the treatment period ongoing, the final follow-up visit to complete the follow-up 2 
period needs to be performed (EOS).  


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Figure 3-1
Study design
* As planned in all versions of this protocol, in the event that the DMC interim analysis selects only one 
active dose to be tested in 75 patients in Part B (90 µg), one of the other originally planned active 
treatment arms (60 µg) will continue with a smaller sample size (20 patients) to confirm the earlier 
24
48
EOT
52
EOS
-10 to Rand.
Study Week
Screening
Treatment Period   
Follow up  
LJN452 140 µg
Placebo
Randomization
Part C
N = 150
1:1:1
LJN452 200 µg
6
12
EOT
16
EOS
***
-5 to Rand.
Study Week
Screening
Treatment Period    
Follow up  
LJN452 Dose 10 µg
Placebo
Randomization
LJN452 Dose 30 µg 
LJN452 Dose 60 µg
Part A
N = 75
1:1:1:1:1
LJN452 Dose 90 µg
Interim Analysis 
at Week 8
6
12
EOT
16
EOS
***
-32
** to Rand.
Study Week
Screening
Treatment Period    
Follow up  
LJN452 90 µg n=75
Placebo n=25
Randomization*
LJN452 60 µg n=20
Part B
N = 120
15:4:5


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findings of this dose observed in Part A. In this scenario, Dose A will be tested in a total of 90 patients, 
Dose B in a total of 35 patients, and placebo in a total of 40 patients.
** Screening period for Part B can take up to approximately 32 weeks depending on the availability of 
the IA results to confirm the doses for Part B.
***Patients who develop medically important laboratory abnormalities or medically important AE that 
are considered related to study drug will be followed as described in Section 3.1.
3.2
Rationale for study design
This randomized, multi-center, double-blind, 3 part, adaptive, placebo-controlled study is 
designed to assess the safety and tolerability and early hepatic response to tropifexor in the 
dose range of 10 µg to 200 µg relative to placebo in patients with NASH. Longer term 
response, assessed by histology in a subset of patients (Part C), will also be examined. The 
principle of an FXR agonist treating NASH has been demonstrated in a Phase 2b trial of 
obeticholic acid, a bile acid FXR agonist (Neuschwander-Tetri et al 2015). Therefore, this 
trial will focus on identifying the appropriate doses of tropifexor, a potent non-bile acid FXR 
agonist. Expansion in Part B, followed by Part C will develop a larger safety data base  for 
two doses of tropifexor (60 µg and 90 µg) in Part B which demonstrated early biochemical 
response and no safety concerns, and two higher doses in Part C (140 µg and 200 µg), to 
further enable the dose finding objectives of this study.  Non-clinical toxicity data, the DMC 
Interim Analysis, and exposure data predicted by pharmacokinetic modeling of Part A data,
support the study of the 140 µg and 200 µg doses (Section 3.3).  The longer term non-clinical 
data support increasing treatment duration to 48 weeks, allowing addition of a histological 
endpoint in Part C. 
Multiple sites are necessary due to low diagnosis rate of this prevalent disease, the high 
number of competing trials, and the historically slow accrual rate to date in publicly disclosed 
trials of NASH (e.g. FLINT trial: Neuschwander-Tetri et al 2015). No known quantitative 
differences exist in regional criteria for the diagnosis of NASH, except that phenotypic NASH 
has been defined by a lower BMI criteria for Asian patients. There may be a greater numbe r 
of patients with “non-obese” NASH in some Asian countries but this entity is difficult to 
diagnose without liver biopsy and is not being studied in this trial.
Although an elevated ALT is frequently associated with NASH, in patients with other 
phenotypic elements of NASH there is a wide overlap of ALT values in those with simple 
fatty liver (52+34) and those with NASH (81+60; Bazick et al., 2015). This issue is further 
complicated by the fact that while there is little technical variation in measuring ALT and 
AST between laboratories, the posted ‘normal’ values often do not correspond to true normal 
values and are gender specific. Based on an extensive review of this subject (Liu et al., 2014) 
the upper limits of normal for ALT are 38 IU in males and 28 IU in females. The ACG 
Clinical Guideline (Kwo et al 2017) suggests ALT levels above 29 to 33 IU/L for males and 
19 to 25 IU/L for females should be assessed.  Additionally, there is a large cadre of NASH 
patients with normal ALT.  The strength of the phenotypic determination of NASH used in 
Parts A and B of this trial rests on the combination of type 2 diabetes mellitus, obesity, and 
high hepatic fat fraction. Based on this information, the population to be studied in this trial is
patients with elevated ALT values who have type 2 DM, obesity, and HFF greater than 10%. 
ALT values in these patients have the potential for reduction to true normal values.  Several 
other measures of efficacy, including reduction of hepatic fat, are measured in this trial. The 


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issue of diagnostic specificity will be approached in three ways: 1) an analysis of the sub-
group of patients in Parts A and B with a histologic diagnosis of NASH, 2) an analysis of 
patients with higher ALT values on entering the trial, and 3) verification of NASH using a) 
more complex published formulas which utilizing other variables captured in this trial (Bazick 
et al., 2015) and b) the use of novel biomarkers in development such as the 
metabolomic/lipidomic signatures developed by OWL Metabolomics (Alonso et al., In Press)
In order to maintain the scientific integrity of the study, the Investigator, the patient and 
Novartis study personnel will remain blinded to their treatment allocation. For the purposes of 
data presentation to the DMC, non-study Novartis personnel may be unblinded to the study 
data. These people will be documented in the DMC charter.
The current study will follow an adaptive design as the accumulating data from the first part 
will be used to guide to which treatment group(s) additional patients will be added. This 
approach will allow for minimizing the overall number of patients required to study a new 
treatment while allowing enlargement of promising treatment regimens in order to increase 
the precision of the treatment effects estimates for further decision making to inform the 
design of future studies.
The duration of 12 weeks of therapy is a suitable timeframe to test the chosen primary 
endpoints in the study. In the FLINT trial of a less potent FXR agonist, ALT and GGT levels 
in the blood dropped as early as after 4 weeks of treatment and most of this effect was noted 
by 12 weeks of therapy (Neuschwander-Tetri et al 2015).
The duration of 12 weeks of therapy in Parts A and B was supported by GLP-toxicology 
studies of 13 weeks in duration.  Subsequently, longer term GLP-toxicology 26 weeks rat and 
39 weeks dog studies allow for longer term treatment. As a result, patients will be treated for
48 weeks in Part C. In addition to longer term safety and efficacy follow up, 48 week 
treatment also provides the opportunity for evaluation of histological improvement by paired 
biopsies at Baseline and Week 48, which will be included in Part C.
The patient population is described in more detail in Section 4 below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The initial range of doses of 10 µg to 90 µg tropifexor studied in Part A was 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 
(Investigator’s Brochure).  The use of doses up to 200 µg in Part C is supported by 1) 
additional preclinical toxicity and efficacy data (animal models of NASH, 26 week rat and 39-
week dog toxicity studies),2) Safety and tolerability data in NASH patients (Part A), and
DMC dose recommendation, and 3) Pharmacokinetic modeling.
3.3.1
Pre-Clinical Animal Studies
In non-clinical studies in rodents, tropifexor was well tolerated with no exacerbation of 
transaminase release in the elevated ALT cholestasis model (ANIT) or fatty liver disease
model.  


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Additional Preclinical studies evaluating higher exposure levels than those currently used in 
Parts A and B of this trial demonstrate that greater FXR activation is possible (both in vitro 
and in vivo) suggesting that increased level of FXR activation would result in greater efficacy.  
In a NASH mouse model higher dosing resulted in lower NAFLD Activity Score and reduced 
fibrosis (Figure 3-2).  A dose of 0.3 mg/kg in mice provides exposure of 129 ng*h/mL, which 
is higher than the predicted exposure of 200 g daily in NASH patients of approximately 80
ng•hr/ml.
Figure 3-2
NAS score (mouse NASH model) 
The safety profile of tropifexor was further evaluated in oral gavage toxicity studies 
conducted in rats for up to 26 weeks and in dogs for up to 39 weeks. 
The direct pharmacological effects of clinical relevance from these studies include decreases 
in bile acids; alterations in cholesterol and triglycerides; increases in fibrinogen (with 
shortening of PT or APTT), BUN and ALP (intestinal and hepatic isoforms) at most dose 
levels. These alterations in serum chemistry parameters were reversible and not adverse in 
their magnitude.
Hepatic effects included hepatocellular hypertrophy along with minimal increases in ALT.
Hepatocellular hypertrophy was only adverse in animal models at exposures (e.g in dogs, 
Mean AUC0-24h of 898 and 507 ng*h/mL in males and females respectively) well above 
those expected in NASH patients (80 ng*h/mL at 200 g) for the doses planned in this study.
Hepatocellular hypertrophy represents an adaptive response to the high hepatic concentrations 
of enzyme-inducing drugs and has limited clinical relevance. 
The proposed NOAEL of 0.03 mg/kg/day is based on the results of the 26-week rat and 39-
week dog toxicity studies.  Systemic exposures in terms of AUC0-24h were 27.1 ng*h/mL in 
rats (16.5 ng*h/mL in males and 37.7 ng*h/mL in females) and 274 ng*h/mL in dogs (210 
ng*h/mL in males and 338 ng*h/mL in females).


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Overall, the nature (mechanism, reversibility, monitorability) of the non-clinical safety 
findings support the dog as the most relevant animal species for risk assessment. Based on 
the systemic exposures (274 ng*h/mL) at the dog NOAEL, the highest proposed daily dose of 
200 g (AUC0-24h ~80 ng*h/mL), for Part C is not considered to pose an additional safety risk 
to patients. 
3.3.2
CLJN452X2101 – Healthy Volunteers
Tropifexor has been studied in healthy subjects in single doses up to 3000 µg and in multiple 
doses up to 100 µg for up to 2 weeks. To date, over 63 healthy subjects have been treated with 
tropifexor. Data from study CLJN452X2101 has demonstrated the following:

In single ascending dose (SAD) (Part 1, 6 cohorts of 8 subjects, each with 6 subjects on 
active and 2 on placebo), a single drug-related AE (Grade 1) of nausea was reported in a 
single subject at 300 µg. The highest exposures tested in healthy subjects were Cmax 
54.2 ng/mL and AUCinf 944 ng*h/mL in the 3000 µg single dose cohort.

In multiple ascending dose (Part 2, with cohorts of 8 subject, each with 6 subjects on 
active and 2 on placebo) with a treatment duration of 14 days, 4 SAEs were reported in 3 
subjects of which 1 SAE was suspected to be related to study drug. Transient non-adverse 
elevation of ALT was noted in 2 subjects at 60 µg (Cmax 1.6 ng/mL and AUCtau 25.3 
ng*h/mL) (2x ULN and <1.2x ULN) and returned to normal limits without cessation of 
study drug. At 100 µg tropifexor (Cmax 3.47 ng/mL and AUCtau 50.2 ng*h/mL)  , 
1 subject had an increase of ALT > 5x ULN and 1 subject had an ALT increase of slightly 
greater than 3x ULN. In both cases AST was also elevated to a lesser degree and elevated 
transaminase levels were not associated with symptoms or signs of hepatic dysfunction or 
elevation of bilirubin. Since study drug was discontinued it is not known if ALT/AST 
would have normalized with continued therapy as it did at the 60 µg dose, however liver 
enzymes normalized soon after study drug discontinuation. Based on the findings at the 60 
µg dose, this isolated ALT/AST increase is consistent with a metabolic adaptation of the 
liver to tropifexor.

Results from the First-in-Human study CLJN452X2101 also showed that when tropifexor
was taken with a high-fat meal, median Tmax was delayed from 4 h to 9 h, and mean 
Tropifexor Cmax and AUCinf increased by approximately 60% compared to the fasted 
state. Individual Tropifexor fed vs. fasted exposure ratios ranged from 1.17 to 2.27-fold 
for Cmax and from 1.24 to 1.94-fold for AUCinf. To avoid variability in drug exposure, it 
is recommended that throughout the treatment period, patients will be directed to take 
study drug at home with ~240 mL (8 ounces) of water in the morning in a fasting state, at 
least 30 min prior to the first beverage apart from water and 60 min prior to first meal of 
the day, preferably at the same time of the day.  For each daily dose, one capsule should 
be taken from each of the 3 bottles dispensed.

The pharmacodynamic marker, FGF19 continues to rise with increasing tropifexor doses 
up to 3000 µg in the SAD study. The 30 µg/day dose resulted in FGF19 elevations 
consistent with likely pharmacological activity in NASH (Neuschwander-Tetri et al 2015).


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3.3.3
Dose Selection
The DMC will closely follow safety data and liver enzymes of this study.
3.3.3.1
Part A
Initial Exposure cap (AUCtau,ss) - 70 ng•hr/ml was based on 13 week animal toxicity studies. 
Therefore, the doses in Part A have been chosen based on the following: 

The 10 µg dose of tropifexor to explore if the lowest dosage form is efficacious as well as 
to fully explore the lower part of the dose response curve

The 30 µg dose has FGF19 elevation consistent with likely pharmacological activity in 
NASH and comparable to FGF19 elevations observed with the OCA dose of 25 mg. This 
dose has shown efficacy in a Phase II trial (Neuschwander-Tetri et al 2015)

The 60 µg dose to result in larger FGF19 elevations; there were no persistent ALT/AST 
elevation in healthy subjects at this dose 

The 90 µg dose to explore a dose with greater FGF19 elevations; based on data at 100 µg, 
this dose is expected to lead to isolated ALT/AST elevation in some patients. It is 
expected that any isolated ALT/AST elevations at this dose will also normalize during 
therapy (as seen at the 60 µg dose) in the first few weeks of therapy. All patients will be 
followed closely for safety in conjunction with the DMC. Patients in Part A of the trial are 
monitored for LFTs at weeks 1 and 2 (and further as per schedule), when such potential 
elevations are expected.

The longer term animal toxicity studies confirm that the exposure in NASH patients at a 
dose of 90 µg maintains a < 1-fold safety margin to the rat NOAEL (slightly > 1-fold 
against the previous cap of 70 ng•hr/ml) but of >2-fold safety margin to the dog NOAEL
3.3.3.2
Part B
Two doses will be selected for Part B based on DMC recommendations after review of a 
formal interim analysis of the safety and efficacy data after ≥ 90% of patients from Part A 
have completed Week 8. See Section 3.5 for further details.  DMC selected use of 90 µg 
tropifexor in Part B.  Therefore, as described in Section 3.1, Part B will include 3 treatment 
arms:  75 patients will be treated with 90 µg, 20 patients with 60 µg tropifexor and 25 patients 
with placebo.
3.3.3.3
Part C
The rationale for investigating tropifexor doses > 90 µg in Part C is supported by the need to 
explore the pharmacological effect at a broader dose range of tropifexor. The current non-
clinical safety profile of tropifexor, preclinical data (see Section 3.3.2), and the DMC’s
recommendation upon review of LJN452A2202 Part A safety, and pharmacokinetic data, all
support the investigation of tropifexor doses of > 90 µg.  


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Summary
The duration of 12 weeks of therapy is a suitable timeframe to test primary endpoints in the 
study. Reduction of hepatic fat content has been demonstrated in studies of similar length in 
response to surgical and pharmacologic therapies. Biochemical response to therapy 
approaches a maximum (i.e. lowest GGT or ALT level) at Week 12, and is detected as soon as 
Week 4, with treatment with another FXR agonist (Neuschwander-Tetri et al 2015, Sanyal et 
al 2009).  The availability of longer term non-clinical toxicology data (Section 3.3.1) allows 
for addition of longer term (48 week) treatment and inclusion of paired biopsies in Part C.
Isolated ALT and AST elevation in the single/multiple ascending dose studies of tropifexor
were seen in less than 2 weeks of therapy and resolved within 7 days of continued therapy or 
drug discontinuation; a 12-week study is thus sufficient to allow assessment of the magnitude 
of effect and whether it resolves during continuing treatment. Planned DMC review of the 
Part A data identified no safety concerns.  The DMC recommendation, supported by Part A 
pharmacokinetic modeling and completed non clinical toxicology studies, support exploring 
doses > 90 μg and specifically 140 and 200 μg in Part C. 
Overall, the considerable safety data published for OCA (Neuschwander-Tetri et al 2015, 
Hirschfield et al 2015) gives a robust starting point for the safety of the FXR class of drugs in 
regards to on-target effects. In comparison to OCA, this non-bile acid FXR agonist is 
expected to have fewer off-target effects due to: 1) greater specificity; ~300× more potent 
with no TGR5 effects, 2) the lack of enterohepatic recirculation, low dosing and hepatic first 
pass metabolism leading to a predicted lower systemic exposure. Nonetheless safety will be 
monitored closely and frequently in conjunction with the DMC. The DMC findings upon 
review of the Part A interim analysis data support these assumptions.  Statistical 
considerations regarding the evaluation of safety are provided in Section 9.8.1.
3.4
Rationale for choice of comparator
Currently there is no treatment approved for patients with NASH. A placebo will be used as a 
comparator in this study to examine the effects of Tropifexor beyond that achieved with a 
placebo.
3.5
Purpose and timing of interim analyses/design adaptations
The first planned interim analysis (IA) of available data will be performed to assess safety and 
biochemical response (surrogate of efficacy) after ≥90% of patients from Part A have 
completed assessments up to and including Week 8. The purpose of this interim analysis is to 
select the dosing for Part B. The timing of Week 8 is based on earlier results seen in the 
FLINT study (Neuschwander-Tetri et al 2015) in which the t½ of ALT reduction was already 
seen at 6 weeks on OCA treatment. It is further supported by findings from the First-in-
Human studies with Tropifexor in which healthy volunteers had ALT or AST elevations 
within the first 7 days of treatment which were all resolved in the next 7 days. Therefore, 8 


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weeks seems an appropriate timing to select the treatment arms for enrichment in Part B of 
this study. 
Unblinded interim analysis of safety, efficacy and PK results will be reviewed by an external 
Data Monitoring Committee (DMC). The DMC will make recommendations concerning the 
dosing arms for Part B. The DMC will be asked to identify the highest safe (and effective) 
dose and the lowest effective (and safe) dose for further study in Part B. Part B of the trial will 
also be conducted as double blind placebo controlled and similar to Part A the doses 
investigated will be known, but the individual treatment allocation will remain blinded.
The details for decision rules that will be used to guide the DMC on the dose selection in Part 
B will be specified in a separate DMC charter. 
It was expected that several of the doses selected for study in Part A would be both safe and 
efficacious. As pre-specified, in the event that the DMC selected only one active dose to be 
tested in 75 patients in Part B, one of the other originally planned active treatment arms would 
continue with a smaller sample size (20 patients) to confirm the earlier findings of this dose 
level observed in Part A. The DMC selected 90 μg to be tested in Part B (75 patients).  As 
pre-specified in the protocol, in this case, another dose, 60 μg, will be tested in 20 patients in 
Part B.  If only one ‘safe’ dose had been identified, then only one tropifexor dose (and 
placebo arm) would be advanced in Part B. 
Additional information is presented in Section 9.
The DMC will review safety, including AEs and laboratory parameters, on a regular basis. In 
particular, in the event that more than 3 patients develop an AE of CTCAE (Common 
Terminology Criteria for Adverse Events) grade ≥3 or higher in the same system organ class, 
the DMC chairman will be alerted. Further details regarding relevant data and actions will be 
specified in the separate DMC charter. 
A second analysis of Part A data, collected up to Week 16, will be performed. The purpose of 
this analysis is for internal decision making by the sponsor (Novartis) and discretionary DMC 
review.
A third analysis of complete Part A and Part B data will be performed when all patients 
randomized to Part B have completed the Week 16 EOS visit (Visit 299) or prematurely 
discontinued from the study.
An interim analysis of Part C data (fourth planned reporting event) will be performed when all 
patients have completed the Week 12 visit or prematurely discontinued from the study prior to 
week 12.  Part C patients will continue through Week 52, so Novartis and CRO associates 
involved with continued direct study site conduct will not be unblinded at the time of the Part 
C Week 12 Interim Analysis.  Novartis and CRO associates involved in data management, 
analysis and reporting, and Novartis management will be unblinded at this Interim Analysis. 
Site personnel, patients and Novartis and CRO field force associates will remain blinded.  
The final data analysis will be performed when all patients randomized to Part C have 
completed the Week 52 visit (Visit 299) or prematurely discontinued from the study. This 
final analysis will include all data from Part C plus data from Parts A and B as appropriate. If 
an extension trial is available at the end of Part B, data for patients from Parts B and C who 
rollover into the extension will be available through EOT only.


