Clinical trial NCT04065841
Conditions: Non Alcoholic Steatohepatitis (NASH)
Keywords: NASH Non alcoholic steatohepatitis Tropifexor LJN452 Licogliflozin LIK066 Placebo
Sponsor: Novartis Pharmaceuticals
Start date: 2019-12-30; Completion date: 2022-10-27
Enrollment: 234 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor \& licogliflozin combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

Detailed description:
The study consisted of 1) a screening period, 2) a treatment period starting from randomization on Day 0 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of study treatment. The study duration from first dose of study medication was 52 weeks.

Arms: arm 1: Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally arm 2: Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally arm 3: Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally arm 4: Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily
Interventions: intervention 1: Tropifexor intervention 2: Licogliflozin intervention 3: Placebo
Intervention descriptions: intervention 1: 100mcg+30mcg+10mcg capsules of tropifexor taken orally every day until the 140 mcg capsule of tropifexor taken orally every day is produced, then patients will switch to the single 140mcg capsule taken orally every day intervention 2: 30mg tablet of licoglifozin taken orally every day intervention 3: licogliflozin placebo + tropifexor placebo

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
LJN452/LIK066 
Clinical Trial Protocol CLJN452D12201C / NCT04065841
A randomized, double-blind, parallel-group, multicenter 
study to assess efficacy, safety, and tolerability of oral 
tropifexor (LJN452) & licogliflozin (LIK066) combination 
therapy and each monotherapy, compared with placebo for 
treatment of adult participants with nonalcoholic 
steatohepatitis (NASH) and liver fibrosis (ELIVATE) 
Property of Novartis Pharma AG 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2019-002324-32 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
IIb 
Release date: 
30-Apr-2021


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 02 (30-Apr-2021) .......................................................................................... 15 
Summary of Previous Amendments .................................................................................. 26 
Amendment 01 (18-Sep-2020) .......................................................................................... 26 
Protocol summary .............................................................................................................. 48 
1 
Introduction ....................................................................................................................... 52 
1.1 
Background ............................................................................................................ 52 
1.1.1 
Non Alcoholic Steatohepatitis (NASH) ................................................ 52 
1.1.2 
Farnesoid X Nuclear Receptor (FXR)................................................... 52 
1.1.3 
Tropifexor ............................................................................................. 53 
1.1.4 
Licogliflozin .......................................................................................... 55 
1.1.5 
Biological rationale for the combination of tropifexor and 
licogliflozin ........................................................................................... 56 
1.1.6 
Drug interactions ................................................................................... 56 
1.1.7 
Toxicology of tropifexor ....................................................................... 58 
1.1.8 
Toxicology of licogliflozin ................................................................... 59 
1.1.9 
Toxicology of the combination ............................................................. 60 
1.1.10 
Rationale for testing the combination of tropifexor and licogliflozin... 60 
1.2 
Purpose .................................................................................................................. 61 
2 
Objectives, endpoints and estimands ................................................................................. 61 
2.1 
Primary estimands ................................................................................................. 63 
3 
Study design ...................................................................................................................... 65 
4 
Rationale ............................................................................................................................ 66 
4.1 
Rationale for study design ..................................................................................... 66 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 67 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 67 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 68 
4.5 
Risks and benefits .................................................................................................. 68 
4.5.1 
Tropifexor ............................................................................................. 68 
4.5.2 
Licogliflozin .......................................................................................... 69 


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4.5.3 
Study conduct ........................................................................................ 71 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 71 
5 
Study Population ............................................................................................................... 71 
5.1 
Inclusion criteria .................................................................................................... 72 
5.2 
Exclusion criteria ................................................................................................... 72 
6 
Treatment ........................................................................................................................... 76 
6.1 
Study treatment ...................................................................................................... 76 
6.1.1 
Investigational and control drugs .......................................................... 76 
6.1.2 
Additional study treatments .................................................................. 76 
6.1.3 
Treatment arms/group ........................................................................... 77 
6.1.4 
Treatment duration ................................................................................ 77 
6.2 
Other treatment(s) .................................................................................................. 78 
6.2.1 
Concomitant therapy ............................................................................. 78 
6.2.2 
Prohibited medication ........................................................................... 79 
6.3 
Participant numbering, treatment assignment, randomization .............................. 81 
6.3.1 
Participant numbering ........................................................................... 81 
6.3.2 
Treatment assignment, randomization .................................................. 81 
6.3.3 
Stratification .......................................................................................... 82 
6.4 
Treatment blinding ................................................................................................. 82 
6.5 
Dose escalation and dose modification .................................................................. 83 
6.5.1 
Dose escalation guidelines .................................................................... 83 
6.5.2 
Definitions of dose limiting toxicities (DLTs) ...................................... 83 
6.5.3 
Dose modifications ................................................................................ 83 
6.5.4 
Follow-up for toxicities ......................................................................... 84 
6.6 
Additional treatment guidance ............................................................................... 84 
6.6.1 
Treatment compliance ........................................................................... 84 
6.6.2 
Emergency breaking of assigned treatment code .................................. 84 
6.7 
Preparation and dispensation ................................................................................. 85 
6.7.1 
Handling of study treatment and additional treatment .......................... 86 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 86 
7 
Informed consent procedures ............................................................................................ 90 
8 
Visit schedule and assessments ......................................................................................... 91 
8.1 
Screening ............................................................................................................. 100 
8.1.1 
Pre-screening ....................................................................................... 100 
8.1.2 
Information to be collected on screening failures ............................... 100 
8.2 
Participant demographics/other Baseline characteristics ..................................... 101 
8.2.1 
Screening visit 2 – additional assessments.......................................... 101 