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Data collected during the follow-up 2 period (i.e., after week 16) will be reported in a 
subsequent separate report.
3.6
Risks and benefits 
As well as the risks and potential risks described in the Investigators’ Brochure, there may be 
unknown risks to tropifexor which may be serious and unforeseen.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring of e.g. liver transaminases, dose reduction steps and stopping rules.
Isolated increases in transaminases ALT and AST were observed at higher doses of tropifexor
in healthy subjects in study CLJN452X2101 as detailed in Section 3.3. These changes 
normalized spontaneously at the 60 µg dose and were not observed at the 30 µg dose. It is not 
known if the isolated ALT or AST elevations noted in healthy volunteers at the 100 µg/day 
would have resolved on continued therapy, however, they did normalize soon after 
discontinuation of study drug. These findings are consistent with hepatic adaptation to higher 
doses of drug. Nonetheless patients’ liver function tests will be followed closely, especially 
early in therapy, in conjunction with the DMC, including frequent checks of a liver s afety 
panel and drug dosage dose reduced or discontinued if necessary. 
Pruritus and LDL elevations have been noted in clinical trials with a bile acid FXR agonist, 
but have not been noted in a first-in-human study with tropifexor, a non-bile acid FXR agonist. 
Both pruritus and serum lipids will be closely monitored in this study.
A maximum of 400 mL of blood is planned to be collected from each patient in Parts A and B
and 900 mL in Part C as part of the study. Additional samples for monitoring of any safety 
findings may be required, and would be in addition to this volume. Over the course of the 4 to 
12 months study period, this is not considered to be a concern for this population.
MRI makes use of powerful magnetic fields and radio waves, which are believed to cause no 
direct adverse consequences when used within FDA-approved specifications. No MRI-
contrast will be administered in this study. Thus in principle, MRI scans can be repeated in the 
same subject as often as necessary. The MRI scanning equipment may cause a feeling of 
claustrophobia in susceptible persons; therefore, sensitivity to enclosed spaces should be 
queried at screening.  Refer to eligibility criteria to exclude patients who are not suitable 
candidates for MRI scanning.
Paired liver biopsies (baseline and Week 48) are required for patients participating in Part C.  
Baseline biopsies will confirm the diagnosis of NASH (steatosis, lobular inflammation, 
hepatocyte ballooning) and presence of fibrosis.  The primary risk of liver biopsy is bleeding 
from the site of needle entry into the liver, although this occurs in less than one per cent of 
patients. Other possible complications include the puncture of organs, such as the kidney, 
lung, colon, or the gallbladder. In order to reduce the risk of bleeding, the coagulation status 
must be assessed in all patients prior to a biopsy.
Patients participating in Parts A and B, might have reductions in hepatic fat; it is possible that 
this is a clinical benefit. However, 12 weeks treatment is unlikely to be sufficient to provide 
benefit in reducing hepatic fibrosis. For this reason, paired liver biopsies in Part C with 48 
weeks of treatment have been included in this study  providing evaluation of longer-term 


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efficacy, with the potential benefit of histologic improvement of NASH and fibrosis. There 
may be patient benefit in the ancillary dietary and exercise counseling accompanyin g the 
pharmacologic intervention.
4
Population
The study population will consist of adult male and female patients with EITHER histologic 
evidence of NASH on liver biopsy within 2 years (within 6 months for Part C) prior to 
randomization and elevated ALT, OR phenotypic diagnosis of NASH based on elevated ALT, 
Type 2 diabetes mellitus or elevated HbA1c and increased BMI, in both cases accompanied by 
liver fat ≥ 10% on centrally-read MRI. The phenotypic definition of NASH will not be used 
for eligibility in Part C.  All patients participating in Part C must meet the histologic criteria 
for NASH as determined by the biopsy central reader.  See Section 4.1 for full details.
The study will include a total of approximately 345 patients of which approximately 75 
patients will enroll in Part A,  approximately 120 patients in Part B, and approximately 150 in 
Part C. 
The study will be conducted in approximately 35 to 90 centers worldwide. Since a 60% 
screening failure rate is expected, approximately 850 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)
3. Presence of NASH as demonstrated by ONE of the following: 

In Parts A & B: Histologic evidence of NASH based on liver biopsy obtained 2 years 
or less before randomization with a diagnosis consistent with NASH, fibrosis level F1, 
F2 or F3, (i.e. fibrosis in the absence of established cirrhosis) no diagnosis of 
alternative chronic liver diseases

Part C (All patients):  Adequate liver biopsy sample for evaluation by Central Reader 
to confirm Histologic evidence of NASH based on liver biopsy obtained during the 
Screening period or within 6 months before randomization with a diagnosis consistent 
with NASH, fibrosis level F2 or F3, and no diagnosis of alternative chronic liver 
diseases.  Permitted therapies must be stable as outlined in Table 5-5 (from 1 month 
prior to biopsy up to and including screening)
AND (all Parts)
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
OR in Parts A and B only

Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
o
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND
o
BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or ≥ 23 
kg/m2 (in patients with a self-identified Asian race) AND


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o
Diagnosis of Type 2 diabetes mellitus by having either:
-
HbA1C ≥ 6.5% or
-
Drug therapy for Type 2 diabetes mellitus (See Section 5.5.8)
4. Liver fat ≥ 10% at screening as determined by the reading of the central MRI laboratory of 
locally produced images
5. Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate 
in the study.  Inclusion of patients with higher weights up to 200 kg (440 lbs) may occur if 
a MRI scanner with a suitable table weight of 200 kg (440 lbs) is available. Patients must 
not have ≥ 4.5 kg (10 lb) weight loss within the last 6 months prior to screening
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study
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 the study drug or its excipients or to drugs of similar 
chemical classes
3. Previous exposure to FXR agonists (including tropifexor)  
4. Patients taking medications prohibited by the protocol. See Section 5.5.8 for further 
details
5. Patients taking the following medicines UNLESS on a stable dose (within 25% of baseline 
dose) for at least 1 month before randomization: (for Part C patients, dose must be stable 
for at least 1 month prior to biopsy through Screening as defined in Table 5-5) anti-
diabetic medications, insulin, beta-blockers, thiazide diuretics,  fibrates, statins, niacin, 
ezetimibe, vitamin E (if  doses > 200 IU/day; doses > 800 IU/day are prohibited), thyroid 
hormone, psychotropic medications, estrogen or estrogen containing birth control
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 5 days (= 5 times the terminal half-life of tropifexor) after stopping 
of study treatment. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 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 


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study treatment. In case of oophorectomy alone, the sterile reproductive status of the 
woman must have been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
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.
9. Sexually active males must use a condom during intercourse while taking study 
medication and for 5 days after stopping study medication and should not father a child in 
this period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid
10. 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 AUDIT questionnaire ≥8
11. Inability to reliably quantify alcohol consumption based upon local study physician 
judgment
12. 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 
13. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y 
gastric bypass) 
14. Uncontrolled diabetes defined as HbAlc ≥ 9.5% within 60 days prior to enrollment
15. Presence of cirrhosis on liver biopsy or clinical diagnosis
16. Platelet count < 120 ×109/L 
17. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the 
presence of any of the following abnormalities:

Serum albumin < 32 g/L 

INR > 1.3

Direct bilirubin > 13 mg/L

ALT or AST > 5× ULN 

Alkaline phosphatase > 3× ULN


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
History of esophageal varices, ascites or hepatic encephalopathy

Splenomegaly
18. Previous diagnosis of other forms of chronic liver disease:

Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)

Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA 

Evidence of ongoing autoimmune liver disease as defined by compatible liver 
histology

Primary biliary cholangitis as defined by the presence of at least 2 of these criteria
o
Biochemical evidence of cholestasis based mainly on alkaline phosphatase 
elevation
o
Presence of anti-mitochondrial antibodies (AMA)
o
Histologic evidence of nonsuppurative destructive cholangitis and destruction of 
interlobular bile ducts

Primary sclerosing cholangitis

Wilson's disease as defined by ceruloplasmin below the limits of normal and 
compatible liver histology

Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver 
histology (confirmed by alpha-1 antitrypsin level less than normal; exclusion at the 
discretion of the study physician)

History of hemochromatosis or iron overload as defined by presence of 3+ or 4+ 
stainable iron on liver biopsy or iron saturation levels interpreted as hemochromatosis.

Drug-induced liver disease as defined on the basis of typical exposure and history

Known bile duct obstruction

Suspected or proven liver cancer

Suspected or confirmed Gilbert's syndrome

Any other type of liver disease other than NASH 
19. Calculated eGFR less than 60 mL/min (using the MDRD formula)
20. History of biliary diversion 
21. History of liver transplantation or current placement on a liver transplant list 
22. Known positivity for Human Immunodeficiency Virus (HIV) infection
23. Active substance abuse including inhaled or injection drugs in the year prior to screening
24. Any other condition which, in the opinion of the investigator, would impede compliance 
or hinder completion of the study
25. Chronic (> 3 months) use of excessive doses of Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs) as evaluated by investigator
26. New use of GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or 
dulaglutide within 3 months of screening.  
27. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as:


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
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
28. Patients with contraindications to MRI imaging, including:

Brain aneurysm clip

Implanted neural stimulator

Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires

Prosthetic heart valves

Cochlear implant

Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)

Other implanted medical devices (e.g., insulin pumps)

Metal shrapnel or bullets still in the body

Severe claustrophobia

Tattoos (as determined by the Investigator and Imager)

Weight in excess of MRI machine capacity
29. History of inflammatory bowel disease 
ALT, platelets, INR and eGFR values must always meet the requirements listed in the 
inclusion and exclusion criteria. For other laboratory values, patients with a single lab value 
outside of the value required for eligibility may be considered eligible for enrolment, as long 
as that value is within 10% of the value required for eligibility.  All other eligibility 
requirements must be met.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Tropifexor
Dosage form:
10 µg, 30 µg, and 100 µg capsules. 
Presentation:
Bottle
Expiry date:
Mentioned on the labels.
Placebo
Dosage form: 
capsules
Presentation:  
Bottle
Expiry date:
Mentioned on the labels.
Novartis Drug Supply Management (DSM) will provide sufficient supplies of tropifexor and 
placebo to last each patient between visits (or more).


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5.1.2
Additional treatment
No additional treatment beyond investigational drug and placebo is provided in this trial.
5.2
Treatment arms
Patients in Part A will be assigned at the baseline visit to one of the following 5 treatment 
arms in a ratio of 1:1:1:1:1 in a blinded manner. Placebo capsules will be given in each 
treatment arm where necessary to maintain blinding:
Arm A: Once daily (morning, fasting) treatment with 10 µg tropifexor for 12 weeks
Arm B: Once daily (morning, fasting) treatment with 30 µg tropifexor for 12 weeks
Arm C: Once daily (morning, fasting) treatment with 60 µg tropifexor for 12 weeks
Arm D: Once daily (morning, fasting) treatment with 90 µg tropifexor for 12 weeks
Arm E: Once daily (morning, fasting) treatment with matching placebo capsules for 12 weeks
Patients in Part B will be assigned at the baseline visit to one of the following 3 treatment 
arms in a ratio of 15:4:5 in a blinded manner. The doses to be used in Part B were decided 
based on data from the first interim analysis and DMC consultation. Placebo capsules will be 
given in each treatment arm where necessary to maintain blinding. 
Arm F: Once daily (morning, fasting) treatment with 90 µg tropifexor as determined after 
DMC review of first Part A interim analysis data for 12 weeks
Arm G: Once daily (morning, fasting) treatment with 60 µg tropifexor as determined after 
DMC review of first Part A interim analysis data for 12 weeks
Arm H: Once daily (morning, fasting) treatment with matching placebo for 12 weeks
Patients in Part C will be assigned at the baseline visit to one of the following 3 treatment 
arms in a ratio of 1:1:1 in a blinded manner. The doses used in Part C were determined based 
on preclinical toxicology data, pharmacokinetic modeling and DMC recommendations based 
on Part A data (Section 3.3). Placebo capsules will be given to maintain blinding. 
Arm I: Once daily (morning, fasting) treatment with 140 µg tropifexor for 48 weeks
Arm J: Once daily (morning, fasting) treatment with 200 µg tropifexor for 48 weeks
Arm K: Once daily (morning, fasting) treatment with matching placebo for 48 weeks
In order to maintain the blind, placebo capsules matching tropifexor 10, 30 and 100 µg 
capsules will be given to patients as indicated in Table 5-1, so that all patients will receive 3 
capsules per day. One capsule from each of the 3 bottles dispensed should be taken in the 
morning after an 8 hour fast.


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Table 5-1
Overview of treatment - type and number of capsules taken per day
Treatment arm
Placebo 
capsules
10 µg capsules
30 µg capsules
100 µg capsules
Placebo
3
-
-
-
10 µg
2
1
-
-
30 µg * 
0 OR 2
3 OR 0
0 OR 1
-
60 µg
1
-
2
-
90 µg
-
-
3
-
140 µg
-
1
1
1
200 µg
1
-
-
2
* Patients in the 30 µg arm will either receive 3 x 10 µg capsules OR 1 x 30 µg capsule AND 2 x 
placebo capsules
In case of necessary dose reductions due to ALT and/or AST elevation (see Section 5.5.5), the 
patient will return his original treatment to the clinic and will receive 3 new bottles assigned 
via Interactive Response Technology (IRT) to keep the blind. 
5.3
Treatment assignment and randomization 
At the baseline visit, all eligible patients will be randomized via 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.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
The randomization scheme for patients will be reviewed and approved by a member of t he 
Randomization Group.
Stratification
Part A:  Randomization will be stratified in Part A by BMI at baseline (<30 kg/m 2 or ≥ 30 
kg/m2 for patients with an Asian race or < 35 kg/m2 or ≥ 35 kg/m2 for all other patients). The 
race is based on the race the patient self-reports as captured on the demography eCRF.  
Part B:  Randomization will be stratified in Part B by BMI at baseline (<30 kg/m 2 or ≥ 30 
kg/m2 for patients with an Asian race or < 35 kg/m2 or ≥ 35 kg/m2 for all other patients). The 
race is based on the race the patient self-reports as captured on the demography eCRF. 
Randomization in Part B will also be stratified by Japanese or non-Japanese, Japanese defined 
as patients residing in Japan.  


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Part C: Randomization in Part C will be stratified by Fibrosis level (F2/F3) as determined in 
the Screening biopsy by the Central Reader and by Type 2 Diabetes status (yes/no) as 
reported on the Medical History eCRF. To ensure balance of patients in Japan among the 3 
treatment arms, the following stratum levels will be implemented (Japanese subgroup is too 
small for additional stratification):
1.
Japan
2. Non-Japan, F2, T2D=No
3. Non-Japan, F2, T2D=Yes
4. Non-Japan, F3, T2D=No
5. Non-Japan, F3, T2D=Yes
5.4
Treatment blinding 
This is a double-blind study: patients, investigator staff, persons performing the assessments, 
and Novartis clinical trial team (or delegates) will remain blinded to the identity of study 
treatments from the time of randomization (until final database lock), using the following 
methods: 1) Randomization data are kept strictly confidential until the time of unblinding and 
will not be accessible by anyone else involved in the study with the following exception: 
bioanalyst. 2) The identity of the treatments will be concealed by the use of study drugs that 
are all identical in packaging, labeling, schedule of administration, appearance, taste and odor. 
Additional placebo capsules will be given in active treatment groups when needed to maintain 
blinding. One capsule from each of the 3 bottles dispensed should be taken daily.
As an interim analysis will be performed at Week 8 in Part A, there will be a database lock / 
freeze when ≥ 90% of patients of Part A have completed their Week 8 assessments. A selected 
Novartis team not involved in the clinical conduct of the study will be unblinded to the Week 
8 results and will support and advise the DMC (see Section 8.4). Part B of the trial will also 
be conducted as double blind placebo controlled and similar to Part A the doses investigated 
will be known, but the individual treatment allocation will remain blinded.
Further, as indicated in Section 3.5, the DMC will review safety, including AEs and 
laboratory parameters, on a regular basis.
A second analysis of Part A data, for all patients collected up to Week 16, will be performed.  
(See Section 3.5). At that time, Novartis and CRO associates will be unblinded to data from 
Part A, only.  
A third analysis will include Part B data collected up to Week 16.  At that time Novartis and 
CRO associates will be unblinded to data from Part B. 
An interim analysis of Part C data (fourth planned reporting event) will be performed when all 
patients have completed the Week 12 visit or prematurely discontinued from the study prior to 
week 12.  Part C patients will continue through Week 52, so Novartis and CRO associates 
involved with continued direct study site conduct will not be unblinded at the time of the Part 
C Week 12 Interim Analysis.  Novartis and CRO associates involved in data management, 
analysis and reporting, and Novartis management will be unblinded at this Interim Analysis. 
Site personnel, patients and Novartis and CRO field force associates will remain blinded.  
The final database lock for the end-of-study analyses will occur when all patients have 
completed the study.  This will include data through EOT (Week 12 for Parts A and B, Week 


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48 for Part C) visit for any patients continuing therapy in an extension protocol (if available), 
or EOS (Week 16 visit for Parts A, and B, or Week 52 for patients in Part C) for all other 
patients, unless prematurely discontinued from the study. 
The Novartis clinical trial team (or delegates), patients, investigator, site personnel performing 
the assessments, and monitors will remain blinded to individual treatment allocation for 
patients randomized in Part A until after the second Interim Analysis for Part A (data through 
Week 16), until after the Part B database lock (through Week 16) for patients randomized in
Part B, and likewise blinded to individual treatment for patients randomized to Part C, until 
the Part C database lock. After all patients complete (EOS Visit) of Part C, designated 
Sponsor and CRO associates will be unblinded to all study data.
The bioanalyst will have access to the randomization list to facilitate analysis of the PK/PD 
samples (i.e. to avoid the unnecessary analysis of placebo samples).
Whenever needed or requested by the clinical team or the DMC, the bioanalyst, supported by
an independent programmer, will share information from PK measurements before clinical 
database lock in a blinded fashion with the pharmacokineticist, pharmacometrician and 
pharmacometrics programmer. The PK results for each study Part will remain blinded to the 
Novartis clinical team until the analysis is completed at the end of each study part respectively.  
If available, the summary and individual PK results may be shared with the DMC through a 
non-study/independent Novartis representative.
Unblinding will only occur for select individuals, in the case of patient emergencies (see 
Section 5.6), at the time of the interim analyses (see Section 9.7), for DMC review, at the time 
of the second Part A interim analysis, at the time of the end of Part B analysis and at the 
conclusion of the study. A Novartis programmer not involved in the clinical conduct (see 
above) will facilitate the data extract for each interim analysis to be forwarded for analysis by 
the 3rd party independent team. Patient data collected subsequent to each interim analysis will 
remain blinded.  During study conduct, DMC members may request patient treatment 
assignments from Cenduit, the Interactive Voice Response vendor.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering,
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator (e.g. 
). Once assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site must 
select the CRF book with a matching Subject Number from the EDC system to enter data. 


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If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
epoch Study Disposition CRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique randomization number is printed on 
each part of this label which corresponds to one of the “n” treatment arms and a [specific visit 
or dose/dose level]. 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. 
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.
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 or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the stud y, 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, at 
approximately the same time each day, except on the days where there are study visits at 
which time the patients should take their doses at the clinic.  On the baseline day, patients will 


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be instructed to take 3 capsules each day during the duration of the study.   One capsule, from 
each of the 3 bottles dispensed, should be taken each day as directed.
Dosing recommendations:

Patients should be fasted for at least 8 hours prior to each dose and should refrain from 
drinking anything but water for at least 30 min post dose. A light breakfast may be taken 
after 60 minutes.

Tropifexor is to be taken by mouth with a glass of ~240 mL water and consumed over as 
short a time as possible.

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.
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed.
The patients will also be instructed to bring back unused medication and empty bottles at 
selected time-points for drug accountability checking.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
All bottles of study treatment assigned by the IRT will be recorded/databased in the IRT.
5.5.4.1
Dietary restrictions 

No alcohol consumption is allowed for 8 hours before dosing and each study visit until 
Study Completion evaluation.
All patients will fast (i.e. no food and liquid except water) for at least 8 hours prior to each 
dose and should refrain from drinking for at least 30 min post dose, and refrain from eating 
for at least 60 min post dose. A light breakfast may be taken after 60 minutes.
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 equivalent if there 
is a country specific recommended diet (see 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 patients who experience significant isolated ALT and/or AST elevations, dose reductions 
are permitted in order to allow the patient to continue on study treatment. The guidance for 
the modification of study treatment is outlined below. In case of significant ALT and/or AST 
elevations, the guidance should be followed.  However, in the short term management of an 


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individual patient, not related to significant ALT and/or AST elevations, investigators must 
use their medical judgments in regards to what they deem as the best interest of the patient. 
In the event of a significant ALT and/or AST elevation, dose reduction to the next lower dose 
level is permitted, see further instructions below and in Table 5-2 and Table 5-3; this will 
allow an evaluation of whether such dose reductions are useful in patient management. The 
ability to reduce dose is clinically relevant when a possible adverse event is a laboratory 
finding that can be easily monitored. In the context of a Phase II trial exploring different dose 
levels, discontinuation of study treatment is not considered optimal as data generated after 
dose reduction will further inform on e.g. the tolerability and safety of tropifexor. 
Study medication dose can be reduced one level in all study Parts as indicated on Table 5-3.  
In Parts A and B one cycle of dose reduction is allowed. If, despite being on a reduced dose, a 
patient has persistent or new significant ALT and/or AST elevations, he must be discontinued 
from study treatment. Increasing the dose to the original level is not permitted for patients in 
Parts A and B, but is permitted in the longer-duration Part C.  After returning to the original 
randomized dose, a subsequent 1 level dose reduction for patients in Part C is allowed.
Significant isolated ALT and/or AST increase 
If the patient has symptoms or other LFTs are also elevated (in particular bilirubin and/or 
PT/INR), please refer to Section 7 and Section 14 for appropriate actions.
A significant ALT and/or AST increase is defined as: 2× Baseline value (see Section 9.5.2.5
for definition of baseline levels).
Actions should be based on whichever of AST and ALT has a higher multiple of ULN or 
baseline value. In order to allow for variation in laboratory results, persisting elevation is 
defined as the value remaining at ≥90% of the original elevated value. When there is a 
marked difference in multiple of ULN between ALT and AST, medical judgment should be 
applied to distinguish between persisting and decreasing. If at any time the repeat testing 
shows levels in a higher category, the guidance for the higher category should be followed.
Patients with a significant increase of ALT and/or AST will be instructed to return to the 
clinic for an additional laboratory evaluation to confirm these results. The laboratory tests to 
be repeated are ALT, AST, GGT, alkaline phosphatase, total bilirubin, and albumin (LFT) and 
PT/INR. Please refer to Table 5-2 for the next actions.


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Table 5-2
Isolated ALT/AST Elevations
ALT and/or 
AST increase4
First 
Action
Result
2nd  Action
Result
3rd Action
>2× baseline5 
AND ≤ 5× ULN
Repeat 
tests1
within 48 
– 72 
hours1
Persistent 
elevation2 of 
ALT and/or 
AST
Repeat tests1 within 48 – 72 hours1 
Persistent 
elevation2 of 
ALT and/or AST
Repeat tests1 within 48 – 72 hours if no 
improvement or within 1 week if improved. Continue 
testing1 until 2 weeks after start original elevation. If 
after 2 weeks ALT and/or AST are persistently 
elevated reduce dose (Table 5-3). 
Continue testing1 within 48 – 72 hours if no 
improvement and within 1 week if improved until 
ALT and AST <3x ULN. 
If ALT and AST levels remain ≥3x ULN three weeks 
after dose reduction, discontinue study treatment
Decreasing ALT 
and AST3
Continue assigned study treatment as per protocol
Decreasing 
ALT and AST3
Continue assigned study treatment as per 
protocol
--
--
Persistent 
elevation2 of 
ALT and/or AST
Repeat tests1 within 48 – 72 hours if no 
improvement or within 1 week if improved. Continue 
testing1 until 2 weeks after start original elevation. If 
after 2 weeks ALT and/or AST are persistently 
elevated, discontinue study treatment
>2× baseline5
AND >5× ULN 
but ≤8× ULN  
Repeat 
tests1
within 48 
– 72 
hours1
Persistent 
elevation2 of 
ALT and/or 
AST
Repeat tests1 within 48 – 72 hours if no 
improvement or within 1 week if improved. 
Continue testing1 until 1 week after start 
original elevation. If after 1 week ALT and/or 
AST are persistently elevated, reduce dose
(Table 5-3). Repeat tests1 within 48 – 72 
hours1 if no improvement and within 1 week if 
improved
Decreasing ALT 
and AST3
Continue with reduced dose. Continue testing1
within 48 – 72 hours if ALT/AST not improving and 
weekly if improving until ALT and AST <3x ULN. 
If ALT and AST levels remain ≥3x ULN three weeks 
after dose reduction, discontinue study treatment
Decreasing 
ALT and AST3
Continue assigned study treatment as per 
protocol
--
--


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ALT and/or 
AST increase4
First 
Action
Result
2nd  Action
Result
3rd Action
>2× baseline5
AND >8× ULN 
Repeat 
tests1
within 48 
hours
Persistent 
elevation of 
ALT and/or 
AST2
Discontinue study treatment
--
--
Decreasing 
ALT and AST3
Repeat tests1 within 48 – 72 hours1 if no 
improvement or within 1 week if improved. 
Persistent 
elevation of ALT 
and/or AST2
Dose reduction (Table 5-3). Continuetesting1 within 
48 – 72 hrs if ALT/AST not improving and weekly if 
improving until ALT and AST <3x ULN. 
If ALT and AST levels remain ≥3x ULN three weeks 
after dose reduction, discontinue study treatment
Decreasing ALT 
and AST3
Follow as per table
1Tests: PT/INR and LFT: Liver function test: ALT, AST, GGT, alkaline phosphatase, total bilirubin, and albumin (see Section 6.4.2); these repeats must 
be performed using the central laboratory if possible and captured via the unscheduled lab CRF. If this is not possible, then the repeats can be 
performed at a local laboratory to monitor the safety of the patient. If tests are performed at local laboratory, results will be captured in source documents 
only. In all cases, a physical examination should be performed and recorded in source documents. 
2Persistent: either ALT and/or AST remain > 90% of the original elevated level 
3Decreasing: both ALT and AST levels decrease to ≤ 90 % of the original elevated level. Medical judgement should be applied if there is a marked 
difference between ALT and AST multiples
4Please also refer to Section 14, Appendix 2, Table 14-2 for additional actions
5Please see Section 9.5.2.5 for definition of baseline values.


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If the additional laboratory evaluation confirms a significant increase of ALT and/or AST 
values, the study treatment will be reduced to the next dose level in a blinded manner (Table 
5-3). The investigator must contact the IRT to register the patient’s dose reduction.  
If the additional laboratory evaluation does not confirm the significant increase of ALT values, 
the patient will continue with the assigned/original treatment.
If the additional laboratory evaluation shows a higher elevation of ALT and/or AST (e.g. > 8x 
ULN) as compared to the original elevation (e.g. > 5x ULN but ≤ 8x ULN), the guidance for 
this higher elevation (e.g. > 8x ULN) should be followed.
Table 5-3
Dose reduction
Original treatment 
(daily dose)
Reduced treatment 
(daily dose)
200 µg
140 µg
140 µg
90 µg
90 µg
60 µg
60 µg
30 µg
30 µg
10 µg
10 µg
Placebo
Second dose reductions are not permitted in Parts A and B. Returning to the original treatment 
is not permitted in Parts A and B.  In Part C, returning to the original dose is allowed upon 
resolution of the lab abnormality and at the investigator’s discretion. Subsequent dose 
reduction cycles are allowed in Part C as necessary after returning to the original dose. Dose 
can only be reduced by one dose level in all Parts of the protocol. 
Patients with a persistent or second cycle of significant ALT and/or AST increase while being 
on a reduced dose will be instructed to return to the clinic for an additional laboratory 
evaluation within 1 week or 2 days, depending on the elevation, to confirm these results. If the 
additional laboratory evaluation confirms the significant increase of ALT and/or AST values, 
the patient will discontinue study treatment, and will enter the follow up period. If the 
additional laboratory evaluation does not confirm the significant increase of ALT and/or AST 
values, the patient will continue with the assigned (reduced) treatment. Data handling rules for 
patients in Part C who experience dose reductions will be described in the Analysis Plan.
Treatment discontinuations: The investigator must contact the IRT to register the patient’s 
discontinuation from study treatment. Further, all study treatment discontinuations must be 
recorded on the eCRF. After discontinuation for a liver-related event, LFT and clinical 
monitoring should continue until the event is resolved (see Table 14-2 in Appendix 2).
5.5.6
Rescue medication
Use of rescue medication is not allowed during the 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 


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significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies 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
Medication or herbal remedies likely to have a significant impact on tropifexor metabolism by 
inhibiting UGT1A1 are prohibited in the study from the first dosing until the end-of-study 
visit Week 16 (visit 299 or visit 399 in relevant patients (see Section 3.1)) has been conducted. 
These include: atazanavir, gemfibrozil, indinavir, itraconazole, ketoconazole, manidipine and 
zafirlukast and Silybum marianum (milk thistle) and Valeriana officinalis (valerian). The non-
selective UGT inhibitors diclofenac, probenecid and valproic acid are also prohibited.  
Alcohol consumption is to be strongly discouraged, and should not exceed 20 g/day in 
females and 30 g/day in males. 
An overview of the prohibited medication is given in Table 5-4, and the summary of 
permitted medication if on stable dose is in Table 5-5.
Patients on medications specified in Table 5-5 can be included if these medications are 
medically necessary, the dose has been stable for at least 1 month, and the investigator feels 
the dose will remain stable for the duration of the double-blind treatment period. A stable dose 
is defined as a dose within 25% of the baseline dose. No new use of these medications is 
allowed after entering the study with the exception of drugs to control medically significant 
elevations in LDL-cholesterol which have been confirmed upon repeat testing
Table 5-4
Prohibited medication
Medication
Prohibited 
Specific UGT1A1 inhibitors:atazanavir, 
gemfibrozil, indinavir, itraconazole, 
ketoconazole, manidipine, and 
zafirlukast
Any use from first drug intake to end-of-
study visit
Herbal remedies inhibiting UGT1A1:: 
Silybum marianum (sylamarin, milk 
thistle) and Valeriana officinalis 
(valerian)
Any use from first drug intake to end-of-
study visit
Non-selective UGT inhibitors:: 
diclofenac, probenecid, valproic acid 
Any use from first drug intake to end-of-
study visit
Vitamin E
Doses >800 IU/day 
GLP-1 agonists such as liraglutide, 
exenatide , lixisenatide, albiglutide or 
dulaglutide^  
Newly initiated use within 3 months prior 
to randomization
^For patients in Part C, these medications must be stable for at least 1 month prior to 
qualifying baseline biopsy through the Screening period.


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Table 5-5
Medications permitted only if dose is stable (within 25 percent of 
baseline dose) for at least 1 month prior to randomization and 
expected to remain stable through the double-blind treatment period
Medication
Oral anti-diabetic medications such as (metformin and/or sulfonylureas)^
Insulin* 
Beta-blockers and thiazide diuretics 
Fibrates**^, statins**, niacin**^, ezetimibe**
Vitamin E*** ^
Thyroid hormone 
Psychotropic medications (phenothiazines or second generation antipsychotics) 
Estrogen or estrogen containing birth control
* unless adjustment is required due to intercurrent illness; 
**unless required to treat medically significant increases in LDL-cholesterol that have been confirmed 
upon repeat testing  
***Only applicable for patients taking >200 IU/day; doses >800 IU/day are prohibited
^ For patients in Part C, these medications must be stable for at least 1 month prior to qualifying 
baseline biopsy through the Screening period.
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
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 patient 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. 


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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 12 weeks of treatment may include:

Enrollment in an extension study, if any, to allow for therapy beyond 12 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 299) should be 
conducted 4 weeks after last treatment (EOT, Week 12 in Parts A, B and Week 48 for patients 
in Part C). The information to be collected at this follow up visit includes concomitant 
medications, adverse events, and laboratory samples, as detailed on Table 6-1.
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 (see Section 6.5.6 and Section 7.6)

Use of prohibited treatment as per recommendations in 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

For ALT, AST, total bilirubin and/or alkaline phosphatase elevations mandating study 
treatment discontinuations, please refer to Section 7.3 and Table 14-2 for further 
instructions and monitoring.

For specified renal events, please refer to Section 7.4 and Table 15-1 for further 
instructions and monitoring. 

Other CTCAE grade 3 that are related to study drug, 

Other CTCAE grade ≥4  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.


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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 eCRF. The investigator must determine the 
primary reason for the patient’s premature discontinuation of study treatment and record this 
information on the eCRF. The investigator must also contact the IRT to register the patient’s 
discontinuation from study treatment.
After study treatment discontinuation, at a minimum, the following data should be collected at 
abbreviated clinic visits or by telephone visits: 

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 planned End of 
Treatment (EOT) (Week 12 in Parts A and B, Week 48 in Part C) and planned End of Study 
(EOS) (Week 16 in Parts A and B, Week 52 in Part C) visits must be performed. The follow 
up 2 visit should be performed in relevant patients (see Section 3.1). 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person if pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Note that a patient choosing to discontinue study treatment is not usually withdrawing 
consent to participate in the study, and such patients should continue follow up as described in 
Section 5.6.2.
Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material 


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In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’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 patient 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.
5.6.4
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, 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 scheduled 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 withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the 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. In 
particular for Part A, every effort should be made to respect the time frame for the Week 8 
visit. 
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 study treatment 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 (EOT visit). At 
this final visit, all dispensed study treatment should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF. See also Section 5.6.2.


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Patients will visit the site for a follow up visit 4 weeks following the last administration of 
study treatment (EOS visit); some patients will have a further visit 4 weeks later. 
Recommended Visit windows
Treatment period:

±2 days for Weeks 1 to 12 visits 

± 7 days for Weeks 16 - 48
For patients who discontinue study treatment prematurely before the end of the treatment 
period for any reason other than withdrawal of informed consent, the planned End of 
Treatment (EOT) and End of Study (EOS) visits must be performed. The follow up 2 visit 
should only be performed in relevant patients (see Section 3.1). 
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. 
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. See Section 3.1 for what is 
considered as medically important.


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Protocol No. CLJN452A2202
Table 6-1
Assessment schedule Parts A and B
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
Screening
Informed consent
X
Inclusion / Exclusion criteria
X
X
X
Demography
X
Serum Pregnancy test12
X
X2
Urine pregnancy 
test during study 
treatment and 
follow up
Medical history/ current 
medical conditions
X
X2
Protocol solicited medical 
history
X
X2
Assessments
Physical examination11
S
S
S
S
S
S
S
Prior and concomitant 
medication
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
Alcohol history / compliance
X16
X
X
X
X
X
X
X
X
X


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
Smoking history
X
Body height, weight, waist 
circumference, hip 
circumference
X
X
X
X
X
X
X
X
X
Height only at 
screening, 
waist/hip 
circumference 
only at 
Screening and 
Week 12
Vital signs
X
X
X
X
X
X
X
X
X
12-lead ECG14
X
X
MRI5 (Quantitative liver fat)
X5
X5
Screening visit 2 
including MRI 
only if 
provisional 
eligibility is 
confirmed
Review of Liver biopsy report 
(only if available), NAS score 
(only if available)
X
Data on liver 
biopsy/ NAS 
score only 
collected if 
results are 
available in 
source 
documents


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
Fibroscan15
X
X15
Optional, see 
Section 6.2.6.2
Adverse Events  / Serious AE
/ Liver, Renal Event review
X
X
X
X
X
X
X
X
X
X
X4
AUDIT questionnaire
X 
C
C
C
C
C
C
C
C
Full 
questionnaire 
(X) at screening, 
short 
questionnaire 
(C) at other visits
VAS (Visual Analog Scale) 
for itch
X
X
X
X
Randomization via IRT
S


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
Contact IRT
X
X
X
X
X
X
Drug dispensing
S
S
S
Drug administration record
X
X
X
X
X
X
X
Drug compliance
S
S
S
S
S
S
AHA Diet Review
S
S
S
S
Diet Compliance
X
X
X
X
Exercise assessment
X
X
X
X
Blood collection
Hepatitis serology
X6
Liver function tests
X
X2
X
X
X
X
X
X
X
X
X4
Serum BUN and Creatinine
X
X
X
X
X
X
X
X4
Coagulation panel
X
X
X
X
Fibrosis biomarker test13
X
X
X
ELF Panel  Including TIMP1, 
HA, PIIINP
X
X
X
Fibrosis markers and scores
X
X
X
X
NAFLD fibrosis score
X
X
X
Fasting lipids
X
X
X
X
X
X
Hematology
X
X
X
X
X
X4


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
Clinical chemistry panel
X7, 16
X
X
X
X
X4
HbA1c
X
X19
PK blood collection10
X
X3
X
X
X
X
Urine
Dipstick / routine Urinalysis 
with Reflex Micro
X
X
X
X
X
X
X
X
X
Urine pregnancy test12
X
X
X
X
X
Serum 
pregnancy at 
screening
Drug screen
X
X2
X
Period completion forms
Screening completion
X
X
Treatment completion
X
Study completion
X4
X4
TD: treatment discontinuation; PSW: Premature study withdrawal; X and C: assessment to be recorded on clinical database; S: assessment to be recorded 
on source documentation; C: Short AUDIT questionnaire
1: Screening visit 2 should only be conducted if eligibility is confirmed; 


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
2: Part B only: Assessments marked with “2” are only to be done in case period between screening visit 1 and anticipated baseline visit > 2 months. All 
other assessments for screening visit 2 are to be done as listed
3: Part A only: Visit 102/ Week 1. In Part B no Week 1 visit is to be done
4: 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 planned post treatment follow-up 1 period until these events have resolved or stabilized. See Section 3.1 for the definition of 
medically important events that need this follow up, and for the scheduling of these follow ups. Data will be collected via unscheduled CRFs. The follow up 
2 period visit/ EOS visit/399 visit should be completed only when these events are resolved or stabilized. 
5: MRI should only be scheduled to occur within 2 weeks of the expected date of randomization. Assessment at visit 199 not to be done in case of 
premature treatment discontinuation unless the patient has received ≥ 8 weeks of therapy. 
6: Not needed if available within 5 years from screening, unless risk factors for viral hepatitis are present after last serologic testing.  
7: See assessments in Section 6.5.4.2. At screening visit 1 this also includes ferritin, transferrin saturation, iron, and if not historically available also ANA, 
ASMA and AMA
 
9: Optional. A separate informed consent needs to be signed before sample collection. Sample can be collected at BSL visit or any subsequent visit
10: Part A: Week 1: pre-dose and 2 hrs post dose. Week 2, 4, 6, 8 and 12: pre-dose. Part B: Week 2: pre-dose and 2 hrs post dose. Week 6: pre-dose and 
4 hours post dose (the last activity of the visit): Week 4,  8 and 12 pre-dose
11: Full physical examination at screening visit 1, baseline and Week 12 
12: Only for pre-menopausal women who are not surgically sterile
13: Fibrosis biomarker test originally called Fibrotest / Fibrosure
14: For any ECGs with patient safety concerns, two additional ECGs must be performed to confirm the safety finding
15: Assessment at visit 199 not to be done in case of premature treatment discontinuation unless the patient has received ≥8 weeks of therapy.
16: 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.


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Protocol No. CLJN452A2202
Parts A and B
Screening
Randomized Treatment
Post 
Treatment 
Follow Up 
1
Post 
Treatment 
Follow Up 
24
Notes
Week
-5 to -2
-2 to 
BSL1,2
BSL
13
2
4
6
8
12
TD
16
/ PSW
≥20 4
Visit number/ Visit name
1
2
101
102
103
104
105
106
EOT / 199
EOS / 299
EOS4 / 399
  
 
19: HbA1c to be tested at Week 12 for patients enrolled in Part B.


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Table 6-2
Assessment schedule Part C
Part C
Screening
Randomized Treatment
Post 
Treat
ment 
F/U 1
Post 
Treat
ment 
F/U 2
Week
-10
to -2
-2 to 
BSL1
,2
BS
L
1
2
4
6
8
12
16
20
24
32
40
48
TD
52
>=56
Visit number/ Visit name
1
2
101
102
103
104
105
106
107
108
109
110
111
112
EOT / 
199
EOS / 
299
EOS4 / 
399
Screening
Informed consent
X
Inclusion / Exclusion 
criteria
X
X
X
Demography
X
Serum Pregnancy test12
X
X2
Medical history/ current 
medical conditions
X
X2
Protocol solicited medical 
history
X
X2
Assessments
Physical examination11
S
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
X
X
X
X
Surgical and medical 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. CLJN452A2202
Part C
Screening
Randomized Treatment
Post 
Treat
ment 
F/U 1
Post 
Treat
ment 
F/U 2
Week
-10
to -2
-2 to 
BSL1
,2
BS
L
1
2
4
6
8
12
16
20
24
32
40
48
TD
52
>=56
Visit number/ Visit name
1
2
101
102
103
104
105
106
107
108
109
110
111
112
EOT / 
199
EOS / 
299
EOS4 / 
399
Alcohol history / 
compliance
X16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking history
X
Body height, weight, waist 
circumference, hip 
circumference20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG14
X
X
X
MRI5 (Quantitative liver 
fat)
X5
X5
X5
X5
Liver biopsy19
X19
X19
Fibroscan15
X
X
X
X
Adverse Events  / Serious 
AE / Liver, Renal Event 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
AUDIT questionnaire3
X 
C
C
C
C
C
C
C
C
C
C
C
C
C
C
VAS (Visual Analog Scale) 
for itch
X
X
X
X
X
X
X


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Protocol No. CLJN452A2202
Part C
Screening
Randomized Treatment
Post 
Treat
ment 
F/U 1
Post 
Treat
ment 
F/U 2
Week
-10
to -2
-2 to 
BSL1
,2
BS
L
1
2
4
6
8
12
16
20
24
32
40
48
TD
52
>=56
Visit number/ Visit name
1
2
101
102
103
104
105
106
107
108
109
110
111
112
EOT / 
199
EOS / 
299
EOS4 / 
399
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
S
Drug administration record
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug compliance
S
S
S
S
S
S
S
S
S
S
S
S
S
AHA Diet Review
S
S
S
S
S
S
S
S
S
S
Diet Compliance
X
X
X
X
X
X
Exercise assessment
X
X
X
X
X
X
Blood collection
Hepatitis serology
X6
Liver function tests
X
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X4


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Protocol No. CLJN452A2202
Part C
Screening
Randomized Treatment
Post 
Treat
ment 
F/U 1
Post 
Treat
ment 
F/U 2
Week
-10
to -2
-2 to 
BSL1
,2
BS
L
1
2
4
6
8
12
16
20
24
32
40
48
TD
52
>=56
Visit number/ Visit name
1
2
101
102
103
104
105
106
107
108
109
110
111
112
EOT / 
199
EOS / 
299
EOS4 / 
399
Serum BUN and 
Creatinine
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
Coagulation panel
X
X
X
X
X
X
Fibrosis biomarker test13
X
X
X
X
X
X
ELF Panel  Including 
TIMP1, HA, PIIINP
X
X
X
X
X
Fibrosis markers and 
scores
X
X
X
X
X
X
X
NAFLD fibrosis score
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X4
Clinical chemistry panel
X7, 16
X
X
X
X
X
X
X
X
X4
HbA1c
X
X
X


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Protocol No. CLJN452A2202
Part C
Screening
Randomized Treatment
Post 
Treat
ment 
F/U 1
Post 
Treat
ment 
F/U 2
Week
-10
to -2
-2 to 
BSL1
,2
BS
L
1
2
4
6
8
12
16
20
24
32
40
48
TD
52
>=56
Visit number/ Visit name
1
2
101
102
103
104
105
106
107
108
109
110
111
112
EOT / 
199
EOS / 
299
EOS4 / 
399
PK blood collection10
X
X
X
X
X
X
Urine
Dipstick / routine 
Urinalysis with Reflex 
Micro
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test12
X
X
X
X
X
X
X
X
X
X
X
Drug screen
X
X2
X
Period completion forms
Screening completion
X
X
Treatment completion
X
Study completion
X4
X4
        


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Protocol No. CLJN452A2202
TD: treatment discontinuation; PSW: Premature study withdrawal; X and C: assessment to be recorded on clinical database; S: assessment to be 
recorded on source documentation; C: Short AUDIT questionnaire
1: Screening visit 2 should only be conducted if eligibility is confirmed; 
2: Assessments marked with “2” are only to be done in case period between screening visit 1 and anticipated baseline visit > 2 months. All other 
assessments for screening visit 2 are to be done as listed
3: Full questionnaire AUDIT (X) at screening, short questionnaire (C) at other visits
4: 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 planned post treatment follow-up 1 period until these events have resolved or stabilized. See Section 3.1 for the 
definition of medically important events that need this follow up, and for the scheduling of these follow ups. Data will be collected via unscheduled 
CRFs. The follow up 2 period visit/ EOS visit/399 visit should be completed only when these events are resolved or stabilized. 
5: MRI should only be scheduled to occur within 2 weeks of the expected date of randomization and subsequently at Weeks 12, 24 and 48. 
Assessment at visit EOT not to be done in case of premature treatment discontinuation unless the patient has received ≥ 8 weeks of therapy. 
6: Not needed if available within 5 years from screening, unless risk factors for viral hepatitis are present after last serologic testing.  
7: See assessments in Section 6.5.4.2. At screening visit 1 this also includes ferritin, transferrin saturation, iron, and if not historically available also 
ANA, ASMA and AMA
 
10: pre-dose and post-dose as the last activity of the visit at week 12, 24 and 48, post-dose as the last activity of the visit at week 6 and 40.
11: Full physical examination at screening visit 1, baseline and Weeks 12, 24, & 48. 
12: Only for pre-menopausal women who are not surgically sterile.  Serum pregnancy at screening - Urine pregnancy test during study treatment and 
follow up
13: Fibrosis biomarker test originally called Fibrotest / Fibrosure
14: For any ECGs with patient safety concerns, two additional ECGs must be performed to confirm the safety finding
15: Post baseline Fibroscan to be conducted at the same visits as MRI:  Weeks 12, 24 and 48.  Assessment at EOT not to be done in case of 
premature treatment discontinuation unless the patient has received ≥8 weeks of therapy.
16: 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.
  