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8.2.2 
Demographic Information ................................................................... 101 
8.2.3 
Medical History ................................................................................... 101 
8.2.4 
Alcohol history and assessments ......................................................... 102 
8.2.5 
Smoking history .................................................................................. 102 
8.2.6 
Prior and concomitant medications ..................................................... 102 
8.2.7 
Treatment exposure and compliance ................................................... 102 
8.3 
Efficacy ................................................................................................................ 102 
8.3.1 
Efficacy assessments ........................................................................... 102 
8.3.2 
Appropriateness of efficacy assessments ............................................ 107 
8.4 
Safety and Tolerability ........................................................................................ 107 
8.4.1 
Assessments & Specifications ............................................................. 107 
8.4.2 
Laboratory evaluations ........................................................................ 108 
8.4.3 
Pregnancy and assessments of fertility ............................................... 111 
8.4.4 
Other safety evaluations ...................................................................... 112 
8.4.5 
Appropriateness of safety measurements ............................................ 113 
 
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9 
Discontinuation and completion ...................................................................................... 117 
9.1 
Discontinuation from study treatment and from study ........................................ 117 
9.1.1 
Discontinuation from study treatment ................................................. 117 
9.1.2 
Discontinuation from study ................................................................. 118 
9.1.3 
Lost to follow up ................................................................................. 118 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ..... 119 
9.3 
Study completion and post-study treatment ........................................................ 119 
9.4 
Early study termination by the sponsor ............................................................... 120 
10 Safety monitoring, reporting and committees ................................................................. 120 
10.1 
Definition of adverse events and reporting requirements .................................... 120 
10.1.1 
Adverse events .................................................................................... 120 
10.1.2 
Serious adverse events ........................................................................ 122 
10.1.3 
SAE reporting...................................................................................... 123 
10.1.4 
Pregnancy reporting ............................................................................ 125 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 125 
10.2 
Additional Safety Monitoring .............................................................................. 126 
10.2.1 
Liver safety monitoring ....................................................................... 126 
10.2.2 
Renal safety monitoring ...................................................................... 127 


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10.2.3 
Adverse events of special interest ....................................................... 127 
10.3 
Committees .......................................................................................................... 130 
10.3.1 
Data Monitoring Committee ............................................................... 130 
11 Data Collection and Database management .................................................................... 130 
11.1 
Data collection ..................................................................................................... 130 
11.2 
Database management and quality control .......................................................... 130 
11.3 
Site monitoring .................................................................................................... 131 
12 Data analysis and statistical methods .............................................................................. 132 
12.1 
Analysis sets ........................................................................................................ 132 
12.2 
Participant demographics and other baseline characteristics ............................... 133 
12.3 
Treatments ........................................................................................................... 133 
12.4 
Analysis of the primary endpoint(s)/estimand(s) ................................................ 133 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ................................... 135 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 135 
12.4.3 
Handling of remaining intercurrent events of primary estimand ........ 138 
12.4.4 
Handling of missing values not related to intercurrent events ............ 139 
12.4.5 
Sensitivity analyses for primary endpoint(s)/estimand(s) ................... 139 
12.5 
Analysis of secondary endpoints ......................................................................... 139 
12.5.1 
Efficacy 
 .................................. 139 
12.5.2 
Safety endpoints .................................................................................. 140 
 
 142 
 
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 142 
12.7 
Interim analyses ................................................................................................... 142 
12.8 
Sample size calculation ........................................................................................ 142 
12.8.1 
Primary endpoint(s) ............................................................................. 142 
12.8.2 
Secondary endpoint(s) ......................................................................... 146 
13 Ethical considerations and administrative procedures .................................................... 146 
13.1 
Regulatory and ethical compliance ...................................................................... 146 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 146 
13.3 
Publication of study protocol and results............................................................. 146 
13.4 
Quality Control and Quality Assurance ............................................................... 147 
14 Protocol adherence .......................................................................................................... 147 
14.1 
Protocol amendments ........................................................................................... 147 
15 References ....................................................................................................................... 148 
16 Appendices ...................................................................................................................... 151 


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16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 151 
16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ....................................................................................................... 152 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 157 
 
 158 
16.5 
Appendix 5: The American Heart Association (AHA) Recommended Diet ...... 160 
 
List of tables 
Table 1-1 
Protocol Summary ................................................................................. 48 
Table 2-1 
Objectives and related endpoints .......................................................... 61 
Table 6-1 
Investigational and control drug ............................................................ 76 
Table 6-2 
Medications permitted only if dose is stable (within 25 percent of 
Baseline dose) and expected to remain stable through the double-
blind treatment period ........................................................................... 79 
Table 6-3 
Prohibited medications .......................................................................... 80 
Table 6-4 
Blinding and unblinding plan ................................................................ 83 
Table 6-5 
Dosing with 3 capsule (10 + 30 + 100 μg) tropifexor supply ............... 87 
Table 6-6 
Dosing with single capsule (140 μg) tropifexor supply ........................ 88 
Table 8-1 
Assessment Schedule ............................................................................ 93 
Table 8-2 
NAFLD Activity Score (NAS) Components ...................................... 105 
Table 8-3 
NASH CRN Fibrosis score criteria ..................................................... 105 
Table 10-1 
SAE reporting requirements in different scenarios ............................. 124 
Table 10-2 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 126 
Table 12-1 
Planned Analyses ................................................................................ 140 
Table 12-2 
Placebo effects on histological responses ........................................... 144 
Table 12-3 
Response rate setting used for sample size and power calculation ..... 144 
Table 12-4 
Powers of different sample sizes under equal allocation .................... 145 
Table 12-5 
Powers of passing at least one of the combination vs. placebo tests 
under various allocations of 380 participants ...................................... 145 
Table 16-1 
Vital signs............................................................................................ 151 
Table 16-2 
Management of Participants with Confirmed ALP, ALT, AST, or 
Bilirubin Elevations With or Without Liver Related Clinical 
Symptoms ............................................................................................ 152 
Table 16-3 
Specific Renal Alert Criteria and Actions ........................................... 157 
 
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List of figures 
Figure 1-1 
Co-ordinated effects of FXR on metabolism ........................................ 53 
Figure 3-1 
Study Design ......................................................................................... 66 
Figure 12-1 
An alpha recycling graph .................................................................... 136 
 


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List of abbreviations 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AESI 
adverse event of special interest 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
Anti-mitochondrial antibodies 
ANA 
Anti-nuclear antibodies 
ANCOVA 
analysis of covariance 
ANIT 
Alpha-naphthylisothiocyanate 
APTT 
Activated Partial Thrombin Time 
ARFI 
Acoustic Radiation Force Impulse 
APRI 
AST to Platelet Ratio Index 
ASMA 
Anti-smooth muscle antibody 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
ATZ 
Atazanavir 
AUDIT 
Alcohol Use Disorders Identification Test  
BA 
bio-availability 
BCRP 
breast cancer resistance protein 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte - The Federal Institute 
for Drugs and Medical Devices 
BMI 
body mass index 
BSL 
Baseline 
BUN 
blood urea nitrogen 
CDT 
carbohydrate deficient transferrin  
CFR 
Code of Federal Regulation 
CK 
Creatine kinase 
Cmb 
Combo 
CO 
Country Organization 
COVID-19 
Coronavirus disease 
CRF 
Case Report/Record Form (paper or electronic) 
CRN 
Clinical Research Network 
CRO 
Contract Research Organization 


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CSR 
clinical study report  
CTA 
Clinical Trial Application 
CYP 
cytochrome P 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribo Nucleic Acid 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EOS 
end of study  
EOT 
end of trial  
eSAE 
electronic serious adverse event 
FAS 
full analysis set  
FCS 
fully conditional specification 
FDA 
Food and Drug Administration 
FGF19 
fibroblast growth factor 19 
FIH 
first in human 
FSH 
follicle stimulating hormone 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
Gamma - Glutamyl transferase  
GI 
Gastrointestinal 
GLP  
glucagon-like peptide 
GSH 
glutathione 
HA 
Health Authority 
HAV 
Hepatitis A Virus 
HbA1c 
hemoglobin A1c 
HBsAg 
Hepatitis B surface Antigen 
HCP 
health care provider 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein  
HDL-C 
High Density Lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
IB 
investigator brochure 


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IL 
interleukin 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio  
IQR 
Interquartile range 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
LC-MS/MS 
liquid chromatography coupled to tandem mass spectrometry 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
Lower Limit of Quantification 
MELD 
Model For End-Stage Liver Disease 
MCAR 
Missing Completely at Random 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MI 
multiple imputation 
MAR 
missing at random 
MRI 
Magnetic Resonance Imaging  
MRI-PDFF 
Magnetic Resonance Imaging Proton Density Fat Fraction 
NAS 
NAFLD Activity Score 
NASH 
non alcoholic steatohepatitis 
NAFLD 
non alcoholic fatty liver disease 
NMR 
Nuclear Magnetic Resonance 
NOAEL 
no observed adverse effect level 
OATP 
organic anion transporting polypeptide 
OCA 
obeticholic acid 
OGTT 
oral glucose tolerance test 
PBC 
primary biliary cholangitis 