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Protocol No. CLJN452A2202
 
 
19: Paired liver biopsies (=< 6 months and at least 2 weeks prior to baseline 
) are required to confirm the diagnosis of NASH (steatosis, 
lobular inflammation, hepatocyte ballooning) and presence of fibrosis.  Baseline Biopsy slides, prepared from biopsies performed during the screening 
period or =< 6 months prior to the randomization visit, will be sent to a Central Reader to determine eligibility
20: Height only at screening, waist/hip circumference only at Screening and Week 12


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Protocol No. CLJN452A2202
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 Screening Phase Disposition CRF. In addition, the 
following CRFs should be completed: Informed Consent, Demography, Inclusion/Exclusion, 
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 CRF 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 
CRF 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 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
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: year of birth, 
gender, race, ethnicity, source of referral, 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 


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recorded in the Medical History CRF. 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 CRF (see Section 7.1 for the timeframe to record AEs during the screening 
period of Part B). Whenever possible, diagnoses and not symptoms will be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF 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 CRF. 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.
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.
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
Biopsy 
For Parts A and B, if liver biopsy was done for the diagnosis of NASH within 2 years prior to 
randomization, the following information will be collected if available: 

Diagnosis 

Metavir, Ishak,  Knodell, Ludwig Batts, or Kleiner-Brunt score, or a liver biopsy score by 
a country specific method 

NAS scoring on steatosis (0-3), ballooning degeneration (0-2), lobular inflammation (0-3),
the NAS (NASH CRN NAFLD activity score) is the sum of the three component scores.
For Parts A and B, if a liver biopsy was done previously, and additional slides are available, 
the patient may be asked for additional consent to allow this material to be used for central 
reading of slides. Central reading of slides is only to be initiated if material from sufficient 
patients is available. 
For Part C, 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


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the Screening period, or within 6 months prior to randomization. For the biopsy to qualify as a 
baseline biopsy, the patient must have been on a stable permitted therapy for at least 1 month 
prior to the biopsy through the screening period (See Table 5-5).  Five to eight Baseline 
Biopsy slides, unstained and prepared from biopsies performed during the screening period or
=< 6 months prior to the randomization visit, will be sent to a Central Reader to determine 
eligibility.  Patients in Part C will be treated for 48 weeks and an end of treatment biopsy will 
be performed and slides submitted to the Central Reader.
For the patients who do not have an historical liver biopsy, Fibroscan may be a useful pre-
screening tool prior to liver biopsy for cases of indeterminate clinical NASH (F2/F3) 
diagnosis.
6.2.6.2
Transient Elastography (FibroScan®) (optional)
If sites have equipment available, a Transient Elastography (FibroScan®) will be done at 
baseline and at the Week 12 visit in Parts A and B and at baseline Weeks 12, 24 and 48 in Part 
C, aligned with the MRI assessments. (see Table 6-1). No other similar technology can be 
substituted. Week 12 assessment is not to be done if the patient prematurely discontinues 
treatment prior to Week 8.
The following information will be collected:

Date and type of evaluation performed

Liver stiffness: Score in kPa 

Probe type used

Interquartile range (IQR)

Corrected attenuation parameter (CAP) if available

CAP IQR if available
The assessment at baseline is not needed if Transient Elastography (FibroScan®) is performed 
within 6 months prior to baseline and all required information is available. The results of such 
a previous scan are to be recorded in the database.
6.2.7
Other baseline characteristics
Baseline characteristic data to be collected on all patients include (all labs are central) (see 
also Table 6-1):
12-lead ECG, vital signs, drug testing, hematology, clinical chemistry, urinalysis, physical 
examination,  anthropometric assessments, past medical history record of HIV, Hepatitis B or 
C serology (not needed if available within 5 years from screening visit, unless risk factors for 
viral hepatitis are present after last serologic testing), Anti-nuclear antibody (ANA), anti-
smooth muscle antibody (ASMA), anti-mitochondrial antibody (AMA) (these last 3 only if 
not historically available),  iron, ferritin, transferrin saturation, Hemoglobin A1c (HbA1c), VAS 
scale for itch 
 
 
 A serum pregnancy test will be performed for women of 
child-bearing potential, 
 


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Sample numbering for 
 biomarkers are shown in Appendix 4, Section 
16. 
6.2.8
Screening visit 2 – additional assessments
In Part A, Part B (if the first screening visit and anticipated randomization baseline date is 
within 2 months) and Part C, the second screening visit should only be conducted if eligibility 
is confirmed. Assessments for this visit include MRI, Liver biopsy for patients in Part C, and 
other non-lab assessments as indicated in Table 6-1.
In Parts B and C, if the period between screening visit 1 and the anticipated randomization / 
baseline visit is > 2 months: screening visit 2 should only be conducted if eligibility is 
confirmed. Assessments for this visit include MRI, liver biopsy in Part C, and other non-lab 
assessments as indicated in Table 6-1 and Table 6-2 AND a repeat of the liver function test 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 
Dosing information for study medication will be collected on corresponding Dosage 
Administration Record eCRFs. Compliance will be assessed by the investigator and/or study 
personnel at each visit using capsule counts and information provided by the patient. This 
information should be captured in the source documents at each visit. All study treatment 
dispensed and returned must be recorded in the Drug accountability Log. Dietary compliance 
will also be assessed as indicated in Table 6-1 and recorded in the eCRF.
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. 
Patient-reported outcomes
PROs should be performed in the following recommended order, prior to any investigator / 
lab assessments:
Part A:

VAS for Itch
Part B and Part C:

VAS for Itch
 


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Efficacy assessments
The efficacy assessments should be completed in the following recommended order. 

MRI

Liver Function Test

Liver Histology

Coagulation test

Markers of liver fibrosis

NAFLD Fibrosis score

Fasting lipids 
All remaining study visits procedures (e.g. laboratory samples collection, vital signs 
measurement, PK sampling etc.) must be completed prior to administration of study treatment. 
6.4.1
Magnetic Resonance Imaging
Patients in Parts A and B will undergo magnetic resonance imaging two times during the 
course of the study to quantitate liver fat, 
 as 
outlined in the assessment schedule (Table 6-1). Week 12 assessment is not to be done if the 
patient prematurely discontinues treatment prior to Week 8.  Patients in Part C will have an 
MRI at Baseline, Weeks 12, 24, and 48.  
All MRI scans will be performed locally and sent to the central MRI laboratory for evaluation. 
They will remain blinded to the investigator, patient and sponsor until after the study (or study 
Part, respectively) has been completed and the database has been locked. However, incidental 
medically significant findings (e.g. tumor) not related to fat content can be disclosed by the 
radiologist obtaining MRI images at the investigative site during the course of conducting the 
clinical trial to the investigator as appropriate to the medical care of the patient. Detailed 
information can be located in the MRI manual.
6.4.2
Liver Function 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, 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 function 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.


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The methods for assessment and recording are specified in the laboratory manual.
6.4.4
Markers of liver fibrosis

Fibroscan®: the following will be collected: Date and type of evaluation performed, 
number of (successful) measurements, liver stiffness (in kPa), probe type and Interquartile 
range (IQR) (optional assessment, only if sites have equipment available)

Enhanced liver fibrosis Test (ELF) panel: the following will be assessed: hyaluronic acid 
(HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of 
procollagen type III (PIIINP)

Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®. The following will be 
assessed: α2-macroglobulin, apolipoprotein A1, total bilirubin, haptoglobin, GGT, and 
ALT
These markers will be assessed as indicated in Table 6-1.
6.4.5
NAFLD fibrosis score
The following formula will be utilized for the calculation of the NAFLD fibrosis score: -1.675 
+ 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG (increased fasted glucose)/diabetes 
(yes = 1, no = 0) + 0.99 × AST/ALT ratio – 0.013 × platelet (×109/l) – 0.66 × albumin (g/dl). 
This score will be calculated programmatically and will not be available to investigators until 
after the database is locked. The fibrosis score will be assessed as listed in the Assessment 
schedule (Table 6-1).
6.4.6
Fasting Lipids
Blood samples will be collected for a fasting lipid panel, including total cholesterol, HDL-
cholesterol and LDL-cholesterol, triglycerides, free glycerol and free fatty acids as per the 
assessment schedule (Table 6-1). Lipid measurements should be collected after an 8-hour 
(overnight) fast. Detailed information will be provided in the lab manual. 


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6.4.9
Liver Biopsy
In Part C, patients will have paired liver biopsies (Baseline and EOT, after 48 weeks of 
treatment).  Fibrosis staging and scores of steatohepatitis markers (steatosis, lobular 
inflammation, and hepatocyte ballooning) 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.  Components of the NAS Scoring are 
provided in Table 6-3.  Additional details regarding liver biopsy requirements can be found in 
the accompanying central biopsy manual.
Table 6-3
NAS Components 
Component
Score
Extent
Definition and Comment
Steatosis
0
<5%
Refers to amount of surface area 
involved by steatosis as evaluated on 
low to medium power examination; 
minimal steatosis (<5%) receives a 
score of 0 to avoid giving excess weight 
to biopsies with very little fatty change
1
5-33%
2
>33-66%
3
>66%
Lobular inflammation
0
No foci
Acidophil bodies are not included in this 
assessment, nor is portal inflammation
1
<2 foci/200x
2
2-4 foci/200x
3
>4 foci/200x
Hepatocyte ballooning
0
None
1
Few balloon cells
The term "few" means rare but definite 
ballooned hepatocytes as well as cases 
that are diagnostically borderline
2
Many cells
Most cases with prominent ballooning 
also had Mallory's hyaline, but Mallory's 
hyaline is not scored separately for the 
NAS
NAS Score
Range: 0-
8
N/A
Sum of the three components
6.4.10
Appropriateness of efficacy assessments 
The primary and 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 as determined by magnetic resonance along with sustained improvement in 
alanine aminotransferase (ALT) is recommended as a valid endpoint for short-term phase 1 
and 2 trials (Sanyal et al 2011).  Part C secondary endpoints also include direct markers of 


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NASH measured by liver biopsy including fibrosis staging and scores of steatohepatitis 
markers.
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).
6.5.2
Vital signs 
Clinically notable vital signs are defined in Appendix 1.
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 6-1. After the patient has been sitting for five minutes, 
with back supported and both feet placed on the floor, systolic (SBP) and diastolic (DBP) 
blood pressure will be measured with an appropriately sized cuff. Note that large cuffs are 
required in overweight and obese patients. If blood pressure is high (i.e., SBP ≥140 mmHg 
and/or DBP ≥100 mmHg, or ≥130/80 for patients with diabetes or chronic renal insufficiency), 
blood pressure measurement will be repeated after a 5 minutes rest and confirmed by other 
arm. All measurements should be recorded in source documents and the lowest reading 
entered in the CRF.
If possible, assessments should be performed using the same equipment and by the same 
qualified study site staff member throughout the study.
6.5.3
Anthropometric assessments
Height, body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes), 
and waist and hip circumference in centimeters (cm), and hip circumference (cm) will be 
measured as indicated in Table 6-1. 
For the assessment of the waist and hip circumference, the patient should be standing upright 
during the measurements, with arms relaxed at the side, feet evenly spread apart and body 
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The waist circumference should be measured on bare skin at the end of several consecutive 
natural breaths, at a level parallel to the floor, midpoint between the top of the iliac crest and 
the lower margin of the last palpable rib in the mid axillary line. The hip circumference 
should be measured on bare skin at a level parallel to the floor, at the largest circumference of 
the buttocks. For both measurements it is advised to use a stretch-resistant tape that is 
wrapped snugly around the patient, but not to the point that the tape is constricting (World 
Health Organization Dec 2008).
Waist-to-Hip ratio (WHR) will be calculated using the following formula:

WHR = Waist circumference (cm) / Hip circumference (cm)
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
6.5.4
Laboratory evaluations
Laboratory evaluations will be assessed as indicated in Table 6-1.
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Section 13 (Appendix 1).
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. These stored samples will be 
destroyed 3 years after study end at the latest.
6.5.4.1
Hematology
Red blood cell (RBC) count, hemoglobin (Hb), hematocrit, mean corpuscular volume (MCV), 
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 (additional assessments at Week 4 and Week 8), serum creatinine 
(additional assessments at Week 4 and Week 8), 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: 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.


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Liver function tests: see Section 6.4.2
Coagulation: see Section 6.4.3
For platelets, see Section 6.5.4.1
Fasting lipid profile: see Section 6.4.6
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.
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.
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 should be labeled with the study number, patient initials, patient number, date and 
time, and kept in the source documents at the study site. For any ECGs with patient safety 
concerns, two additional ECGs must be performed to confirm the safety finding. Clinically 
significant ECG findings at baseline must be discussed with the sponsor before administration 
of study treatment. Clinically significant abnormalities must be recorded on the relevant 
section of the medical history/Current medical conditions/AE CRF page as appropriate.
6.5.6
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Screening Visit followed by a urine pregnancy test at Baseline Visit before study drug 
administration. The urine pregnancy test will be repeated every four weeks up to the follow up 
visit (see Table 6-1). The tests will be performed at the clinical center.


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A positive test at Screening Visit and/or Baseline Visit is an exclusion criterion for 
participating in the study. 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.
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
6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Patient Reported Outcomes (PRO)
The impact of tropifexor on various aspects of patient’s health status will be assessed by the 
following measures:
Part A:

VAS for Itch
Part B and Part C:

VAS for Itch
VAS for Itch 
A 10 cm visual analogue scale (VAS) will be used to assess the severity of patients itch 
(ranging from 0 = no itch at all to 10 = the worst imaginable itch) 
 
 The score (distance from left) 
on the VAS will be recorded 
by the patient marking with a line and used 
to test for an effect of tropifexor over placebo.
The questionnaire will be completed by patients as indicated in Table 6-1.


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6.6.2
Resource utilization 
Not applicable.
6.6.3
Pharmacokinetics 
Peripheral blood samples for PK will be collected from all patients according to the schedule 
defined in Table 6-1 and Table 6-2 and further detailed below in Table 6-4. Further details on 
sample collection, numbering, processing and shipment can be found in the Laboratory 
Manual. 
All samples will be given a unique sample number (as listed in Appendix 4, Table 16-1 (Part 
A) and Table 16-2 (Part B)).
Table 6-4
Timing of PK samples
Part A
Part B
Part C
Week 1
Pre-dose and 2 hrs 
post-dose
Not applicable
NA
Week 2
Pre-dose
Pre-dose and 2 hour 
post-dose
NA*
Week 4
Pre-dose
Post-dose as last 
activity
NA
Week 6
Pre-dose
Pre-dose and 4 hour 
post dose
Post-dose as last 
activity
Week 8
Pre-dose
Post-dose as last 
activity
NA
Week 12
Pre-dose
Post-dose as last 
activity
Pre-dose and  post 
dose as last activity
Week 24
NA
NA
Pre-dose and  post 
dose as last activity 
Week 40
NA
NA
Post-dose as last 
activity
Week 48
NA
NA
Pre-dose and post 
dose as last activity
Tropifexor will be determined in plasma using a validated LC-MS/MS method (liquid 
chromatography coupled to tandem mass spectrometry). The lower limit of quantification 
(LLOQ) for tropifexor is 20 pg/mL or less for plasma. 
 
 
 
 
 


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The dates and times (to the nearest minute) for all blood sample collections along with the 
dates and times (to the nearest minute) for study medication administration over at least the 
preceding 2 days shall be recorded in the source documents and on the CRF. Sampling 
problems will be noted in the Comments page of the eCRFs.


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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 [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject. For part A, AE will be collected after providing written 
informed consent for participation in the study until the end of study visit. For patients 
participating in Part B, AEs will be collected after providing written informed consent and up 
to one month after the assessments of screening visit 1, and continued to be collected from 
screening visit 2 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.
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 defined in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the Common Toxicity Criteria (CTC) AE grade
If CTCAE grading does not exist for an adverse event, use
1=mild
2=moderate
3=severe
4=life-threatening (see Section 7.2 for definition of SAE)
CTCAE Grade 5 (death) is not used, but is collected in other CRFs (Study Completion/Death).
There may be cases where a CTCAE with a grade of 4 (life-threatening) may not necessarily 
be an SAE (e.g. certain laboratory abnormalities in the absence of meeting other seriousness 
criteria).

its relationship to the study treatment:


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
Yes

No

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 study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

study treatment dosage increased/reduced 

study treatment interrupted/withdrawn 

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
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 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 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


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
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 (specify what this includes)

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 (see Annex IV, ICH-E2D Guideline).
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 (see Annex IV, ICH-E2D 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 after the last study visit must be reported to 
Novartis 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 if the investigator suspects 
a causal relationship to study treatment. 
All SAEs reported up to the patient’s last visit will be reported in the AE eCRF. SAEs beyond 
the last visit will only be recorded in the Novartis Drug Safety and Epidemiology database.
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 


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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 study treatment,
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 (new occurrence) and 
is thought to be related to the study treatment a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a process for identification, monitoring and evaluation of liver events has 
to be followed. For this study in patients likely to have altered liver function at baseline, an 
adapted monitoring process will be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of liver laboratory 
parameters

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard Liver CRF pages
Please refer to Table 5-2 in Section 5.5.5 for definition of significant ALT and AST triggers 
and required follow up actions, as well as to Table 14-1 in Appendix 2 for complete 
definitions of other liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Table 5-2 (Section 5.5.5) and Table 
14-1 of Appendix 2 should be followed up by the investigator or designated personal at the 
trial site as summarized below. Detailed information is outlined in Section 5.5.5 and Table 14-
2 in Appendix 2.
For liver laboratory triggers:


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
Repeat the liver function tests (LFT) after 48 to 72 hours if >2× baseline and no 
improvement on retest, or within 1 week if improved, unless a different time frame is 
stated, to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats must then be performed at central laboratory as soon as possible. If a liver 
event is subsequently reported, any local LFTs previously conducted that are associated with 
this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For liver events:

Repeat the LFT to confirm elevation as appropriate

Discontinue the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event by consideration of possible alternative causes 
(e.g., disease, co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages and on SAE forms when appropriate.
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; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

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 
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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 DAR (dose administration record) eCRF 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 (see Table 7-1).
Table 7-1
Treatment errors and appropriate actions
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not associated 
with a SAE
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology 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.
7.7
Monitoring for clinically significant LDL-cholesterol increases
LDL-cholesterol elevations have been noted in clinical trials with a bile acid FXR agonist 
(Neuschwander-Tetri et al 2015), but have not been noted in treatment with tropifexor, a non-
bile acid FXR agonist. 
Tests for monitoring fasted lipid levels (total cholesterol, HDL-cholesterol and LDL-
cholesterol, triglycerides, free glycerol and free fatty acids) are performed at regular time 
points during the study (see Table 6-1 and Table 6-2). 


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Patients with significant LDL-cholesterol increases that are confirmed upon repeat laboratory 
testing and not found to be due to dietary indiscretions and are deemed medically important 
should be managed according to local standards. Changes or initiation of therapy for increased 
LDL-cholesterol should be recorded in the CRF.
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 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 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After study 


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completion and final database lock, the investigator will receive copies of the patient data for 
archiving at the investigational site.
8.3
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database.
Patients will fill in their PRO data in a site based tablet. The system will be supplied by a 
vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel (or designated CRO).
MRI assessments will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. An 
interim analysis of Part A data collected up to Week 16 will be performed. The database will 
be locked at the end of Part B. Any changes to the database after that time can only be made 
after written agreement by Novartis Development management.


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8.4
Data Monitoring Committee
This study will use the tropifexor program level external DMC. The committee will consist of 
at least two physicians and a statistician who are not otherwise associated with the study, and 
who are experienced in multicenter trials in hepatology and general medicine. The main tasks 
of the Committee for this study will be to review emerging safety data and primary efficacy 
data and provide recommendations to the Sponsor concerning safety. Further, the DMC will 
review available safety and efficacy data when ≥90% of the patients in Part A have
completed the week 8 assessments prior to making a recommendation for the doses to use in 
Part B of the study. 
The program Data Monitoring Committee Charter provides detail on the committee 
composition and processes.
The DMC will review safety, including AEs and laboratory parameters, on a regular basis. In 
addition, in the event that more than 3 patients develop an AE of CTCAE grade 3 or higher in 
the same system organ class, the DMC chairman will be alerted. Further details regarding 
relevant data and actions will be specified in the separate DMC charter.  
The DMC may conduct a safety and efficacy review at the time of the second interim analysis 
when patients from Part A have finished the study.
8.5
Adjudication Committee 
Not required.
9
Data analysis
The final (end-of-study) analysis will be conducted on all patient data collected up to the EOS
Visit or the premature treatment discontinuation visit (i.e., EOT  Visit  for patients 
discontinuing during the treatment period or EOS (Visit  for patients discontinuing during the 
Follow-up 1 period).  For patients in Parts A and B, EOT is at week 12 and EOS is at Week 
16.  For patients in Part C, EOT is at Week 48 and EOS at Week 52.  
Data collected during the Follow-up 2 period Visit will be described in a separate supplement 
to the primary CSR.
Data from Parts A and B will be pooled in each treatment arm for the analysis at the end of 
Part B.  Placebo data from Part C might be pooled with placebo data from Parts A or B as 


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appropriate. Any data analysis carried out independently by an investigator should be 
submitted to Novartis before publication or presentation.  
Interim analyses will be conducted 1) for DMC review at Week 8 in Part A, when ≥ 90% of 
patients in Part A have completed their Week 8 assessments, 2) at Week 16 in Part A. 3) when 
all patients have completed Week 16 in Part B, 4) when all patients in Part C have completed 
Week 12 and 5) the final analysis will be conducted when all patients have completed Part C.
9.1
Analysis sets 
The following analysis populations will be defined for the statistical analysis:

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. Of note, in Parts A and B, patients with dose reduction due to AE 
will be analyzed according to the treatment they received up to the dose reduction. In Part 
C, patients with a dose reduction due to AE will be analyzed according to the treatment 
received >= 24 weeks.
* 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.
The number and percentage of patients in the randomized set who completed the study, who 
discontinued the study and the reason for discontinuation will be presented for each treatment
group and all patients. The frequency (%) of patients with major protocol deviations as well as 
the criteria leading to exclusion from analysis sets will be presented in separate tables for the 
randomized 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.