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PCR 
protein to creatinine ratio 
PD 
pharmacodynamic(s) 
PDFF 
Proton Density Fat Fraction 
Plc 
Placebo 
PK 
pharmacokinetic(s) 
PIIINP 
amino-terminal pro-peptide of procollagen type III 
PTH 
parathyroid hormone 
QMS 
Quality Management System 
RAN 
randomized analysis set 
RBC 
red blood cell(s) 
RNA 
Ribonucleic acid  
SAE 
serious adverse event 
SAF 
Safety analysis set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCR 
screened analysis set 
sCR 
serum creatinine 
SGLTs 
sodium glucose co-transporters 
SHP 
small heterodimer partner 
SMQ 
Standardized MedDRA Query 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
T2DM 
Type-II Diabetes Mellitus  
TFQ 
Trial Feedback Questionnaire 
TIMP 
tissue inhibitor of metalloproteinases 
TNF 
Tumor necrosis factor 
TT 
Thrombin Time 
UDCA 
Ursodeoxycholic Acid 
UG 
Unblinded at the Group level 
UGTs 
uridine 5'-diphosphoglucuronosyltransferases 
UI 
Unblinded to Individual participant treatment codes 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
WBC 
white blood cell(s) 
WHR 
waist-to-hip ratio 
WoC 
withdrawal of consent 
WOCBP 
women of child bearing potential 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Coded Data 
Personal Data which has been de-identified by the investigative center team 
by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug. 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use 
of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol). The action of enrolling one or more participants. 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of 
the treatment effect reflecting the clinical question posed by the trial objective. 
It summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes 
of an estimand include the population, variable (or endpoint), as well as the 
specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation 
or the existence of the measurements associated with the clinical question of 
interest. 
Investigational drug 
The study 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”. 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 


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Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Mis-randomized 
participant 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
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 participants with 
established disease and in those with newly-diagnosed disease. 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection 
Participant number 
A unique number assigned to each participant upon signing the Informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant, corresponding to 
a specific treatment arm assignment 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after medical 
judgment and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the participant came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study drug 
discontinuation 
When participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Study 
drug/treatment 
Any drug or combination of drugs or intervention administered to the 
participant as part of the required study procedures; includes investigational 
drug (s), control (s) or background therapy. 


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Study treatment 
discontinuation 
When the participant permanently stops taking study treatment prior to the 
defined study treatment completion date 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might 
include whether the participant experiences an intercurrent event. 
Withdrawal of 
consent (WoC)/ 
Opposition to use 
of data /biological 
samples 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to use 
data and biological samples) AND no longer wishes to receive study 
treatment, AND does not agree to further protocol required assessments. 
This request should be in writing (depending on local regulations) and 
recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal 
reason than consent. 
 
 
 


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Amendment 02 (30-Apr-2021) 
Amendment Rationale 
The key purposes of this amendment are to: 
• Introduce the tropifexor single 140 µg hard gelatin capsule as a replacement for 3 lower 
dose hard gelatin capsules that made up this dose (one each of 10 µg, 30 µg and 100 
µg).  
• Correct the definition of “no worsening of NASH” to align with definitions 
in the following guidance documents.  Details of these definitions will be 
included in the study Statistical Analysis Plan. 
o FDA Draft Guidance for Industry in Noncirrhotic Nonalcoholic 
Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment: 
December 2018 and  
o EMA Reflection paper on regulatory requirements for the 
development of medicinal products for chronic non-infectious liver 
diseases (PBC, PSC, NASH) 15 November 2018.   
• Include additional emerging guidance for study conduct in the context of the COVID-
19 or other public health emergency as declared by Local or Regional authorities, i.e., 
pandemic, epidemic or natural disaster. 
• Make editorial clarifications throughout and align with Novartis’ Clinical Trial Protocol 
Template Version 4.0 (15-Feb-2021). 
 
 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Changes to the Protocol  
  
Protocol Section 
Change 
Rationale for change 
List of abbreviations 
Glossary of terms 
Protocol summary 
Editorial changes 
To align with Novartis’ 
Clinical Trial Protocol 
Template Version 4.0 
(15-Feb-2021). 
Section 1.1.3 
Text Added 
During the course of this ongoing CLJN452D12201C 
study tropifexor (and its matching placebo) has been 
offered in two forms; a) initially as 3 hard gelatin 
capsules containing 10, 30 and 100 μg tropifexor (or 
matching placebo) and b) to reduce the pill burden for 
the participants, as a single hard gelatin capsule 
containing 140 μg tropifexor (or matching placebo). 
This change in capsule number is not expected to 
alter the absorption of tropifexor since the same 
formulation principle is used for all dose strengths (10, 
30, 100 and 140 µg): dry blend in hard gelatin capsule 
using the same excipients. 
 
 
 
 
 
Use of the tropifexor 
single 140 µg hard 
gelatin capsule to 
replace 3 hard gelatin 
capsules; one each of 
10 µg, 30 µg and 100 
µg, will reduce the 
participant burden from 
6 to 4 pills daily and 
will eliminate the 
production challenges 
of the 10 μg tropifexor 
capsule. 
Section 2 and Section 12 
 
Table 2-1 and Table 12-1 
Objectives and related 
Endpoints 
Primary endpoint modified  
From: 
Whether the participant achieves at least one stage of 
improvement in fibrosis without worsening of NASH 
(no worsening of hepatocellular ballooning or lobular 
inflammation) at Week 48 compared to baseline 
To:  
Whether the participant has at least a one stage 
improvement in fibrosis without worsening of NASH at 
Week 48 compared to baseline 
 
Key secondary objective was modified  
From: 
To evaluate the efficacy of combination therapy and 
two monotherapies in NASH or fibrosis with a 
composite endpoint. 
To: 
To evaluate the efficacy of combination therapy and 
two monotherapies in NASH or fibrosis with a 
composite endpoint after 48 weeks of treatment. 
 
AND 
 
From: 
To align with NASH 
endpoint definitions 
according to FDA and 
EMA Guidance 
documents 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
To evaluate improvement in fibrosis by at least one 
stage. 
To: 
To evaluate improvement in fibrosis by at least one 
stage after 48 weeks of treatment. 
Key secondary endpoint was modified  
From: 
Whether the participant achieves resolution of NASH 
and no worsening of fibrosis OR improvement in 
fibrosis by at least one stage without worsening of 
NASH (no worsening of hepatocellular ballooning or 
lobular inflammation) at Week 48 compared with 
baseline. 
To: 
Whether the participant achieves resolution of NASH 
and no worsening of fibrosis OR improvement in 
fibrosis by at least one stage without worsening of 
NASH at Week 48 compared with baseline. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.1 and 
Section 12.4 
Changed the summary measure of first primary 
estimand  
From: 
Proportion of the participants with at least one stage 
improvement in fibrosis without worsening of NASH at 
Week 48 compared with Baseline. 
To: 
To clarify that odds 
ratio is the summary 
measure of pairwise 
comparisons for the 
primary estimand. 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Odds ratio of the participants achieving at least one 
stage improvement in fibrosis without worsening of 
NASH, at Week 48 compared with Baseline, of the 
two treatments for each pairwise comparison. 
 
Changed the summary measure of second 
primary estimand  
From: 
Proportion of the participants with resolution of NASH 
and no worsening of fibrosis at Week 48 compared 
with Baseline. 
To: 
Odds ratio of the participants obtaining resolution of 
NASH and no worsening of fibrosis, at Week 48 
compared with Baseline, of the two treatments for 
each pairwise comparison. 
 
Changed the summary measure in analysis of the 
of primary endpoints(s)/estimand(s)  
From: 
Proportion of participants achieving histological 
response at Week 48 for the following comparisons 
for each primary endpoint: combination vs. placebo, 
monotherapies vs. placebo, and combination vs. 
monotherapies. 
To: 
Odds ratio of participants achieving histological 
response at Week 48 for the following comparisons 
for each primary endpoint: combination vs. placebo, 
monotherapies vs. placebo, and combination vs. 
monotherapies. 
Section 4.6  
Section 6.7 
Section 8.4 
Text Added 
During a public health emergency as declared by 
Local or Regional authorities, i.e. pandemic, epidemic 
or natural disaster, mitigation procedures to ensure 
participant safety and trial integrity are listed in 
relevant sections. Notification of the public health 
emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and should 
be permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate. 
Emerging guidance 
has been added 
allowing mitigation 
procedures for study 
conduct in the context 
of the COVID-19 or 
other public health 
emergency as declared 
by Local or Regional 
authorities 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Section 5.2 
Exclusion 3 and 
Exclusion 13 
From: 
3. Weight change > 5% compared to Baseline since 
qualifying liver biopsy. 
To: 
3. Weight at Baseline changed by > 5% since 
qualifying liver biopsy. 
 
From: 
13. History or current diagnosis of ECG abnormalities 
indicating significant risk of safety for 
participants participating in the study such as: 
To: 
13. History or current diagnosis of ECG 
abnormalities based on Central ECG report 
indicating significant risk of safety for participants 
participating in the study such as: 
Text updated for 
clarity. 
 