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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-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). 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 the SAF):

Occurrence of SAE

Occurrence of AE resulting in permanent discontinuation or dose reduction of study 
treatment

Occurrence of AE of special interest 
Efficacy (to be assessed in the FAS):

Change from baseline to Week 12 in ALT

Change from baseline to Week 12 in AST

Relative change from baseline to Week 12 in percentage of fat in the liver assessed using 
MRI  
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 and efficacy variables are outlined in Table 9-1.
Table 9-1
Primary variables and methods of analysis
Variable
Method of analysis
Occurrence of  SAE
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of AE resulting in discontinuation or 
dose reduction of study treatment
Summary table of absolute and relative 
frequency, overall and by preferred term


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Variable
Method of analysis
Occurrence of AE of special interest
Summary table of absolute and relative 
frequency, overall and by type of AE (risk 
definition as per SPP)
Change from baseline to Week 12 of ALT
Baseline adjusted mean estimates and  
pairwise differences from repeated measures 
ANCOVA, descriptive statistics
Change from baseline to Week 12 of AST
Baseline adjusted mean estimates and  
pairwise differences from repeated measures 
ANCOVA, descriptive statistics
Relative change from baseline to Week 12 in 
percentage of fat in the liver assessed using MRI
Baseline adjusted mean estimates and  
pairwise differences from ANCOVA, 
descriptive statistics
Summary tables will be presented by treatment group and visit (as applicable) using 
descriptive statistics, which include absolute and relative frequencies for categorical variables 
and arithmetic mean, standard deviation, minimum, maximum, median and first and third 
quartile for continuous variables.
Repeated measures ANCOVA models will include time (visit) and treatment group as 
categorical explanatory variables. The stratification factor (BMI group) and the baseline 
assessment will be included as covariates. The interaction terms of time with baseline 
assessment and treatment will be included as well. An unstructured covariance matrix will be 
assumed for the within subject repeated measurements, and Kenward-Rogers type degrees of 
freedom will be used. 95% confidence intervals will be calculated for treatment differences 
(without adjustment for multiple comparisons).  An ANCOVA model for the relative change 
in the percentage of liver fat will include baseline assessment and BMI stratification group as 
covariates, and treatment group as explanatory variable, with no interaction terms.
For ALT and AST and relative change in the percentage of liver fat, a multiple contrast test to 
confirm a general trend over placebo will be performed in addition. A one-sided p-value ≤ 
0.05 will be considered as a confirmation of a dose-response relationship, without adjustment 
for multiple comparisons (due to testing more than one parameter). Contrast vectors will be 
derived from pre-specified alternative dose-response shapes using weights proportional to 
total sample sizes for each arm.
The multiple contrast test will be run on combined doses from Parts A, B and C after the 
completion of Part C Week 12. 
9.4.3
Handling of missing values/censoring/discontinuations
Missing data for the efficacy variables in Table 9-1 will be accounted for by the use of 
repeated measures ANCOVA (MMRM), assuming data are missing at random (MAR). In 
case of dose reduction, any ALT and AST assessments after reduction will be set to “missing” 
for the respective analyses.
9.4.4
Sensitivity analyses 
The missing data pattern will be explored graphically at the final analysis. If the exploration 
raises concerns about deviation from the MAR assumption, and/or the proportion of missing 


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data is large (e.g., >10%), the possible impact will be discussed. As there are no formal 
hypothesis tests and no confirmatory claims based on the results, no alternative analyses are 
pre-planned.
9.4.5
Supportive analyses of the primary variables
Primary variables will also be summarized, using descriptive statistics, in the subgroups 
defined by the stratification factors, and additionally in the subset of patients who have 
historical biopsy data, both overall and by fibrosis score and/or NAS score.
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
Absolute change from baseline to Week 12 in 
percentage of fat in the liver assessed using MRI
Baseline adjusted mean estimates and  pairwise 
differences from ANCOVA, descriptive statistics
Weight, BMI, waist-to-hip (WTH) ratio
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA
FGF19, C4
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from ANCOVA
Liver stiffness (in kPa) by Fibroscan®, enhanced 
liver fibrosis panel (ELF) score, and score of 
fibrosis biomarker test (originally known as 
Fibrotest®/ FibroSure®)
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA
GGT
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA
Fasting lipids (total cholesterol, trigylcerides, LDL-
cholesterol and HDL cholesterol, free glycerol, 
free fatty acids)
Descriptive statistics (including geometric mean 
and CV) by visit (including %change and log 
transformed ratio to baseline), and pairwise ratio 
versus placebo with 95% CI from repeated 
measures ANCOVA (back transformed from log 
scale)
Itch VAS
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA
At least a one point improvement of fibrosis stage 
without worsening of steatohepatitis at Week 48 
compared to baseline
Descriptive statistics (absolute and relative 
frequency), differences, odds ratio and relative 
risk reduction versus placebo with 95% CI 
Proportion of patients who have at least a two 
point improvement in fibrosis without worsening of 
Descriptive statistics (absolute and relative 
frequency), differences, odds ratio and relative 


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Variable
Analysis
steatohepatitis at Week 48 compared to baseline
risk reduction versus placebo with 95% CI
Resolution of steatohepatitis without worsening of 
fibrosis stage at Week 48 compared to baseline
Change of NAS from baseline to Week 48
Descriptive statistics 
Absolute and relative change from baseline to 
Week 48 in percentage of fat in the liver assessed 
using MRI
Baseline adjusted mean estimates and  pairwise 
differences from repeated measures ANCOVA, 
descriptive statistics
Change from baseline to Week 48 of ALT and 
AST
Baseline adjusted mean estimates and  pairwise 
differences from repeated measures ANCOVA, 
descriptive statistics
Summary tables will be presented by treatment group and visit (as applicable) using 
descriptive statistics, which include absolute and relative frequencies for categorical variables 
and arithmetic mean, standard deviation, minimum, maximum, median and first and third 
quartile for continuous variables. All efficacy variables will be analyzed in the FAS and, with 
the exception of ALT and AST, assessments obtained after dose reduction will be included. 
Graphical displays will be provided as appropriate.
Repeated measures ANCOVA will be performed as described in Section 9.4.2.Standard 
ANCOVA for absolute change of liver fat to Week 12 will include baseline assessment and 
BMI stratification group as covariates, and treatment group as explanatory variable, with no 
interaction terms.
Binary biopsy based endpoints will be analyzed using logistic regression, including baseline 
fibrosis stage and BMI stratification group as covariates. Missing follow-up biopsy results 
will not be imputed, so that the primary analysis of these parameters will only be based on 
subjects with valid paired biopsies who have received >= 24 weeks of the baseline assigned 
treatment. However, additional supportive analyses addressing different estimands will be 
described in the analysis plan.
No adjustment of the type I error for multiplicity is planned. Any resulting p-values should 
only be considered descriptive.  
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. Patients with dose reduction will be analyzed according to the 
treatment received before dose reduction. Assessments obtained after dose reduction will be 
included in safety summary tables.
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 (where placebo groups from Parts A and B will be combined, whereas the 


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placebo group from Part C will be reported as a separate group), the number and percentage 
of patients having experienced:

any AE,

any serious AE (SAE),

any AE by primary system organ class (SOC),

any AE by preferred term,

any AE by severity (CTCAE grade),

any AE possibly related to study treatment (investigator assessment),

any AE resulting in dose reduction or discontinuation of study treatment ,

any AE of special interest for tropifexor treatment.
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. Separate summaries 
will be provided for death.
To account for the longer duration of exposure to study treatment in Part C (48 weeks) 
compared to Parts A and B (12 weeks), exposure adjusted incidences for the types of events 
listed above will be presented additionally. The placebo groups from Parts A, B and C will be 
pooled for this type of analysis.
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.
Safety laboratory parameters which are also part of the efficacy analyses will be included in 
the safety tables as well (liver enzymes, lipids, glucose).
9.5.2.3
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.


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9.5.2.4
ECG
ECG data will be summarized by treatment and visit. 
Notable QTc values and change from baseline will be summarized. A notable value is defined 
as a QTc interval of greater than 450 ms. The categories used for the change (increase) in QTc 
are - less than 30 ms, 30 to 60 ms and greater than 60 ms. 
The Fridericia QT correction formula (QTcF) will be used for clinical decisions. 
9.5.2.5
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 1 
and Baseline visits (Screening 2 and Baseline if a test was performed during Screening 2 visit).
9.5.3
Resource utilization 
Not applicable.
9.5.4
Pharmacokinetics 
Plasma concentrations will be expressed in ng/mL. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the Limit of Quantification will be treated as zero in summary statistics 
for concentration data only. 
Tropifexor plasma concentration data will be listed by part, cohort, treatment group, subject, 
and visit/sampling time point. Descriptive summary statistics will be provided by part, cohort, 
treatment group, and visit/sampling time point. Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. Concentrations below LLOQ will be treated as zero in summary statistics. Any 
other PK analyses will be described in a separate report (e.g. a CSR addendum).
Due to the sparse blood sampling scheme, a population PK modeling approach will be used to 
estimate individual subject AUC within a dosing interval. Available data and analyses will be 
provided to the DMC as needed 


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9.5.6
Biomarkers
 
 
9.5.7
PK/PD 
 
 
 
 


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9.7
Interim analyses
Two interim analyses will be performed in the study.  An interim analysis will be conducted 
when ≥90% of the patients in Part A have completed the Week 8 assessments. The analysis 
will, however, include all data available at the resulting data cutoff point. An independent 
DMC will review the safety profile, efficacy variables, and PK data. Estimates for the efficacy 
variables will also include time points beyond Week 8 (using a repeated measures ANCOVA) 
if sample sizes allow. Graphical displays will be used to support the data review.
Unblinded data analysis will be performed by a study independent statistician and 
programmer, and provided to the DMC. Semi-blinded analysis is not considered in this case 


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because tables and particularly graphs should display dose groups in ascending order to 
facilitate review.  
Based on the results of the IA, the DMC will make recommendations on the treatment groups 
to be studied in Part B of the study. There are no strict quantitative rules for the DMC 
decision and no hypothesis tests. In brief, the DMC will determine which doses in Part A are 
safe, and among the safe doses, which are efficacious based on biomarker results (primarily 
ALT and AST). Target thresholds for desired biomarker response and further guidance will be 
provided in the DMC charter. Up to two of the doses are planned to be selected for Part B. 
The DMC also provides recommendations for the range of doses > 90 µg to be considered for 
Part C dose selection.
As pre-specified, in the event that the DMC selected only one active dose (safe and 
efficacious) to be tested in 75 patients in Part B, one of the other originally planned active 
treatment arms (e.g. highest safe but inefficacious dose) was continued with a smaller sample 
size (20 patients) to confirm the earlier findings of this treatment arm observed in Part A. The 
DMC selected the 90 µg dose for Part B, so 60 µg will be tested in 20 patients. If only one 
dose was deemed safe then only one experimental group would have been studied in Part B.
If none of the doses is considered safe, or no sufficient efficacy is observed with safe doses, 
Part B may not be initiated. There is no adaptation of the type I error to account for this 
interim analysis. Further details will be described in the DMC charter.
In addition, the DMC will review safety, including AEs and laboratory parameters, on a 
regular basis. In the event that more than 3 patients develop an AE of CTCAE of grade 3 or 
higher in the same system organ class, the DMC chairman will be alerted. Further details 
regarding relevant data and actions will be specified in the separate DMC charter. 
In addition to the interim analysis conducted for DMC review, a second analysis of Part A 
data collected up to Week 16 will be performed.
A third analysis will include Part B data collected up to Week 16.  At that time Novartis and 
CRO associates will be unblinded to data from Part B. 
An interim analysis of Part C data (fourth planned reporting event) will be performed when all 
patients have completed the Week 12 visit or prematurely discontinued from the study prior to 
week 12.  Part C patients will continue through Week 52.  Novartis and CRO associates 
involved in data management, analysis and reporting will be unblinded at the time of the Part 
C Week 12 Interim Analysis.  
The final database lock for the end-of-study analyses will occur when all patients have 
completed the study.  This will include data through EOT (Week 12 in Parts A and B, or 
Week 48 for Part C) visit for any patients continuing therapy in an extension protocol (if 
available), or EOS (Week 16 visit for Parts A and B or Week 52 for Part C) for all other 
patients, unless prematurely discontinued from the study. 
9.8
Sample size calculation
The primary objective of the study is to determine a safe dose or dose range. However, the 
assessment will be made based on the whole safety profile and not on quantitatively 


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formulated hypotheses for distinct parameters. Therefore, the sample size is based on 
practicability with respect to expected speed of enrolment 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 observed with > 95% probability in 
samples of 10 and above. This would include, for example, the isolated ALT elevations 
observed at high doses in healthy volunteers. Events with true incidences below 10% down to 
3% are still very likely to be observed in combined sample sizes from Parts A and B, and also 
each dose in Part C, while events are observed with less than 50% probability in Part A if the 
true incidence is less than about 4% (Figure 9-1). It is noteworthy, however, that a single 
patient constitutes 6.7% in a sample of 15.
Figure 9-1
Binomial probability to observe an event with given sample size
In the interim analysis, predictions of the probability of an event (incidence) will be based on 
the observed number of events, to support the decision to continue or drop a dose for Part B.
Probabilities of the incidence being below a certain threshold are plotted in Figure 9-2 for a 
sample size of 15 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 that the incidence is ≤ 5% would be 
87%. If an event is observed in one patient, the probability that the incidence is ≤ 5% would 
be 38%. Similarly, if an event is observed in 5 patients (one third), the probability that the 
incidence is ≤ 50% would be 90%, but the probability that the incidence is ≤ 30% would be 39% 
(calculated using R function pbeta).
9.8.2
Power considerations with given sample size for efficacy assessment
A consideration for primary efficacy analyses is given in the following. 
Neuschwander-Tetri et al (2015) reported a mean change of ALT from baseline to week 12 of 
-28 for obeticholic acid (OCA) and -11 for placebo, with standard deviations of 48 and 33, 
respectively. Assuming for simplicity a common standard deviation of 45, this translates into 
an effect size (mean difference / standard deviation) of approximately 0.38, which can be 
considered as a benchmark. The power for a t-test to compare two groups (1-sided type I error 
0.05) based on such an effect size would be 63% (59%) with a sample size of 90 (50) in the 
active and 40 (50) in the placebo group. If the active dose were slightly better than OCA (-33 
versus -11), the power would be 81% (78%) Numbers in parentheses refer to comparisons in 
Part C with 50 subjects in the active arm(s) and 50 in the placebo arm where no pooling with 
subjects in the placebo arms of Parts A and B is considered (calculations with NQuery 


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Advisor 7.0).   Based on pre-clinical data for tropifexor and OCA, it is expected that the effect 
size achieved with an optimal dose of tropifexor maybe even larger, therefore resulting in a 
power above 80%.
For relative reduction of liver fat, no data are available for OCA. In the Novartis sponsored 
study CLCQ908A2216 in patients with NAFLD, with a baseline percentage of approximately 
16%, the relative decrease after 12 weeks of treatment was about 2% in the placebo group and 
21% in the highest active dose group, with a common standard deviation of approximately 30, 
resulting in an effect size of 0.63. If we assume a slightly smaller effect size of at least 0.5 for 
a tropifexor dose in the NASH study population, a power of ≥ 83% (79%) is achieved for 
pairwise comparisons with assumptions as described above.
Alternatively, we can consider the power of a multiple contrast test to demonstrate a trend 
over placebo across multiple dose arms, in this case 10 µg, 30 µg, 60 µg, 90 µg, 140 µg and 
200 µg. We assume the dose-response curves in Figure 9-3. A beta shape is included as a 
possibility because the ALT elevations that may occur with high doses could, on average, 
interfere with the desired effect of ALT decrease.
Figure 9-3
Potential dose-response curves


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Table 9-4
Power for multiple contrast test for trend over placebo
Sample size in  Doses (µg)
Power for model (%)
0
10
30
60
90
140
200
Emax 
Linear 
Beta
Logistic
Average
90
15
15
35
90
50
50
82 (98)
75 (89)
83 (96)
85 (99)
81 (95)
Contrasts for multiple contrast test are optimal for each model type and sample size; assumptions: placebo 
response: -11, maximal response: -28 (in brackets: -33), common standard deviation: 45, type I error: 0.05 
(one-sided);
Only Part B and C sample sizes after DMC recommendation were considered.
The average power for this type of test is at least 81% for a pooled Week 12 analysis of all 
study parts:

50 subjects assigned to two doses (140 and 200 µg) and 50 to placebo in Part C,
An average power of ≥95% is achieved if the effect size is moderately better than that of 
OCA (Table 9-4, calculations using powMCT function of DoseFinding package in R). Power 
calculations for a multiple contrast test on relative reduction of liver fat were not performed, 
but are expected to be in a similar range based on the effect size considerations above. 
As the first interim analysis will be conducted with only 13-15 patients per arm who have 
completed the Week 8 assessments, the power to compare the effect on ALT or AST 
reduction between groups will be considerably lower. Furthermore, only a certain percentage 
of the patients will have data up to Week 12 available at that time point, depending on the 
speed of enrollment. The assessment of efficacious doses in the interim analysis will therefore 
be primarily based on the relative size of the point estimates (mean changes) and the shapes of
the curves over time for the liver enzymes in each group.   
9.8.3
Power consideration for biopsy endpoints in Part C
The longer treatment duration in Part C is due to the DMC recommendation to include paired 
biopsy assessments. Therefore, the sample size in Part C is partly based on the following 
assumptions for biopsy based outcomes:

Response parameter: Achievement of at least one stage improvement of fibrosis with no 
worsening of steatohepatitis at Week 48 compared to baseline (binary).

Placebo response rate: 13%, based on interpolated results from Neuschwander-Tetri et al 
(2015). This assumes a linear improvement over time (a placebo rate of 19% was reported 
at week 72).

Tropifexor response rate: 37% (best case assumption) with at least one of the doses.
For a 2-group continuity corrected χ2 test of proportions with type error 0.05 (1-sided, no 
adjustment for multiple comparisons), a sample size of 50 per group results in a power of 82%
(nQuery Advisor 7.0). The actual power might be smaller due to missing follow-up biopsies.     


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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 Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after 
such consent has been provided by a legally acceptable representative(s) of the patient. In 
cases where the patient’s representative gives consent, the patient must be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, 
he/she must indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting 
any study-specific procedures (e.g. all of the procedures described in the protocol). The 
process of obtaining informed consent must be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
 
 
 
 
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 


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his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
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 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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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 may be implemented immediately provided the health authorities are 


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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 
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.


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12
References
References are available upon request
Alonso C, Fernández-Ramos D, Varela-Rey M et al (2017 In Press) Metabolomic 
Identification of Subtypes of Nonalcoholic Steatohepatitis. Gastroenterology
Bazick J, Donithan M, Neuschwander-Tetri BA et al (2015) Clinical Model for NASH and 
Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in 
NAFLD Diabetes Care; 38:1347–1355.
Browning JD, Szczepaniak LS, Dobbins R et al (2004) Prevalence of hepatic steatosis in an 
urban population in the United States: impact of ethnicity. Hepatology; 40:1387-1395.
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 AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear 
sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol; 13(4):213-224.
Cariou B (2008) The farnesoid X receptor (FXR) as a new target in non-alcoholic 
steatohepatitis. Diabetes Metab; 34(6 Pt 2):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.
Chalasani N, Younossi Z, Lavine JE et al (2012) The diagnosis and management of non-
alcoholic fatty liver disease: practice Guideline by the American Association for the Study of 
Liver Diseases, American College of Gastroenterology, and the American Gastroenterological 
Association. Hepatology; 55(6):2005-20023 
CLCQ908A2216 Clinical Study Report (2015) Table 14.2-1.5 IND 101013 Serial No. 0222
Ekstedt M, Franzen LE, Mathiesen UL et al (2006) Long-term follow-up of patients with 
NAFLD and elevated liver enzymes. Hepatology; 44:865-873.
Goodwin B, Jones SA, Price RR et al (2000) A regulatory cascade of the nuclear receptors 
FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell; 6(3):517-526.
Hirschfield GM, Mason A, Luketic V et al (2015) Efficacy of Obeticholic Acid in Patients 
with Primary Biliary Cirrhosis and inadequate response to ursodeoxycholic acid. 
Gastroenterology; 148(4):751 -761.
Kwo P, Cohen S M, Lim J K (2017) ACG Clinical Guideline: Evaluation of Abnormal Liver 
Chemistries.  Am J Gastroenterol; 112:18–35.
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Mudaliar S, Henry RR, Sanyal AJ et al (2013) Efficacy and safety of the farnesoid X receptor 
agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. 
Gastroenterology; 145(3):574-582.


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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.
Patrick DL, Burke LB, Powers JH, et al (2007) Patient-reported outcomes to support medical 
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Pattni SS, Brydon WG, Dew T et al (2012) Fibroblast Growth Factor 19 and 7a-hydroxy-4-
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Gastroenterol; 3: e18.
Porez G, Prawitt J, Gross B et al (2012) Bile acid receptors as targets for the treatment of 
dyslipidemia and cardiovascular disease. J Lipid Res; 53:1723-1737.
Ratziu V, Bellentani S, Cortez-Pinto H et al (2010) A position statement on NAFLD/NASH 
based on the EASL 2009 special conference. J Hepatol; 53:372-384.
Sanyal A, Mudaliar S, Henry R et al (2009) A new therapy for nonalcoholic fatty liver disease 
and diabetes? INT-747 – the first FXR Hepatic therapeutic study. Hepatology; 50(4 suppl): 
389A – 390A.
Sanyal A Brunt EM, Kleiner DE et al (2011). Endpoints and Clinical Trial Design for 
Nonalcoholic Steatohepatitis. Hepatology; 54(1):344-353.
Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and 
hepatocellular carcinoma: a weighty connection. Hepatology; 51(5):1820-1832.
Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to 
measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. 
Am J Physiol Endocrinol Metab; 288:E462-E468.
Targher G, Bertolini L, Poli F et al (2005) Nonalcoholic fatty liver disease and risk of future 
cardiovascular events among type 2 diabetic patients. Diabetes; 54:3541-3546.
Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with 
nonalcoholic fatty liver disease. N Engl J Med; 363:1341-1350.
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measures for pain clinical trials. IMMPACT recommendations. Pain; 125(3):208-215.
Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther; 34:274-285.
Walters JR, Johnston IM, Nolan JD et al (2015) The response of patients with bile acid 
diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharmacol Ther; 
41(1):54-64.
Wong RJ, Aguilar M, Cheung R et al (2015) Nonalcoholic steatohepatitis is the second 
leading etiology of liver disease among adults awaiting liver transplantation in the United 
States. Gastroenterology; 148:547–555.
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expert consultation. Geneva, Switzerland.


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Younossi ZM, Guyatt G, Kiwi M et al (1999) Development of a disease specific questionnaire 
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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 are used to alert investigators to the results, and should not be used as 
reference ranges to establish a clinical diagnosis. 


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Post Baseline Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

ALT or AST > 2× baseline value

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow Up Requirements for Post-Baseline Liver Events and 
Laboratory Triggers
Criteria
Actions requiredd
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Repeat LFT within 48 hours

If elevation persists, discontinue study 
treatment 

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and INR > 
1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 – 72 hours

If elevation persists, reduce dose (Section 
5.5.5), and continue follow-up monitoring

If with reduced dose elevation persists for 
more than 1 week, discontinue the study 
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)


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Protocol No. CLJN452A2202
Criteria
Actions requiredd
Follow-up monitoring
drug

Establish causality

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within 48 – 72 hours

If elevation is confirmed, initiate close 
observation of the patient, and repeat LFT 
within the next week

If elevation persists, reduce dose (Section 
5.5.5), and continue follow-up monitoring

If with reduced dose elevation persists for 
more than 3 weeks, discontinue dose 
(Section 5.5.5) and continue follow up 
monitoring
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study 
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three 
subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) 
liver transplantation, and (5) death.
dFor elevated ALT and/or AST, please also refer to Table 5-2 (Section 5.5.5) for additional scenarios and actions


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions for Post Baseline Values
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 ≥3.4
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or >17 
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 CRF: 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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16
Appendix 4: Sampling schedules and sample logs
Refer to the central laboratory manual for sample collection, preparation and shipping 
information.
Table 16-1
Blood collection log for pharmacokinetics – Part A
Week
Time point
PK sample number*
Dose reference ID
Week 1
Pre-dose
101
1
Week 1
2 hr post dose
102
1
Week 2
Pre-dose
103
2
Week 4
Pre-dose
104
3
Week 6
Pre-dose
105
4
Week 8
Pre-dose
106
5
Week 12
Pre-dose
107
6
* If a PK sample is collected at an unscheduled visit, the sample numbers will follow the pattern 1001, 
1002, 1003 etc
Table 16-2
Blood collection log for pharmacokinetics – Part B
Week
Time point
PK sample number*
Dose reference ID
Week 2
Pre-dose
101
1
Week 2
2 hr post dose
102
1
Week 4
Pre-dose
103
2
Week 6
Pre-dose
104
3
Week 6
4 hr post dose
107
3
Week 8
Pre-dose
105
4
Week 12
Pre-dose
106
5
* If a PK sample is collected at an unscheduled visit, the sample numbers will follow the pattern 1001, 
1002, 1003 etc


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Table 16-4
Blood collection log for biomarkers – Parts A and B
Week*
Time 
point
Fibrosis 
biomarker 
test1
Screening 
Visit 1
--
501
BSL
Pre-dose
502
Week 6
Pre-dose
503
4 hours 
post dose
Week 12
Pre-dose
504
1 Fibrosis biomarker test originally called Fibrotest/Fibrosure
* If other assessments listed in the protocol do require sample numbering, the sample numbers will 
follow the pattern 801, 802 etc for assessment 1, and 901, 902 for assessment 2, and if collected at an 
unscheduled visit, the sample numbers will follow the pattern 1801, 1802, or 1901, 1902 etc. 
Table 16-5
Blood collection log for pharmacokinetics – Part C
Week
Time point
PK sample number*
Dose reference ID
Week 6
Post-dose as last 
activity
108
1
Week 12
Pre-dose and  post 
dose as last activity
109, 110
2
Week 24
Pre-dose and  post 
dose as last activity
111, 112
3
Week 40
Post-dose as last 
activity
113
4
Week 48
Pre-dose and post 
dose as last activity
114, 115
5


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Table 16-6
Blood collection log for biomarkers – Part C
Week*
Time 
point
Fibrosis 
biomarker 
test1
Screening 
Visit 1
--
521
BSL
Pre-dose
522
Week 6
Pre-dose
523
Week 6
4 hours 
post dose
Week 12
Pre-dose
524
Week 24
Pre-dose
525
Week 40
Pre-dose
526
Week 48
Pre-dose
527
1 Fibrosis biomarker test originally called Fibrotest/Fibrosure
* If other assessments listed in the protocol do require sample numbering, the sample numbers 
will follow the pattern 821, 822 etc. for assessment 1, and 921, 922 for assessment 2, and if 
collected at an unscheduled visit, the sample numbers will follow the pattern 1821, 1822, or 
1921, 1922 etc.


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17
Appendix 5: The American Heart Association (AHA) 
Recommended Diet
Optimization of nutrition-related practices can result in a marked triglyceride-lowering effect 
that ranges between 20% and 50%. These 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
LJN452
CLJN452A2202 / NCT02855164
A randomized, double-blind, placebo controlled, 2- part, 
adaptive design, multicenter study to assess safety, 
tolerability and efficacy of tropifexor (LJN452) in patients 
with non-alcoholic steatohepatitis (NASH)
FLIGHT-FXR
Statistical Analysis Plan (SAP)
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final 4.0
Release date:
02-July-2019
Number of pages:
46
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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SAP
CLJN452A2202
Document History – Changes compared to previous final version of SAP
Time point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Protocol  
Amendment 2  
Clarification for 
R programming
Additional specification added to 
allow for more flexible 
programming approach for MCP-
Mod implementation
2.5.2 Statistical 
hypothesis, model, and 
method of analysis
Protocol  
Amendment 2  
Clarification for 
programming
Added that posterior probability 
plot should be based on flat prior 
(using only likelihood of observed 
data)
2.5.2 Statistical 
hypothesis, model, and 
method of analysis
Protocol  
Amendment 2  
Information from 
phase I study
Changed MMRM for FGF19 and 
C4 to simple ANCOVA at week 6 
because elevation is expected to 
be seen only within few hours 
post-dose.
2.7.1 Secondary 
endpoints and 2.7.2 
Statistical hypothesis, 
model, and method of 
analysis
Protocol  
Amendment 2  
Better 
understanding 
of assessment 
schedule
Changed MMRM for Fibroscan, 
ELF and fibrosis biomarker test to 
simple ANCOVA because there is 
only one post-baseline 
assessment.
2.7.1 Secondary
endpoints
Protocol  
Amendment 2  
Clarification
Additional specification that 
log(ratio) from baseline is 
analyzed for lipids
2.7.1 Secondary 
endpoints
Protocol  
Amendment 2  
Clarification
Deleted sentence that any efficacy 
assessment after dose reduction 
would be set to missing for 
respective analyses, because this 
was only meant for MMRM based 
analyses.
2.7.3 Handling of missing 
values/censoring/
discontinuations
  
  
 
 
  
  
 
Protocol  
Amendment 2  
Clarification
Aligned bullet points in AE section 
with TFL shells
2.8.1 Adverse events
Protocol  
Amendment 2  
New mandatory 
text
Added mandatory text for 
EudraCT disclosure.
2.8.1 Adverse events
Protocol  
Amendment 2  
Update
AE coding / grading updated as 
per Amendment 1 and approved 
eCRS
5.2
Protocol  
Amendment 2  
Protocol 
deviation
Modified SAF definition to account 
for dosing errors
2.2
Protocol  
Amendment 2  
Protocol 
Amendment 2
Added reporting event “End of 
Part A”
1, 2.1, 2.14


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CLJN452A2202
Time point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Protocol  
Amendment 2  
Clarification
Additional specification for 
geographical region as a possible 
covariate, in case Japan/Non-
Japan will be used as stratification 
factor in Part B 
2.1
Protocol  
Amendment 2  
Protocol 
Amendment 2
Moved analysis of relative change 
of liver fat to primary variables.
2.5.1, 2.5.2, 2.5.3, 2.7.1, 
2.7.3, 3.1.2
Protocol  
Amendment 2  
DMC request
Added individual lipid profile plots 
and summary statistics for FGF19 
and C4 to 1st interim analysis / 
DMC review
2.14, TFL shells
  
  
 
 
Protocol  
Amendment 2  
Clarification
Split regression model for 
anthropometric assessments into 
MMRM and ANCOVA because 
there are no repeated post-
baseline assessments of WTH 
ratio 
TFL shells, 2.7.1
Protocol  
Amendment 2  
Request from 
GPMD, BSL
Added subgroup table of lipid 
summary by use of lipid reducing 
concomitant medication (and 
definition) 
TFL shells, 5.3
  
  
 
Protocol  
Amendment 3  
Protocol  
Amendment 3  
All sections updated to include 
study Part C with additional 
reporting events, objectives,  
endpoints and doses
All sections, TFL shells
Protocol  
Amendment 3  
Change of PD 
criteria definition
OTH11 was changed and OTH14 
added. OTH11 no longer results in 
exclusion from any analyses, but 
instead OTH14 does.
5.5
Prior to Week 
12 Part C 
DBL
Protocol  
Amendment 3
Title updated
Title page
Prior to Week 
12 Part C 
DBL
Unexpected 
subject journey
Handling of data from subjects 
who discontinued study treatment 
but stayed in study with regular 
visit schedule
2.4.2, 2.8.1, 2.8.3
Prior to Week 
12 Part C 
DBL
Clarification
Precise definition of biopsy based 
endpoints
5.3.11
Prior to Week 
12 Part C 
DBL
DMC 
recommendation
More detailed analysis of Pruritus
2.8.1.1


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CLJN452A2202
Time point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Prior to Week 
12 Part C 
DBL
Leaning
Analysis of ALT and AST spikes 
removed for Part C
2.8.3
Prior to Week 
12 Part C 
DBL
Leaning
Biomarker listing removed
2.12


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Table of contents
Table of contents .................................................................................................................5
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................11
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................14
2.2
Analysis sets ..........................................................................................................14
2.2.1
Subgroup of interest ..............................................................................15
2.3
Subject disposition, demographics and other baseline characteristics ..................16
2.3.1
Subject disposition ................................................................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................17
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.7.1
Secondary endpoints .............................................................................20
2.7.2
Statistical hypothesis, model, and method of analysis..........................21
2.7.3
Handling of missing values/censoring/discontinuations.......................21
2.8
Safety analyses.......................................................................................................22
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................24
2.8.3
Laboratory data .....................................................................................24
2.8.4
Other safety data ...................................................................................25
2.9
Pharmacokinetic endpoints....................................................................................25
2.10
PD and PK/PD analyses.........................................................................................26
26
2.12
Biomarkers.............................................................................................................27
28


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2.14
Interim analysis......................................................................................................29
3
Sample size calculation .....................................................................................................30
3.1.1
Power considerations with given sample size for safety assessment....30
3.1.2
Power considerations with given sample size for efficacy 
assessment.............................................................................................32
3.1.3
Power consideration for biopsy endpoints in Part C.............................34
4
Change to protocol specified analyses ..............................................................................34
5
Appendix ...........................................................................................................................35
5.1
Imputation rules.....................................................................................................35
5.1.1
Study drug.............................................................................................35
5.1.2
AE date imputation ...............................................................................35
5.1.3
Concomitant medication date imputation .............................................36
5.2
AEs coding/grading ...............................................................................................38
5.3
Derivations.............................................................................................................38
5.3.1
Laboratory parameters ..........................................................................38
39
5.3.3
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®.......39
5.3.4
FIB-4 .....................................................................................................40
40
5.3.6
Derived baseline characteristics............................................................40
5.3.7
NASH diagnosis by historical biopsy ...................................................41
5.3.8
Disease scores and diagnostic algorithms.............................................41
5.3.9
Quality of life scores .............................................................................41
5.3.10
Vital signs..............................................................................................42
5.3.11
Definitions for biopsy based endpoints.................................................42
5.4
Statistical models...................................................................................................43
5.4.1
Primary analysis....................................................................................43
5.4.2
Key secondary analysis.........................................................................45
5.5
Rule of exclusion criteria of analysis sets..............................................................45
5.6
Other statistical aspects..........................................................................................45
5.6.1
Crude incidence and related risk estimates...........................................45
6
References .........................................................................................................................46


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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 Classification
AUC
Area Under the Curve
BMI
Body mass index
CI
Confidence interval
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Sheet
eGFR
Estimated glomerular filtration rate
ELF
Enhanced liver fibrosis panel
EOS
End of study
EOT
End of treatment
FAS
Full analysis Set
FIB-4
Fibrosis-4 score
GGT
Gamma glutamate transaminase
HDL
High density lipoprotein
INR
International Normalized Ratio
ITT
Intent-to-treat
LDL
Low density lipoprotein
LLOQ
Lower limit of quantification
MAR
Missing at random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed model repeated measures
MRI
Magnetic resonance imaging
NAFLD
Non-alcoholic fatty liver disease
NAS
NAFLD activity score
NASH
Non-alcoholic steatohepatitis
OCA
Obeticholic acid
PD
Pharmacodynamics


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PK
Pharmacokinetics
PRO
Patient-reported Outcomes
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
TBC
To be confirmed
TBL
Total bilirubin
TFLs
Tables, Figures, Listings
ULN
Upper limit of normal range
ULOQ
Upper Limit of Quantification
VAS
Visual analogue scale
WHO
World Health Organization


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1
Introduction
The purpose of this document is to provide the detailed implementation of statistical analysis 
plan for study LJN452A2202. The analysis will result in one final study report when all patients 
have completed the study (Part A, Part B and Part C). In addition, this SAP provides details for 
the interim analysis (when at least 90% of the patients have completed the Week 8 assessment 
in Part A) and regular safety DMC analyses, as well as analyses at the end of Part A, at the end 
of Part B and when all patients have completed the Week 12 visit of Part C. 
1.1
Study design
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose 
finding, 3-part, adaptive, study to assess the safety, tolerability and efficacy of six doses of 
tropifexor as compared to placebo in patients with non-alcoholic steatohepatitis (NASH).
Patients can be included if they have either histologic evidence of NASH or phenotypic 
diagnosis of NASH (In Parts A & B), as further specified in Section 4.1 of the protocol.
Histologic evidence of NASH (with fibrosis stage 2 or 3), per central read, during the Screening 
period or within 6 months of randomization is required for all patients in Part C.  The composite 
criterion for phenotypic diagnosis has been shown to be nearly as precise as locally read liver 
biopsy which can be frequently re-read as ‘non-NASH’ [Neuschwander-Tetri et al (2015)].
The study will start with screening and enrolling patients for Part A. Screening will continue 
without pause, even after all patients for Part A have been enrolled, but randomization for Part 
B will not start until after the interim analysis in Part A. When ≥ 90% of the patients in Part A 
have completed 8 weeks of treatment, an interim analysis will be performed using all available 
data to allow for the DMC to recommend  dose selection for the arms in Part B (see protocol 
Section 3.5 and Section 9.7). The treatment arms of Part A are planned to be completed without 
adaptation.
Randomization for Part B will only be started after the DMC recommendations on the dose(s) 
to be used in Part B are implemented by the Sponsor.
Part C was introduced as a result of the DMC recommendation to pursue doses > 90 µg after 
the planned interim analysis and DMC review of the Part A data, as well as the preclinical and 
pharmacokinetic data described in protocol section 3.3.  Randomization into Part C will 
commence after Part B randomization is complete.  
Patients in Part A will be assigned at the baseline visit to one of the following 5 treatment arms 
in a ratio of 1:1:1:1:1 in a blinded manner. Placebo capsules will be given in each treatment arm 
where necessary to maintain blinding:
Arm A: Once daily (morning, fasting) treatment with 10 µg tropifexor for 12 weeks
Arm B: Once daily (morning, fasting) treatment with 30 µg tropifexor for 12 weeks
Arm C: Once daily (morning, fasting) treatment with 60 µg tropifexor for 12 weeks
Arm D: Once daily (morning, fasting) treatment with 90 µg tropifexor for 12 weeks
Arm E: Once daily (morning, fasting) treatment with matching placebo capsules for 12 weeks


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Patients in Part B will be assigned at the baseline visit to one of the following 3 treatment arms 
in a ratio of 15:4:5 in a blinded manner. The doses to be used in Part B were decided based on 
data from the first interim analysis and DMC consultation. Placebo capsules will be given in 
each treatment arm where necessary to maintain blinding. 
Arm F: Once daily (morning, fasting) treatment with 90 µg tropifexor.
Arm G: Once daily (morning, fasting) treatment with 60 µg tropifexor.
Arm H: Once daily (morning, fasting) treatment with matching placebo for 12 weeks
Patients in Part C will be assigned at the baseline visit to one of the following 3 treatment arms 
in a ratio of 1:1:1 in a blinded manner. The doses used in Part C were determined based on 
preclinical toxicology data, pharmacokinetic modeling and DMC recommendations based on 
Part A data.  Placebo capsules will be given to maintain blinding. 
Arm I: Once daily (morning, fasting) treatment with 140 µg tropifexor for 48 weeks 
Arm J: Once daily (morning, fasting) treatment with 200 µg tropifexor for 48 weeks
Arm K: Once daily (morning, fasting) treatment with matching placebo for 48 weeks
In order to maintain the blind, placebo capsules matching tropifexor 10, 30 and 100 µg capsules 
will be given to patients, so that all patients will receive 3 capsules per day.
Part A:  Randomization will be stratified in Part A by BMI at baseline (<30 kg/m2 or ≥ 30 kg/m2
for patients with an Asian race or < 35 kg/m2 or ≥ 35 kg/m2 for all other patients). The race is 
based on the race the patient self-reports as captured on the demography eCRF.  
Part B:  Randomization will be stratified in Part B by BMI at baseline (<30 kg/m2 or ≥ 30 kg/m2
for patients with an Asian race or < 35 kg/m2 or ≥ 35 kg/m2 for all other patients). The race is 
based on the race the patient self-reports as captured on the demography eCRF. Randomization 
in Part B will also be stratified by Japanese or non-Japanese, Japanese defined as patients 
residing in Japan.  
Part C: Randomization in Part C will be stratified by Fibrosis level (F2/F3) as determined in the 
Screening biopsy by the Central Reader and by Type 2 Diabetes status (yes/no) as reported on 
the Medical History eCRF. To ensure balance of patients in Japan among the 3 treatment arms, 
the following stratum levels will be implemented (Japanese subgroup is too small for additional 
stratification):
1.
Japan
2. Non-Japan, F2, T2D=No
3. Non-Japan, F2, T2D=Yes
4. Non-Japan, F3, T2D=No
5. Non-Japan, F3, T2D=Yes
The primary analysis timepoint for efficacy assessments is Week 12 (end of treatment in Parts 
A and B) in all three study parts.


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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Time Frame
Primary
To determine safety and tolerability of 
different doses of LJN452
Occurrence of SAE, AE resulting in 
discontinuation of study treatment 
and/or dose reductions, and AE of 
special interest
up to End of 
Study 1
To determine the dose relationship of 
LJN42 on markers of hepatic 
inflammation in NASH (ALT and AST)
Change from baseline to Week 12
up to Week 12
To determine the dose-response 
relationship of LJN452 on liver fat 
content by changes in quantitative MRI 
determined fat
Change from baseline to Week 12 in % 
of fat in the liver assessed using MRI
baseline, 
Week 12
Secondary
To determine the effect of different 
doses of LJN452 on anthropometric 
assessments (weight, BMI, waist-to-hip 
(WTH) ratio) after 12 weeks of 
treatment
Changes from baseline to Week 12
up to Week 12
To determine the dose-response 
relationship of LJN452 on FGF19 over 
time, a marker of FXR target 
engagement in the gut, and C4, a 
marker of hepatic target engagement
Changes from baseline to Week 12
up to Week 12
To determine the dose-response 
relationship of LJN452 on markers of 
liver fibrosis commonly available such 
as Fibroscan®, enhanced liver fibrosis 
panel (ELF), and fibrosis biomarker test 
(originally known as Fibrotest®/ 
FibroSure®)
Changes from baseline to Week 12
up to Week 12
To determine the dose-response 
relationship of LJN452 on GGT, a 
marker of cholestasis
Changes from baseline to Week 12
up to Week 12
To determine the effect of LJN452 on 
fasting lipid profile
Changes from baseline to Week 12
up to Week 12
To determine the pharmacokinetics 
(PK) of LJN452
Ctrough, C2h
up to Week 12
To determine the effect of LJN452 
compared to placebo with respect to 
occurrence of potential itch based on a 
visual analog scale (VAS) rating scale
The score (distance from left) on the 
VAS will be recorded by the patient 
marking with a line. The distance 
marked will be converted to a score 
between 0 and 10
up to Week 12


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Objective
Endpoint
Time Frame
To determine effects of LJN452 on 
primary endpoints in the subset of 
patients who have historical biopsy 
data, both overall and by fibrosis score 
and/or NAS score subsets as feasible 
(based on the extent of available data)
Subgroup analysis with respect to: 
occurrence of SAE, AE resulting in 
discontinuation of study treatment 
and/or dose reductions, and AE of 
special interest, relative change from 
baseline to Week 12 in % of fat in the 
liver assessed using MRI, and change 
from baseline to Week 12 of ALT and 
AST and GGT
up to Week 12
Additional Secondary Endpoints for Part 
C:
To demonstrate the efficacy of 
tropifexor in patients with NASH and 
F2/F3 fibrosis as assessed by 
histological improvement  from baseline 
after 48 weeks of treatment compared 
to placebo
Proportion of patients who have at least 
a one point improvement in fibrosis 
without worsening of steatohepatitis at 
Week 48 compared to baseline
Proportion of patients with resolution of 
steatohepatitis without worsening of 
fibrosis at Week 48 compared to 
baseline
up to Week 48
To determine the effect of tropifexor on 
markers of hepatic inflammation in 
NASH (ALT and AST) in Part C
Change from baseline to Week 48 
up to Week 48
To determine the effect of tropifexor on 
liver fat content by changes in 
quantitative MRI determined fat in Part 
C
Relative change from baseline to Week 
48 in % of fat in the liver assessed using 
MRI
baseline, 
Week 48
To determine safety and tolerability of 
different doses of tropifexor, adjusted 
for length of exposure
Exposure adjusted incidence of SAE, 
AE resulting in discontinuation of study 
treatment and/or dose reductions, AE of 
special interest and other AE
up to Week 52
1 End of follow-up in Parts A and B can be Week 16 or the flexible Week 20 visit ; End of follow-up in 
Part C can be Week 52 or the flexible Week 56 visit
2
Statistical methods
2.1
Data analysis general information
This SAP includes analyses planned for the interim analyses as well as safety DMC reports.
Analyses will be run using SAS 9.3 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. 
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 (“statset1”). Where indicated, 
geometric mean and coefficient of variation will also be displayed, and the ratio instead of 
percentage change (“statset2”). 


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The final analysis will be performed after the final clinical database lock, when all patients have 
completed the study (Parts A,  B and C), and will thefore include all collected data.
The final (end-of-study) analysis will be conducted on all patient data collected up to the Week 
16/52 visit (EOS/Visit 299) or the premature treatment discontinuation visit (i.e., EOT (Week 
12/48 visit, Visit 199) for patients discontinuing during the treatment period or EOS (Week 
16/52 visit, Visit 299) for patients discontinuing during the Follow-up 1 period).
Data collected during the Follow-up 2 period will be described in a separate supplement to the 
primary CSR.
Unless noted otherwise, Part A and Part B data will be combined and analyzed jointly after end 
of Part B. Part C data will be analyzed separately except where indicated. 
The first interim analysis, with the purpose to determine doses for Part B, will include all 
available clean data after at least 90% of the patients (67) have completed Week 8 in Part A or 
discontinued prior to Week 8. Of note, all clean data and complete data up to the date of the last 
patient with a Week 8 will be included as available. Data domains to be cleaned and required 
for the interim analysis will de described in the Data management Plan.
A second interim analysis (End-of-Part A analysis) will be performed when all subjects of Part 
A have completed the Week 16 visit, including only the subjects randomized to Part A. This 
analysis will not be performed by an independent team. However, as Part A and Part B cohorts 
use separate sections of the randomization list, only Part A treatment allocation information 
will be made available to the statisticians and programmers at this stage. The analyses 
performed will be a subset of the analyses planned for the final CSR and will be defined in a 
separate tracking sheet. A similar process will be applied after completion of Part B, when the 
joint analysis of Part A and B data will be performed.
At the Week 12 interim analysis of Part C, the Novartis study team and external statisticians 
and programmers working on the study will be unblinded to Part C treatment allocation, i.e. the 
Part C Week 12 analysis will not be performed by an independent team. 
Data cutoffs for the safety DMC analyses will occur approximately every 6 months after start 
of randomization into Part B and Part C, as appropriate.
For the Part B and Part C analyses, geographical region will be included as a covariate in 
addition to the stratification factor (BMI category) in some of the analyses. Geographical 
regions are defined as follows, with countries known to participate in Part A and / or expected 
for Part B:

Europe: Austria, France, Germany, Netherlands, Italy, Belgium, Slovakia, Spain

America / Australia: USA, Canada, Australia, Argentina

East Asia: Taiwan, South Korea, Singapore, Japan
Additional countries and regions (if necessary) may be added. If geographical region categories 
are used for stratified randomization, only the randomization strata will be used as covariate in 
respective analyses, in addition to the BMI category.


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2.1.1
General definitions 
Each patient in this study receives only one type of study drug, each of which is to be taken 
orally once daily. The term “study drug” therefore refers to LJN452 (10 µg, 30 µg, 60 µg, 90 
µg, 140 µg or 200 µg), or matching placebo.
Date of first administration of study drug: Date of first administration as recorded in the CRF 
(Drug Administration Record page) 
Date of last administration of study drug: 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 drug, which is 
defined as Day 1.
Baseline: 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 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). Note that the follow-up period may consist of two follow-up epochs in some subjects. 
2.2
Analysis sets
The following analysis sets will be defined for the statistical analysis:

Screened set (SCR) – All subjects who signed the informed consent. Data from screen 
failures, as available, should be included in the analysis datasets even if not used for any 
CSR relevant analysis.

Randomized set (RAN) – All subjects who received a randomization number, regardless 
of receiving trial medication.

Full analysis set (FAS) – All subjects to whom study treatment has been assigned*. 
Following the intent-to-treat (ITT) principle, subjects are analyzed according to the 
treatment they have been assigned to at randomization.