 
 
 
 
 
 
Clarification that ECG 
eligibility is determined 
by the central reader 
Section 6.1.1 and 
Section  6.1.3 
Text Added 
The 140 μg dose of tropifexor and its matching 
placebo are each now available as a single hard 
gelatin capsule. Participants participating at the time 
of availability of the single tropifexor/placebo capsule, 
may continue on the 3-capsule tropifexor (100 μg + 30 
μg + 10 μg) or matching placebo regimen described in 
protocol v01 until the available 3-capsule supply is 
depleted. After the 3-capsule supply is depleted, 
participants will take one 140 μg tropifexor or 
matching placebo capsule daily as described in 
Table  6-1. No change has been made to licogliflozin 
dosing.  
Use of the tropifexor 
single 140 µg hard 
gelatin capsule to 
replace 3 hard gelatin 
capsules; one each of 
10 µg, 30 µg and 100 
µg will reduce the 
participant burden from 
6 to 4 pills daily and 
will eliminate the 
production challenges 
of the 10 μg tropifexor 
capsule  
Table 6-1 Modified  
From: 
Tropifexor 
(LJN452) 140 μg 
 
10 μg, 30 μg and 100 
μg hard gelatin 
capsules 
Placebo 
Tropifexor 
(LJN452) 140 μg 
Hard gelatin capsules 
matching to tropifexor 
(LJN452) 10 μg, 30 μg 
and 100 μg 
 
To: 
Tropifexor 
(LJN452) 140 μg 
 
140 μg hard gelatin 
capsule 
Placebo 
Tropifexor 
(LJN452) 140 μg 
Hard gelatin capsule 
matching to tropifexor 
(LJN452) 140 μg  


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Section 6.1.3.1 
Text Modified 
Until 3 capsule tropifexor (100 μg + 30 μg + 10 μg) 
and matching placebo is replaced by the 140 μg hard 
gelatin single capsule, in order to maintain the blind, 
placebo capsules matching tropifexor (LJN452) 10, 30 
and 100 µg and placebo tablets matching licogliflozin 
(LIK066) 10 mg will be given to participants as 
indicated in Table 6-5, so that all participants will 
receive 3 capsules and 3 tablets per day. One capsule 
from each of the 3 bottles, and 3 tablets from the 
blister pack should be taken close to the evening 
meal; either just prior to (within 5 minutes) consuming 
the evening meal or no more than 30 minutes after 
consuming the evening meal and at about the same 
time each day. 
Updated to clarify 
dosing process while 
tropifexor 3-capsule 
supply is used after 
availability of single 
capsule supply. 
Section 6.1.3.2 
Text Added 
After tropifexor and matching placebo is replaced by 
the 140 μg hard gelatin single capsule, in order to 
maintain the blind, placebo capsules matching 
tropifexor (LJN452) 140 µg and placebo tablets 
matching licogliflozin (LIK066) 10 mg will be given to 
participants as indicated in Table 6-6, so that all 
participants will receive 1 capsule and 3 tablets per 
day. One capsule from the bottle, and 3 tablets from 
the blister pack should be taken close to the evening 
meal; either just prior to (within 5 minutes) consuming 
the evening meal, or no more than 30 minutes after 
consuming the evening meal and at about the same 
time each day. 
Text added to reflect 
dosing regimen when 
the tropifexor 140 μg 
hard gelatin single 
capsule replaces the 3-
capsule regimen. 
Section 6.1.2, 
Section  6.2.1.1 and Table 
6-2 2 
Text Added 
There are no restrictions related to COVID-19 
vaccines, and these are allowed throughout study 
participation as permitted by local regulations. 
 
 
Clarification 
Clarified in Table 6-2 that only phenothiazines, not all 
psychotropic medications, must be at a stable dose 
To acknowledge and 
confirm no restriction to 
the ongoing COVID-19 
vaccination campaigns 
implemented globally 
 
Psychotropic 
medications were 
required to be stable in 
early studies with 
tropifexor out of an 
abundance of caution.  
However, no DDI or 
other issues have been 
identified for these 
compounds or the 
indications treated, so 
restrictions regarding 
stable dosing no longer 
apply. However, 
phenothiazine 
compounds are 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
associated with 
substantial weight gain, 
and so these 
compounds must be at 
a stable dose and 
expected to remain 
stable from screening 
visit 1 onwards.  
Table 6-3 
Text Added 
 
Drugs approved in any 
market for treatment of 
NASH 
Stop at least 6 months 
prior to baseline 
 
As drugs gain approval 
in select markets for 
NASH (e.g. 
Saroglitazar in India) it 
is necessary to prohibit 
these confounders 
prior to, and during, 
study participation. 
Section 6.4 
Table 6-4 
Text Added 
2a. The randomization codes will be disclosed to an 
independent analysis team to prepare safety and 
efficacy reports for the DMC. The independent 
analysts will keep randomization data confidential until 
data base lock. Data will be shared with the study 
team under blinded conditions. 
 
Unblinding a single participant’s treatment at a site for 
safety reasons (necessary for participant 
management) will occur via an emergency system in 
place at the site. As a result the participant should be 
discontinued from the study treatment. 
 