Safety set (SAF) - All subjects who received at least one dose of study drug and have at 
least one post-baseline safety assessment. Of note, the statement that a subject had no 
adverse events also constitutes a safety assessment. Subjects will be analyzed according to 
the treatment received. Of note, subjects with dose reduction due to AE will be analyzed 
according to the treatment they received up to the dose reduction. In case of dose 
administration errors, e.g. if a subject did not adhere to the intended medication schedule, 
subjects will be analyzed according to the following rules in the SAF, as far as they can be 
programmed based on recorded data:


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1. If LJN452 was administered to a subject in the placebo group, the subject will be 
placed in the respective LJN452 dose group, independent of how long LJN452 was 
administered. Only the planned dose groups will be used (10, 30, 60, 90, 140 and 200
µg), so that a subject will be placed in the lowest dose group with daily dose equal or 
greater to the maximum daily dose that the subject received for at least one day. 
2. If only placebo was administered to a subject in a LJN452 group, the subject will be 
placed in the placebo group.
3. If placebo was administered for a certain period to a subject in a LJN452 group, the 
subject will be placed in the respective LJN452 dose group. This refers in particular to 
subjects who took placebo erroneously for several days (e.g., 10 days) because they 
used capsules of a single bottle only instead of all three bottles.
4. If a higher than assigned dose of LJN452 was administered to a subject for at least 7 
days (or an unknown period), the subject will be placed in the higher dose group. 
Same applies, accordingly, to cases where various doses of LJN452 were erroneously 
administered to a subject.

If deviations from the assigned dose are unknown or cannot be derived from recorded 
data, the subject will be grouped into the assigned treatment arm. 
* excluding subjects who were mis-randomized and did not take investigational drug. Mis-
randomized subjects are those who were not qualified for randomization, but were inadvertently 
randomized into the study.
2.2.1
Subgroup of interest
The following subgroups of interest will be used for primary efficacy and safety analyses at the 
final analysis (subgroup analyses will be performed for the defined subgroup and its 
complement):

NASH diagnosis confirmed by historic biopsy results (definition in 5.3.7) (only for Part A 
and Part B analyses at respective reporting events)

BMI strata:
1. non-obese (<30 kg/m2 if Asian, < 35 kg/m2 if Non-Asian)
2. obese  (≥ 30 kg/m2 if Asian, ≥ 35 kg/m2 if Non-Asian).
Additional subgroups analyses may be performed to assess the specificity of the selection 
criteria for the studied NASH population (for example, in patients with a history of diabetes of 
at least 5 years, or in those with NASH based on an algorithm [Bazick et al. (2015)]). However, 
given the sample size of the study, such additional analyses will only be considered if the 
subgroups and their complements are of a relevant size (e.g., at least 30% of the total sample 
size). Furthermore, these are not required for Part C of the study.
Additional subgroup tables of key outcomes will be produced by race and/or geographical 
region/country (e.g., Japan / Non-Japan in Parts B and C), as required.
Stratified and subgroup analyses will be based on actual (derived) BMI from eCRF data, not 
BMI recorded in the IRT data, unless the required eCRF data are missing.


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2.3
Subject disposition, demographics and other baseline 
characteristics
Demographic variables and other baseline characteristics will be summarized for the FAS. In 
addition, all relevant medical history, and protocol solicited medical history will be summarized 
for the FAS. As protocol solicited medical history can be entered at both screening visits, only 
one value per subject resulting in Yes, No  or missing will be derived (Yes > No > missing).  
In addition to the baseline characteristics directly recorded in the eCRF or derived in the Oracle 
Clinical database, or loaded from third party databases, the following will be derived in the 
statistical database (see section 5.3 for derivation rules) and included in the summary of baseline 
characteristics:

Diabetes status

NAFLD fibrosis score

Fibrosis stage (biopsy based)

Fibrosis biomarker test

FIB-4

Diagnosis of NASH based on algorithm [Bazick et al. (2015)]

Age category (<65 years, ≥65years)
The summary of demographic variables and other baseline characteristics will be produced for 
Part A alone, Part B alone, Part C alone and all parts combined.
2.3.1
Subject 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, follow-up), and the reason for discontinuation will be 
presented for each treatment group and all subjects.
The frequency (%) of subjects with eCSR reportable protocol deviations as well as the criteria 
leading to exclusion from analysis sets will be presented in separate tables for the randomized 
set.
These summaries will be produced for Part A alone, Part B alone, and both parts combined.
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 drug – date of first administration of study drug + 1) / 7


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If a patient was randomized, but did not receive any dose of randomized double blind study 
medication (protocol deviation) then the exposure is set to 0. 
The duration of exposure to study drug (in weeks) will be summarized for the SAF, using  
descriptive statistics, and additionally by duration category in steps of “week”:

≥0 week- < 1 weeks

≥1 week- < 2 weeks

(…)

≥ 11 weeks - < 12 weeks

≥ 12 weeks - < 20 weeks

≥ 20 weeks - < 28 weeks

≥ 28 weeks - < 36 weeks

≥ 36 weeks - < 48 weeks

≥48 weeks
Note that 1-week intervals are only used up to 12 weeks. For Part C, this allows a summary in 
comparison to Parts A and B.
Furthermore, the proportion of subjects with dose reduction will be summarized for the SAF.
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 treatment and follow-up period (i.e., until end of study visit). 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). 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 study 
participation as well as significant non-drug therapies will be provided in separate tables.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The following are the primary variables and endpoints:
Safety (to be assessed in the SAF):

Occurrence of SAE

Occurrence of AE resulting in permanent discontinuation or dose reduction of study 
treatment


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
Occurrence of AE of special interest 
Efficacy (to be assessed in the FAS):

Change from baseline to Week 12 in ALT

Change from baseline to Week 12 in AST

Relative change from baseline to Week 12 of percentage of liver fat
2.5.2
Statistical hypothesis, model, and method of analysis
No confirmatory statistical hypothesis testing will be performed in this study. The methods to 
analyze the primary safety and efficacy variables are outlined in Table 2-1.
Table 2-1
Primary variables and methods of analysis
Variable
Method of analysis
Occurrence of  SAE
Summary table of absolute and relative 
frequency, overall and by preferred term 
Occurrence of AE resulting in discontinuation or 
dose reduction of study treatment
Summary table of absolute and relative 
frequency, overall and by preferred term
Occurrence of AE of special interest
Summary table of absolute and relative 
frequency, overall and by type of AE (risk 
definition as per SPP)
Change from baseline to Week 12 of ALT
Baseline adjusted mean estimates and  
pairwise differences from repeated measures 
ANCOVA; descriptive statistics; dose-response 
modelling
Change from baseline to Week 12 of AST
Baseline adjusted mean estimates and  
pairwise differences from repeated measures 
ANCOVA; descriptive statistics; dose-response 
modelling
Relative change from baseline to Week 12 in 
percentage of fat in the liver assessed using MRI
Baseline adjusted mean estimates and  pairwise 
differences from ANCOVA, descriptive statistics; 
dose-response modelling
Repeated measures ANCOVA models will include time (visit) and treatment group as 
categorical explanatory variables. The stratification factor (BMI group), geographical region 
and the baseline assessment will be included as covariates. At the Part A interim analysis, 
however, geographical region will not be included, due to the small sample size. BMI group 
may be dropped as well if necessary to obtain a model fit. The interaction terms of time with 
baseline assessment and treatment will be included as well. An unstructured covariance matrix 
will be assumed for the within subject repeated measurements, and Kenward-Rogers type 
degrees of freedom will be used. 95% confidence intervals will be calculated for treatment 
differences (without adjustment for multiple comparisons). Estimates will be derived for all 
time points up to Week 12. In Part A + B and A + B + C pooled analyses, as applicable, Week 
1 data (only available in Part A) will not be used in the model.
For ALT and AST, a multiple contrast test to confirm a general trend over placebo will be 
performed in addition. A one-sided p-value ≤ 0.05 will be considered as a confirmation of a 


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dose-response relationship, without adjustment for multiple comparisons (due to testing more 
than one parameter). Optimal contrast vectors will be derived from pre-specified alternative 
dose-response shapes, and estimates and covariance matrix at Week 12 will be obtained from 
the reperated measures model. For this purpose, a random effects model with a random intercept 
(subject as a random effect) and same fixed effects as mentioned above will be used, but no 
specification of covariance structure and degrees of freedom are required (to enable running it 
in R/lme4, alternatively nlme/gls equivalent to specification above, without using Kenward-
Roger adjustment if not available). In a second step, an averaged model will be fit to the data 
using a bootstrap procedure selecting the best model in each bootstrap sample based on Akaike 
Information Criterion (AIC). Estimates will be shown with 90% confidence intervals. A similar 
dose-response analysis will be performed for relative change from baseline to Week 12 of the 
percentage of liver fat. However, as there is only one post-baseline assessment, direct 
ANCOVA estimates will be used instead of the repeated measures estimates, which can be done 
in functions of the Dosefinding R package directly. 
Graphical displays will be used as appropriate and will be defined in the specification of Tables, 
Figures and Listings (TFL shells). These will include, but not necessarily be restricted to:

Line plots of ALT and AST mean change from baseline over time (estimates from 
repeated measures analysis)

Spaghetti plots of ALT and AST change from baseline over time

Individual subject profiles of liver enzymes over time (at least for Part A interim analysis)

Plot of posterior probability of superiority over placebo for a range of differences, with 
respect to ALT and AST change from baseline at Week 8 (for Part A interim analysis) and 
Week 12, assuming a flat prior (therefore based on the likelihood estimation from 
observed data only)
2.5.3
Handling of missing values/censoring/discontinuations
Missing data for the liver function tests in Table 2-1 will be accounted for by the use of repeated 
measures ANCOVA (MMRM), assuming data are missing at random (MAR). In case of dose 
reduction or treatment discontinuation, any ALT and AST assessments after reduction / 
discontinuation will be set to “missing” for all efficacy analyses.
The repeated measures ANCOVA for ALT and AST will additionally be run on all obtained 
assessments, including those taken after any dose reduction or discontinuation.
The missing data pattern will be explored graphically at the final analysis. Missing data, in this 
context, also refers to assessments that were set to missing as described above. If the exploration 
raises concerns about deviation from the MAR assumption, and/or the proportion of missing 
data is large (e.g., >10%), the possible impact will be discussed.
Missing data for liver fat will be imputed by the baseline value for the Week 12 analysis. No 
imputation will be applied for the final analysis in Part C, where a MMRM model is used. In 
case of treatment discontinuation, assessments obtained more than 4 weeks after last treatment 
will be set to “missing”.
In general, in summaries by nominal visit follow-up visits will be included as recorded, 
regardless to the time interval between last study treatment and follow-up visit.


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As there are no formal hypothesis tests and no confirmatory claims based on the results, no 
other alternative analyses are pre-planned.
2.5.4
Supportive analyses
Primary variables will also be summarized, using descriptive statistics, in the subgroups defined 
in 2.2.1. Primary efficacy variables will, in addition, be summarized for subjects who had a 
significant change of lifestyle during the study (diet, exercise), indicated by a weight loss of 
more than 10% from baseline to any post-baseline visit (versus subjects without such weight 
loss). These supportive analyses will only be included in the CSR as required, but will be part 
of graphical data exploration using, e.g., a ShinyApp.
Furthermore, primary efficacy variables will be analyzed excluding the subset of patients who 
have shown early spikes of ALT, defined as an increase from baseline by more than 100 U/L 
during the first two weeks after first administration of study drug (only applicable for Part A/B).
2.6
Analysis of the key secondary objective
There are no “key secondary” objectives defined in the protocol of this study. 
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
Table 2-2
Secondary efficacy variables and methods of analysis
Variable
Analysis
Absolute and relative change from baseline by 
visit in percentage of fat in the liver assessed 
using MRI
Baseline adjusted mean estimates and  pairwise 
differences from ANCOVA (repeated measures 
for Part C), descriptive statistics
Weight
BMI
Waist-to-hip (WTH) ratio
Descriptive statistics by visit, including change 
from baseline, pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA (weight and BMI) or simple ANCOVA 
(WTH ratio)
FGF19
C4
Descriptive statistics (statset2) by visit, including 
change from baseline, pairwise ratio versus 
placebo with 95% CI from ANCOVA (ratio post-
dose versus pre-dose (and versus baseline for 
C4) at week 6 back-transformed from log scale)
Liver stiffness (in kPa) by Fibroscan®
Enhanced liver fibrosis panel (ELF) score
Score of fibrosis biomarker test (originally known 
as Fibrotest®/ FibroSure®)
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from ANCOVA (repeated 
measures for Part C)
GGT
Descriptive statistics by visit (including change 
from baseline), pairwise differences versus 
placebo with 95% CI from repeated measures 
ANCOVA


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Variable
Analysis
Fasting lipids:
Total cholesterol
Trigylcerides
LDL and HDL cholesterol
LDL / HDL ratio
Free glycerol
Free fatty acids
Descriptive statistics (statset2) by visit 
(including %change and log transformed ratio to 
baseline), and pairwise ratio versus placebo with 
95% CI from repeated measures ANCOVA (ratio 
to baseline back transformed from log scale)
Additional covariate: use of lipid reducing 
concomitant medication (see 5.3).
At least a one point improvement in fibrosis
(NASH CRN staging) without worsening of 
steatohepatitis at Week 48 compared to baseline
Descriptive statistics (absolute and relative 
frequency), differences, odds ratio and relative 
risk reduction versus placebo with 95% CI
At least a two point improvement in fibrosis
(NASH CRN staging) without worsening of 
steatohepatitis at Week 48 compared to baseline
Descriptive statistics (absolute and relative 
frequency), differences, odds ratio and relative 
risk reduction versus placebo with 95% CI
Resolution of steatohepatitis without worsening of 
fibrosis (NASH CRN staging) at Week 48 
compared to baseline
Descriptive statistics (absolute and relative 
frequency), differences, odds ratio and relative 
risk reduction versus placebo with 95% CI
Change of NAS from baseline to Week 48
Descriptive statistics
2.7.2
Statistical hypothesis, model, and method of analysis
Methods of analysis are listed in Table 2-2. Summary tables will be presented by treatment 
group and visit (as applicable) using descriptive statistics. All efficacy variables will be 
analyzed in the FAS and assessments obtained after dose reduction will be included. 
Repeated measures ANCOVA will be performed as described in 2.5.2. Standard ANCOVA for 
change of liver fat will include baseline assessment and BMI stratification group as covariates, 
and treatment group as explanatory variable, with no interaction terms. Standard ANCOVA for 
ratio post-dose versus pre-dose at week 6 for FGF19 and C4 will include pre-dose assessment 
and stratification group as covariate and treatment group as explanatory variable, with no 
interaction terms. This analysis will be performed on log transformed data (ratio as well as pre-
dose) and resulting estimates will be transformed back to provide adjusted geometric mean and 
95% confidence intervals for the within-group and between-group estimates.
Binary biopsy based endpoints will be analyzed using logistic regression, including baseline 
fibrosis stage and BMI stratification group as covariates. See 5.3.11 for definitions.
Graphical displays will be used as appropriate and will be defined in the specification of Tables, 
Figures and Listings (TFL shells).
2.7.3
Handling of missing values/censoring/discontinuations
Missing data for the efficacy variables in Table 2-2 will be accounted for by the use of repeated 
measures ANCOVA (MMRM), as applicable, assuming data are missing at random (MAR). 
For variables with only one post-baseline assessment, a missing post-baseline value will be 
imputed by the baseline value. The same applies, correspondingly, to the pre-dose versus post-
dose analysis of FGF19 and C4.


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Missing follow-up biopsy results will not be imputed, so that the primary analysis of these 
parameters will only be based on subjects with valid paired biopsies who have received ≥24 
weeks of the assigned treatment.
In addition, the following supportive analyses addressing different estimands will be performed
for binary biopsy endpoints (response criteria):

Non-responder imputation: all binary variables based on biopsy results will be considered 
as “non-response” if the value is missing and NAS score will be imputed by the baseline 
score in case of missing follow-up biopsy.

Analysis corresponding to a hypothetical estimand: follow-up biopsy results for subjects 
who discontinue study treatment prematurely are discarded (set to missing), and missing 
results are imputed by multiple imputation (see 5.1.3.3).
2.8
Safety analyses
All safety analyses described in this section will be carried out using the Safety set (SAF). 
Patients will be analyzed according to the treatment they received.  
All safety listings will indicate the actual treatment the patient was on during the treatment 
period.
2.8.1
Adverse events (AEs)
Treatment emergent adverse events (TEAE), defined as events that started after the first dose 
of study drug or were present prior to the first dose of study drug but increased in severity based 
on preferred term, will be summarized. All AE with onset until 28 days after last dose of study 
drug are considered treatment emergent.
The summary tables for these TEAE will present, for each treatment group, the number and 
percentage of subjects having experienced:

any AE by primary system organ class (SOC) and preferred term (PT) (including “Any 
AE”),

any SAE by primary system organ class (SOC) and preferred term (PT) (including “Any 
SAE”),

any AE by preferred term (PT), which was reported in more than 5% of the subjects in any 
treatment group of Part B, or more than one subject in any of the treatment groups in Part 
A (can be produced manually for the CSR by cutting down the long table version)

any AE by Standardized MedDRA Query (SMQ) and preferred term

any AE belonging to Drug Related Hepatic Disorders – Comprehensive Search (SMQ) by 
preferred term

any AE by SOC, PT and maximum severity,

any AE possibly related to study treatment (investigator assessment) by SOC and PT

any AE resulting in dose reduction or discontinuation of study treatment by SOC and PT,

Incidence of potential cases of safety risks as defined in the safety profiling plan (SPP), 
including risks not based on AE records.


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If a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable.
To account for the longer duration of exposure to study treatment in Part C (48 weeks) compared 
to Parts A and B (12 weeks), exposure adjusted incidences for the types of events listed above 
will be presented additionally. The placebo groups from Parts A, B and C will be pooled for 
this type of analysis.
Summary reports will be based on the newest MedDRA version available at the time of 
generating the reports, the version will be specified in a footnote.
Listings will also be provided for SAEs that occurred in screening failures, and (by treatment 
group) for:

SAEs 

AEs causing study drug discontinuation 

AEs requiring dose adjustment or interruption 

AEs suspected to be drug-related

AEs defined as identified or potential risks
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, Part A, Part B and Part C combined) 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.
2.8.1.1
Adverse events of special interest / grouping of AEs
The number and percentage of subjects having experienced any event of special interest for 
LJN452 treatment will be summarized by class of identified or potential risk (as defined in the 
Safety Profiling Plan) and respective subcategories for each treatment group..


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Definitions can be found in 5.2. Only treatment emergent events, as defined in 2.8.1, will be 
considered.
For the evaluation of pruritus, the time to resolution of pruritus will be analyzed using Kaplan-
Meier analysis in subjects with pruritus. If the event has not yet resolved at the time of 
completion or the data extraction (for DMC and interim analysis) the observation will be 
censored at the End-of-study date/day or data cutoff date/day, respectively. Time to onset of 
pruritus will be analyzed with summary statistics in subjects with pruritus event. A pruritus 
event is defined as any event as defined in the respective eCRS category.
2.8.2
Deaths
The number and percentage of subjects who died will be summarized by primary cause of death 
for each treatment group.
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 subjects with both baseline and post baseline values. Relative and absolute 
frequencies of subjects with liver events as defined in 5.3.1 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.
For ALT and AST, the following summaries will be shown in addition, by treatment group:

Number and percentage of subjects with spikes (increase from baseline by more than 100 
U/L) during the first two weeks after first administration of study drug.

Maximum post-baseline value of each subject, in terms of change from baseline and 
multiple of upper limit of normal range.

In subjects with ALT spikes, number and percentage of subjects unresolved and resolved 
with or without intervention at end of study.

In subjects with ALT spikes, summary statistics for time to resolution of spikes (resolution 
defined as ≤ baseline + 25 U/L).
The summaries for ALT and AST spikes will not be produced for Part C of the study, but the 
“spike” flag will still be derived and included in the analysis datasets.
Safety laboratory parameters which are also part of the efficacy analyses will be included in the 
safety tables, too (enzymes, lipids, glucose). All available data will be used for safety summaries.
For visits belonging to the treatment period in Part C (i.e., up to Week 48), assessments after 
discontinuation of study treatment will not be included in the summaries. Follow-up visits, 
however, will be included as reported, regardless of time interval between last study treatment 
and follow-up.


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The number and percentage of subjects with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory results, for those parameters where ranges are 
available, are presented in 5.3.1. The most extreme post-dose value will be considered. Only 
subjects with laboratory results at baseline and post-baseline from the central laboratory will be 
included in the tabulations.
In addition to summary tables, a listing of subjects with any treatment emergent notable lab 
results,  defined as results obtained in the treatment period, will be provided by treatment group 
and subject number, along with their values at all visits, including repeated, unscheduled and 
follow-up lab values. In the listing, all abnormal values outside of normal range and notable 
values will be flagged, e.g., L/H for a value being below/above normal range, LN/HN for a 
value being in notable low/high range. Laboratory “Visit dates” from the visit panel on eCRF 
will not be listed, instead laboratory listings will present the date and day of the sample 
collection (obtained directly from lab panel). Comprehensive subject listings of all laboratory 
assessments (i.e., a data dump) will not be produced for the CSR.
Results from urine dipstick and routine urinalysis with Reflex Micro will not be reported in 
CSR outputs, but will be included in analysis datasets.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
ECG data will be summarized by treatment and visit. No cardiac imaging will be performed.
Notable QTc values and change from baseline will be summarized. A notable value is defined 
as a QTc interval of greater than 450 ms. The categories used for the change (increase) in QTc 
are - less than 30 ms, 30 to 60 ms and greater than 60 ms.
The Fridericia QT correction formula (QTcF) will be used for clinical decisions.
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 and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Subjects with notable vital signs as defined in 5.3.9
will be listed.
2.9
Pharmacokinetic endpoints  
All subjects with valid PK data will be included in the pharmacokinetic (PK) data analysis.  
Plasma concentrations will be expressed in ng/mL.  LJN452 plasma concentration data will be 
listed by part, cohort, treatment group, subject, and visit/sampling time point. Descriptive 
summary statistics will be provided by part, cohort, treatment group and visit/sampling time 
point. Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic 
and geometric), median, minimum and maximum. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the Limit of Quantification (LLOQ) will be treated as zero in summary 


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statistics for concentration data only, and summary tables will also show the number and 
percentage of such values.
Any other PK analyses will be described in a separate report (e.g. a CSR addendum). For 
instance, a population PK modeling approach will be used to predict exposure. PK data from 
study CLJN452X2101 in healthy subjects will be used to build the PK model. Subsequently, a 
population PK model for PK data from this study (CLJN452A2202) will be established. If 
necessary, the combined data sets from the two studies will be used. Once an adequate model 
is established, to be verified by applying various model diagnostics tools, the exposure within 
a dosing interval will be calculated for each subject. 
2.10
PD and PK/PD analyses
All subjects with valid PK and PD data will be included in the data analysis. 
 
 
 
 
Correlation between PD markers (FGF19, C4) and efficacy markers (ALT, GGT, fibrosis 
markers) will also be explored graphically (not necessarily to be included in the CSR Appendix).
 