 
 
At the time of safety review, the DMC will review 
unblinded reports created by an independent analysis 
team. More details will be provided in the DMC 
charter. 
 
Modifications 
Abbreviations for blinding and unblinding terminology 
updated. 
Clarifications to the 
unblinding process 
implemented to align 
with Novartis’ Clinical 
Trial Protocol Template 
Version 4.0 (15-Feb-
2021).  
Section 6.7.2  
Text Added 
Once the protocol amendment v02 is approved and 
after the tropifexor (LJN452) 10, 30 and 100 µg and 
matching placebo hard gelatin capsule supply is 
depleted, the participant will receive 9 blister packs in 
a box (10 mg licogliflozin or matching placebo tablets) 
and 1 bottle of 140 µg hard gelatin capsules (replacing 
 
 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
the 10, 30 and 100 µg tropifexor or matching placebo 
capsules) for each 4 week period every 4 weeks 
through Week 20. At the Week 24, Week 32 and 
Week 40 visits 2 sets of 4 week supplies of study 
medication will be distributed to accommodate the 8 
weekly visit schedule (Table 8-1). The participants will 
take 3 tablets from the blister pack and 1 capsule 
from the bottle daily as described above.  
 
Text Added 
 
 
 
 
 
 
At site dosing – Baseline and Week 4:  
• Participants should take study drug either just 
prior to (within 5 minutes) consuming the morning 
meal, or no more than 30 minutes after 
consuming the morning meal. 
•  Participants should be instructed to swallow 
whole capsules and not to chew or open them. 
• If vomiting occurs during the course of treatment, 
participants should not take the study treatment 
again before the next scheduled dose. 
• No evening dose should be taken on the days of 
the Baseline and Week 4 visits as the daily dose 
is taken at the site on those 2 days. 
Section 6.7.2.1 
Text Added 
The 140 μg dose of tropifexor and its matching 
placebo are each available as a single hard gelatin 
capsule. Participants on the study at the time of 
availability of the single tropifexor/placebo capsule, 
may continue on the 3-capsule tropifexor (100 μg + 30 
μg + 10 μg) or matching placebo regimen, as shown 
in Table 6-5, until the available 3 capsule supply is 
depleted. 
 
After the 3-capsule supply is depleted, participants will 
take 1-capsule of 140 μg tropifexor or matching 
placebo daily as described in Table 6-6. No change is 
made to licogliflozin dosing. 
 
IMPORTANT: Please ensure that the date of the 
change, and the number of capsules (from 3 capsule 
to 1 capsule) is accurately captured in the eCRF 
Change in Dosing log for each participant. 
Use of the tropifexor 
single 140 µg hard 
gelatin capsule to 
replace 3 hard gelatin 
capsules; one each of 
10 µg, 30 µg and 100 
µg will reduce the 
participant burden from 
6 to 4 pills daily. 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Table 6-6 
Table Added 
Table 6-6 Dosing with single capsule (140 μg) 
tropifexor supply 
Table 6-6 provides 
guidance and 
clarification for dosing 
with the single 
tropifexor 140 μg hard 
gelatin capsule 
Table 8-1  
Footnote # 4 
 
Section 8.3.1.10 
Text Modified 
From: 
4. Baseline MRI should be done at least 4 weeks after 
biopsy.  
To: 
4. Screening MRI should be done only in participants 
who are scheduled for liver biopsy. MRI should be 
acquired at any time during the screening period after 
Screening 1 eligibility has been confirmed. Every 
effort should be made to perform Screening MRI 
before liver biopsy (exception: historical liver biopsy 
not performed during the screening period). If not 
possible to obtain the MRI before a biopsy performed 
during the screening period, MRI should be performed 
3 weeks or more after the liver biopsy.  
This provision has 
been added to allow 
sites sufficient flexibility 
to schedule the MRI 
with external facilities 
during the screening 
period, while providing 
sufficient time to avoid 
artifacts due to biopsy 
from appearing on the 
MRI.  
Section 8.3.1.8 
Text Modified 
From: 
Participants will have paired liver biopsies (Screening 
and EOT, after 48 weeks of treatment). Fibrosis 
staging and NAFLD Activity Score (NAS) based on 
steatosis, lobular inflammation, and hepatocyte 
ballooning assessment will be determined by a Study 
Central Reader 
To:  
Participants will have paired liver biopsies (Screening 
and EOT, after 48 weeks of treatment). Fibrosis 
staging and NAFLD Activity Score (NAS) based on 
steatosis, lobular inflammation, and hepatocyte 
ballooning assessment will be determined by a Study 
Central Reader, at the time of submission of each 
biopsy (Screening and EOT) and again, as a pair, 
temporally blinded, at the completion of the trial. 
Clarity around the 
paired biopsy at the 
completion of trial 
Section 8.4.2 
Text Added 
Local lab collection may be used during a public 
health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural 
disaster that limits or prevents on-site study visits. 
If participants cannot visit the site for protocol 
specified safety lab assessments, an alternative local 
lab, collection site or relevant clinical facility that are 
certified for lab diagnostics may be used. 
Emerging guidance 
has been added 
allowing mitigation 
procedures for study 
conduct in the context 
of the COVID-19 or 
other public health 
emergency as declared 
by Local or Regional 
authorities 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Safety samples (specifically hematology, clinical 
chemistry and coagulation panels) that can be 
collected locally will be collected and analyzed in line 
with the study laboratory manual. Where samples are 
collected and analyzed at a local laboratory instead of 
the central laboratory.  
Unscheduled local laboratory assessments may be 
performed if medically indicated to document a 
(potential) AE, if central laboratory results are 
unevaluable, inconclusive or cannot be obtained due 
to public health emergencies, or when the treating 
physician cannot wait for central laboratory results for 
decision making.  
The results of the local laboratory will be recorded in 
the eCRF 
Section 8.4.4.1 
Text Added 
Determination of eligibility will be based on the ECG 
report from the central ECG review, not on the ECG 
machine-generated report. 
 