2.11
Patient-reported outcomes
The impact of LJN452 on various aspects of patient’s health status will be assessed by the 
following patient reported outcome (PRO) tools:

VAS for Itch
Table 2-3
Patient reported outcome tools and methods of analysis
Variable
Method of analysis
VAS for Itch
Descriptive statistics by visit (including change from baseline), pairwise 
differences versus placebo with 95% CI from repeated measures ANCOVA
 
 


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Variable
Method of analysis
 
 
 
 
Summary tables will be presented by treatment group and visit (as applicable) using descriptive 
statistics. All PRO variables will be analyzed in the FAS and assessments obtained after dose 
reduction will be included. With the exception of the VAS for Itch 
, PRO tools are 
only used in Part B and C of the study and therefore only Part B and C treatment groups will be 
displayed in the corresponding analyses.
 
 
 
Repeated measures ANCOVA will be performed as described in 2.5.2.


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2.14
Interim analysis
An interim analysis will be conducted when ≥90% of the subjects in Part A have completed the 
Week 8 assessments. The analysis will, however, include all data available at the resulting data 
cutoff point. An independent DMC will review the safety profile and primary efficacy variables. 
Estimates for the efficacy variables (ALT, AST and GGT) will also include time points beyond 
Week 8 (using a repeated measures ANCOVA).
The following analyses will be performed:

Demographic & background characteristics: as in 2.3

Subject disposition: as in 2.3.1

Duration of exposure to study drug, by treatment: as in 2.4.1

ALT, AST and GGT over time: summary statistics by visit and treatment group, estimates 
of difference versus placebo in each group using a repeated measures model (as described 
in 2.5.2), dose-response testing and modelling for ALT change from baseline at Week 8 
and Week 12

Change from baseline in % hepatic fat at Week 12: summary statistics by treatment group 
(only for subjects with available data), and individual subject profiles

Adverse events: as in 2.8.1 (including 2.8.1.1 and 2.8.2)

Newly occurring or worsening notably abnormal laboratory values: as described in 2.8.3

Urinalysis: as described in 2.8.3

Vital signs: as in 2.8.4.2

Pharmacokinetic data (listings of individual concentrations and predicted exposure as 
available)

Individual lipid profiles over time

Summary statistics for FGF19, C4, 
if data are 
available
Interim data analysis will be performed by an independent statistician and programmer, using 
unblinded treatment group information, and provided to the DMC.  
Based on the results of the IA, the DMC will make recommendations on the treatment groups 
to be studied in Part B of the study. There are no strict quantitative rules for the DMC decision 
and no hypothesis tests. In brief, the DMC will determine which doses in Part A are safe, and 
among the safe doses, which are efficacious based on biomarker results (primarily ALT and 
AST). 
A benchmark for biomarker response is a decrease from baseline of at least 27 U/L for ALT 
(mean displayed in [Neuschwander-Tetri et al (2015) ] for obeticholic acid at week 12). Target 
thresholds for desired biomarker response and further guidance may be provided in the DMC 
charter.
Up to two of the doses are planned to be selected for Part B. In the event that the DMC selects 
only one active dose (safe and efficacious) to be tested in 75 subjects in Part B, one of the other 


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originally planned active treatment arms (highest safe but inefficacious dose) will continue with 
a smaller sample size (20 subjects) to confirm the earlier findings of this treatment arm observed 
in Part A.  If only one dose is deemed safe then only one experimental group will be studied in 
Part B.
If none of the doses is considered safe, or no sufficient efficacy is observed with safe doses, 
Part B may not be initiated. As there are no formal hypothesis test, an adjustment of the type I 
error is not necessary to account for this interim analysis.
A second interim analysis (End-of-Part A analysis) will be performed when all subjects of Part 
A have completed the Week 16 visit, including only the subjects randomized to Part A. This 
analysis will not be performed by an independent team. However, as Part A and Part B cohorts 
use separate sections of the randomization list, only Part A treatment allocation information 
will be made available to the statisticians and programmers at this stage. The analyses 
performed will be a subset of the analyses planned for the final CSR and will be defined in a 
separate tracking sheet. 
In addition, the DMC will review safety, including AEs and laboratory parameters as decribed 
above, on a regular basis after start of Part B. The independent statistician and programmer will 
prepare these  safety reports using semi-blinded treatment group information.
The standard tables and listings produced for safety DMC reviews are a subset of the final CSR 
tables and listings and are listed in the DMC charter. They will also be identified in the TFL 
shell documentation.
A full analysis of Part A and B data will be performed when all subjects of Part B have 
completed the Week 16 visit, including all subjects randomized to Part B, but not any data from 
subjects randomized to Part C. Therefore, Part C will remain blinded at this stage (process as 
described above for the End-of-Part A analysis). 
An additional interim analysis will be conducted when all patients randomized into Part C have 
completed the Week 12 visit. The scope of this analysis will be similar to the analysis at end of 
Part A. The analysis will be performed by the regular study team, which will be unblinded to 
Part C treatment allocation at this stage. Investigators, site personnel and study subjects will 
remain blinded until completion of the study.
3
Sample size calculation
The primary objective of the study is to determine a safe dose or dose range. 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 practicability with 
respect to expected speed of enrolment and duration of the study, not on formal statistical 
criteria.
3.1.1
Power considerations with given sample size for safety assessment
Events with a true incidence of 30% and above are observed with almost 100% probability in 
samples of 15 (Part A), 40 (combined Part A+B placebo) and 90 (combined Part A+B active 
dose) patients. This would include, for example, the isolated ALT elevations observed at high 
doses in healthy volunteers. Events with true incidences below 10% down to 3% are still very 


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likely to be observed in combined sample sizes from Parts A and B, and also in each dose in 
Part C , while events are observed with less than 50% probability in Part A if the true incidence 
is less than about 4% (Figure 3-1). It is noteworthy, however, that a single patient constitutes 
6.7% in a sample of 15.
Figure 3-1
Binomial probability to observe an event with given sample size
IIn the interim analysis, predictions of the probability of an event (incidence) will be based on 
the observed number of events, to support the decision to continue or drop a dose for Part B.
Probabilities of the incidence being below a certain threshold are plotted in Figure 3-2 for a 
sample size of 15 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
For example, if 0 events are observed, the probability that the incidence is ≤ 5% would be 87%. 
If an event is observed in one patient, the probability that the incidence is ≤ 5% would be 38%. 
Similarly, if an event is observed in 5 patients (one third), the probability that the incidence is 
≤ 50% would be 90%, but the probability that the incidence is ≤ 30% would be 39% (calculated 
using R function pbeta).
3.1.2
Power considerations with given sample size for efficacy assessment
A consideration for primary efficacy analyses is given in the following.
[Neuschwander-Tetri et al (2015) ] reported a mean change of ALT from baseline to week 12 
of -28 for obeticholic acid (OCA) and -11 for placebo, with standard deviations of 48 and 33, 
respectively. Assuming for simplicity a common standard deviation of 45, this translates into 
an effect size (mean difference / standard deviation) of approximately 0.38, which can be 
considered as a benchmark. The power for a t-test to compare two groups (1-sided type I error 
0.05) based on such an effect size would be 63% (59%) with a sample size of 90 (50) in the 
active and 40 (50) in the placebo group. If the active dose were slightly better than OCA (-33 
versus -11), the power would be 81% (78%) Numbers in parentheses refer to comparisons in 
Part C with 50 subjects in the active arm(s) and 50 in the placebo arm where no pooling with 
subjects in the placebo arms of Parts A and B is considered (calculations with NQuery Advisor 


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7.0). Based on pre-clinical data for LJN452 and OCA, it is expected that the effect size achieved 
with an optimal dose of LJN452 maybe even larger, therefore resulting in a power above 80%. 
For relative reduction of liver fat, no data are available for OCA. In the Novartis sponsored 
study CLCQ908A2216 in patients with NAFLD, with a baseline percentage of approximately 
16%, the relative decrease after 12 weeks of treatment was about 2% in the placebo group and 
21% in the highest active dose group, with a common standard deviation of approximately 30, 
resulting in an effect size of 0.63. If we assume a slightly smaller effect size of at least 0.5 for 
a LJN452A dose in the NASH study population, a power of ≥83% (79%) is achieved for 
pairwise comparisons with assumptions as described above.    
Alternatively, we can consider the power of a multiple contrast test to demonstrate a trend over 
placebo across multiple dose arms, in this case 10 µg, 30 µg, 60 µg, 90 µg, 140 µg and 200 µg. 
We assume the dose-response curves in Figure 3-3. A beta shape is included as a possibility 
because the ALT elevations that may occur with high doses could, on average, interfere with 
the desired effect of ALT decrease.
Figure 3-3
Potential dose-response curves
  


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Table 3-1
Power for multiple contrast test for trend over placebo 
Sample size in  Doses (µg)
Power for model (%)
0
10
30
60
90
140
200
Emax 
Linear 
Beta
Logistic
Average
90
15
15
35
90
50
50
82 (98)
75 (89)
83 (96)
85 (99)
81 (95)
Contrasts for multiple contrast test are optimal for each model type and sample size; assumptions: placebo 
response: -11, maximal response: -28 (in brackets: -33), common standard deviation: 45, type I error: 0.05 (one-
sided);
Only Part B and C sample sizes after DMC recommendation were considered.
The average power for this type of test is at least 81% for a pooled Week 12 analysis of all 
study parts:

50 subjects assigned to two doses (140 and 200 µg) and 50 to placebo in Part C,
An average power of ≥ 95% is achieved if the effect size is moderately better than that of OCA
(Table 3-4, calculations using powMCT function of DoseFinding package in R). Power 
calculations for a multiple contrast test on relative reduction of liver fat were not performed, 
but are expected to be in a similar range based on the effect size considerations above.
As the first interim analysis will be conducted with only 13-15 patients per arm who have 
completed the Week 8 assessments, the power to compare the effect on ALT or AST reduction 
between groups will be considerably lower. Furthermore, only a certain percentage of the 
patients will have data up to Week 12 available at that time point, depending on the speed of 
enrollment. The assessment of efficacious doses in the interim analysis will therefore be 
primarily based on the relative size of the point estimates (mean changes) and the shapes of the 
curves over time for the liver enzymes in each group.
3.1.3
Power consideration for biopsy endpoints in Part C
The longer treatment duration in Part C is due to the DMC recommendation to include paired 
biopsy assessments. Therefore, the sample size in Part C is partly based on the following 
assumptions for biopsy based outcomes:

Response parameter: Achievement of at least one stage improvement of fibrosis with no 
worsening of steatohepatitis at Week 48 compared to baseline (binary).

Placebo response rate: 13%, based on interpolated results from [Neuschwander-Tetri et al 
(2015)]. This assumes a linear improvement over time (a placebo rate of 19% was 
reported at week 72).

Tropifexor response rate: 37% (best case assumption) with at least one of the doses.
For a 2-group continuity corrected χ2 test of proportions with type error 0.05 (1-sided, no 
adjustment for multiple comparisons), a sample size of 50 per group results in a power of 82% 
(nQuery Advisor 7.0). The actual power might be smaller due to missing follow-up biopsies.
4
Change to protocol specified analyses
No relevant changes from protocol specified analyses were made.


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5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The date of the end-of-treatment visit (EOT, Week 12) will be used if the date of last 
adminstration  of study drug 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)
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


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(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. 
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


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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 
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.


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5.1.3.3
Multiple imputation of missing biopsy outcomes
A multiple imputation approach will be applied to missing follow-up biopsies in a supportive 
analysis. It is assumed that biopsy results are missing at random (MAR). Available results for 
subjects who discontinued study drug prior to 24 weeks of exposure (but still have a biopsy 
read-out) are also 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 variables) and the baseline 
NAS score (continuous variable). 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 same logistic model is used to analyze the multiple imputed 
datasets, and pooled results are obtained based on Rubin’s combination rules. The
implementation can be done in SAS procedures MI (FCS LOGISTIC statement) and 
MIANALYZE. It is suggested to use 50 imputations.
5.1.3.4
Other imputations
Not applicable.
5.2
AEs coding/grading
AEs are coded using the MedDRA dictionary.
AE severity is classified using CTC grades if available. Grades represent 1=mild, 2=moderate, 
3=severe, 4=life-threatening. If CTC grades are not available, these respective categories are 
collected in the eCRF.
AEs of special interest
AEs of special interest are those classified as identified or potential risks in the Safety Profiling 
Plan. In addition to risks based on AE terms, the following risks will also be tabulated at least 
for the final CSR (criteria to be defined in eCRS or separate document; list may be updated 
without amending this SAP):

QTc prolongation

Liver injury (lab data)

Effects on lipid parameters (lab data)

Increased ALT (lab test only) 

Renal effects (effects on renal function,) (lab data)
5.3
Derivations
5.3.1
Laboratory parameters
Liver events defined by laboratory parameter abnormalities (additional non-lab criteria as 
provided in the protocol are ignored):

ALT or AST > 5 × ULN

ALP > 2 × ULN


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
TBL > 2 × ULN

ALT or AST > 3 × ULN and INR > 1.5

ALT or AST > 3 × ULN and TBL > 2 × ULN AND ALP to ≤ 2 × ULN (Potential Hy’s 
Law cases)

ALT or AST > 3 × ULN
Criteria for other laboratory parameters:
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
5.3.3
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®
The score is calculated as:


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z = 4.467 × log10(α2-macroglobulin) − 1.357 × log10(Haptoglobin) + 1.017 × log10(GGT ) + 
0.0281 × Age + 1.737 × log10(Bilirubin) − 1.184 × ApoA1 + 0.301 × Sex (0=female, 1=male) 
−5.540.
Where:
α2-macroglobulin is given in g/L,
Haptoglobin is given in g/L,
GGT is given in U/L,
Age (at baseline) is given in years,
Bilirubin is given in µmol/L,
ApoA1 is given in g/L,
Sex is given as 0 for female and 1 for male.
Reference: [http://www.google.com/patents/US6631330]
5.3.6
Derived baseline characteristics
5.3.6.1
Diabetes
The diabetes status at baseline is determined as follows:
Diabetes = Yes if:

Type 1 diabetes mellitus is ticked “Yes” in Protocol Solicited Medical History OR

Type 2 diabetes mellitus is ticked “Yes” in Protocol Solicited Medical History OR

Baseline fasting glucose > 5.6 mmol/L (100 mg/dL).
Otherwise Diabetes = No.
5.3.6.2
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.  


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5.3.7
NASH diagnosis by historical biopsy
Diagnosis of NASH by historical biopsy (as opposed to phenotypic NASH) is determined by 
all of the following:

Liver biopsy CRF page with date of assessment 2 years or less before randomization date,

Fibrosis stage not indicating cirrhosis:
Batts-Ludwig score not 4,
Ishak score not F6,
Knodell score not 4,
Metavir score not 4,
Kleiner-Brunt score not 4

Diagnosis “NASH” in the liver biopsy CRF page.
5.3.8
Disease scores and diagnostic algorithms 
5.3.8.1
NAFLD fibrosis score
The NAFLD fibrosis score is calculated as [Angulo et al. (2007)]:
z = -1.675 + 0.037 * age + 0.094 * BMI + 1.13 * diabetes (0=no, 1=yes)  + 0.99 * (AST/ALT) 
– 0.013 * platelets – 0.66 * albumin,
where age is given in years, BMI in kg/m2, platelets in 109/L, albumin in g/dL, and age and 
diabetes (see 5.3.6.1) are referring to the baseline condition.
5.3.8.2
Algorithm for diagnosis of NASH
A diagnostic algorithm was developed by [Bazick et al. (2015)]:
Logit(P) = 27.00 + 0.106 * BMI (kg/m2) – 0.035 * waist (cm) + 0.068 * AST (U/L) – 0.016 * 
ALT (U/L) + 0.71 * albumin (g/dL) + 0.24 * HbA1c (%) + 0.0570 *  
 
 + 0.0014 * ferritin (ng/dL) + 0.57 * white (0=no, 1=yes).
A subject is classified as having NASH if the calculated probability P is ≥ 0.77.


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5.3.10
Vital signs
Table 5-2
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
5.3.11
Definitions for biopsy based endpoints
5.3.11.1 Improvement of fibrosis compared to baseline
The determination of fibrosis improvement will be based on NASH CRN staging. Only main 
stages (0, 1, 2, 3, 4) will be considered. For example, a change from 1c to 1b or 1a will not be 
counted as a one point change.
Table 5-3
Fibrosis stages and possible outcomes
Baseline
Week 48
1 point improvement
2 point improvement
2
0
Yes
Yes


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Baseline
Week 48
1 point improvement
2 point improvement
2
1
Yes
No
2
≥2
No
No
3
≤1
Yes
Yes
3
2
Yes
No
3
≥3
No
No
5.3.11.2 Worsening of steatohepatitis at Week 48 compared to baseline:
Several outcome variables will be derived to allow comparison with published data:

Total NAS Score at Week 48 greater than at Baseline

Any component score (Steatosis, Lobular inflammation or Hepatocyte ballooning) at 
Week 48 greater than at Baseline (definition in FDA draft guidance) – used for primary 
estimand

Any component score of Lobular inflammation or Hepatocyte ballooning at Week 48 
greater than at Baseline OR component score of Steatosis at Week 48 more than 1 point 
greater than at Baseline (definition in EMA reflection paper)
5.3.11.3 Resolution of steatohepatitis at Week 48 compared to baseline
Several outcome variables will be derived to allow comparison with published data:
Subjective definition:

Resolution of steatohepatitis will be determined as diagnostic category "not NAFLD" or 
"NAFLD, not NASH" as provided in the central biopsy report.
Based on NAS:

Lobular inflammation ≤1 AND Hepatocyte ballooning = 0 AND any value for steatosis 
(definition in FDA draft guidance as well as EMA reflection paper) – used for primary 
estimand

Lobular inflammation ≤1 AND Hepatocyte ballooning ≤1 AND any value for steatosis 
(Novartis proposal to account for noise in assessment of balloning)
5.4
Statistical models
5.4.1
Primary analysis
There is no formal hypothesis testing in this exploratory study.
Repeated measures models for continuous dependent variables will be analyzed using SAS 
PROC MIXED, assuming an unstructured covariance matrix and Kenward-Roger type degrees 
of freedom.
The general model for the response vector of patient i = 1,...,n,  = (	
, … , 	)′ , is:
~(, )


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where  , are stochastically independent, (, ) denotes the d-dimensional Normal 
distribution and
	
, … , 	 are repeated measures in time

 × -matrix of covariates

p-dimensional vector of parameters

 × -covariance matrix 
The covariates are treatment (categorical), visit (categorical), the baseline value of the response 
variable, and the interactions between treatment and visit and baseline value and visit. In 
addition, the stratification factor (BMI group) and geographical region will be included as 
categorical covariates.
Estimates of the treatment effect within groups and differences between groups will be obtained 
using the LSMEANS and ESTIMATE statements, respectively, for individual time points. 95% 
confidence intervals will be calculated.
Model assumptions will be checked based on diagnostic plots, but as there are no formal 
hypothesis tests, the possible impact of questionable models will only be described.
The multiple contrast test to confirm a general trend over placebo for ALT and AST changes 
from baseline to week 12 will be performed using the R package “DoseFinding” according to 
the following approach:
1. Fit a MMRM model for the response as decribed above (using SAS PROC MIXED), or 
alternatively a random intercept model with fixed effects as above and subject as random 
factor, using R/lme4 or nlme (specification of covariance structure of the R matrix and 
Kenward-Roger adjustment of degrees of freedom are not important for this purpose).
2. Extract estimates and variance-covariance matrix at Week 12 from fitted model.
3. Perform multiple contrast test with pre-defined model types and optimal contrasts, using 
weights according to the sample sizes of each group (MCTtest function).
4. Draw bootstrap samples (at least 1000) and fit each of the pre-defined models to the 
data in each sample. Select the model with the best fit based on AIC and predict the 
dose-response curve with this model in each sample.
5. Derive median and other quantiles for predicted response over the dose range from the 
bootstrap samples. This will result in an averaged model.
The pre-defined model types corresponding to the contrast vectors are:

Emax model f(d, θ)=E0+Emax*d/(ED50 + d) with ED50 = 10

Linear model f(d, θ)=E0+δ*d

Beta model f(d, θ)=E0+Emax*B(δ1, δ2)*(d/scal)^ δ1*(1-d/scal)^ δ2 with δ1 = 0.9, δ2 = 
0.9

Logistic model f(d, θ)=E0+Emax/(1+exp((ED50-d)/δ)) with ED50 = 40 and δ = 10
The shapes of these models are displayed in Figure 3-3. 


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In brief, for each candidate model a contrast test statistic, based on a linear combination of the 
treatment estimates per dose will be derived. The contrast coefficients will be chosen to 
maximize the power to detect the pre-specified candidate models. The global test decision is 
based on the maximum of the contrast test statistics. A critical value q controlling the type I 
error rate can be derived from the fact that the four test statistics approximately follow a 
multivariate normal distribution and the distribution of the maximum of a multivariate normal 
distribution. If the maximum contrast test statistic exceeds the critical value q, the overall null 
hypothesis of a constant dose-response curve is rejected. In practice, a one-sided p-value ≤ 0.05 
will be considered as a confirmation of a dose-response relationship. See [Pinheiro et al (2006)].
5.4.2
Key secondary analysis
There are no “key secondary” objectives defined in the protocol of this study. For repeated 
measures models used in other secondary analyses, see 5.4.1.
5.5
Rule of exclusion criteria of analysis sets 
Table 5-4
Protocol deviations and other conditions that cause subjects to be 
excluded
Deviation ID
Description of Deviation
Exclusion from
OTH12
Patient was rescreened but did not sign a new ICF
All analysis sets
OTH14
ICH-GCP non-compliance of study site with impact on data 
quality
All analysis sets
TRT04
No drug taken after randomization
SAF
ICF not signed
All analysis sets
5.6
Other statistical aspects
5.6.1
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 100*(1-α)% confidence interval
For an investigational drug group with n1 patients at risk, independent from placebo with n0
patients at risk, of whom x1 and x0 experience a certain event with probability π1 and π0
respectively, the odds ratio is estimated as
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p


  with p1= x1/n1 and p0=x0/n0.  A conditional exact 100*(1-α)% confidence interval 
will be obtained by using the SAS procedure PROC FREQ with statement EXACT OR.
Risk difference and 100*(1-α)% confidence interval
For an investigational drug group with n1 patients at risk, independent from placebo with n0
patients at risk, of whom x1 and x0 experience a certain event, the risk difference is estimated 


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as p1-p0 with p1= x1/n1 and p0=x0/n0. 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.
Geometric mean and coefficient of variation
The geometric mean 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
References
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that 
identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45:846-54.
Bazick J, Donithan M, Neuschwander-Tetri BA, et al. Clinical Model for NASH and Advanced 
Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD. 
Diabetes Care 2015; 38:1347-55.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet 2015; 385(9972):956-65.
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies combining 
multiple comparisons and modeling procedures. J Biopharm Stat 2006; 16:639-56.