Text Added 
Local ECG collection may be used during a public 
health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural 
disaster that limits or prevents on-site study visits. 
If participants cannot visit the site for protocol specified 
safety ECG assessments, an alternative local facility, 
collection site or relevant clinical facility that are 
certified for ECG collection may be used. 
Clarification that ECG 
eligibility is determined 
by the central reader 
 
 
 
Emerging guidance 
has been added 
allowing mitigation 
procedures for study 
conduct in the context 
of the COVID-19 or 
other public health 
emergency as declared 
by Local or Regional 
authorities 
Section 9 
Updates to definitions of Discontinuation and 
completion 
Align with Novartis’ 
Clinical Trial Protocol 
Template Version 4.0 
(15-Feb-2021). 
Section 9.1.1 
Text Added 
Discontinuation from study treatment is required in 
cases of serious COVID-19 infection requiring 
hospitalization. 
Recommended by 
DMC 
Section 12.4.2 
Mentioned 
While the model used for primary analyses will be the 
typical logistic regression in most cases, it should be 
set as the Firth logistic regression if some arm (such 
as the placebo) has a low response rate. 
Typical logistic 
regression returns 
biased results from 
data with rare events.  


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol Section 
Change 
Rationale for change 
Table 16-2 
Text Added 
From: 
ALT and/or AST 
 > 3 × ULN but ≤ 5 × baseline 
To: 
ALT and/or AST 
 > 3 × ULN but ≤ 5 × baseline 
AND  
total bilirubin > 2 × ULN  
(in Gilbert’s syndrome, see footnotef) 
Clarification of 
conditions requiring 
dosing interruption in 
the context of Gilbert’s 
syndrome. 
Text Added 
Potential DILI cases defined as [AST or ALT > 2 x 
baseline] OR [AST or ALT >7 × ULN] whichever 
occurs first combined with [total bilirubin > 2 x 
baseline AND > 2.0 x ULN] 
Definition added for 
conditions requiring 
dosing interruption in 
the context of elevated 
transaminase values at 
baseline. 
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 Informed 
Consent has been adapted accordingly to reflect the above changes. 
No additional risks related to COVID-19 pandemic were identified, and therefore the benefit 
risk is unchanged. 
 
 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Summary of Previous Amendments 
Amendment 01 (18-Sep-2020) 
Amendment rationale 
 
The key purposes of this amendment are to: 
• Implement commitments and recommendations received from individual national 
regulatory authorities which were initially implemented as country specific 
amendments.  
• Include a placebo arm to minimize sources of bias and to ensure reliable inference 
with respect to the safety and effectiveness of the treatments as prompted by: 
o Strong recommendation from the study Data Monitoring Committee (DMC) 
and Health Authorities (HAs) during the initial review of the protocol 
o Recent trials which have shown unexpectedly high placebo response rates, 
raising concerns about the interpretability of outcomes in a non-placebo 
controlled trial.  
• Increase sample size to accommodate addition of placebo arm, change of hypothesis 
tests, update in response rate assumptions and to increase statistical power.  
• Provide guidance for study conduct in the context of the COVID-19 or other pandemic 
• Update where applicable relevant sections as per the latest version of the Investigator 
Brochure (IB). 
• Implement editorial changes throughout the document to align with Novartis’ Clinical 
Trial Protocol Template Version 3.0 (31-Jan-2020). Notably, ‘participant’ replaces 
‘patient’. 
At the time of preparation of this protocol amendment (V01) document, 225 participants have 
been screened and 27 participants randomized as of 18-Sep-2020. 
 
Changes to the Protocol  
 
Protocol 
Section 
Change 
Rationale for 
change 
Protocol title 
From:  
A randomized, double-blind, parallel-group, multicenter study to assess 
efficacy, safety, and tolerability of oral tropifexor (LJN452) & licogliflozin 
(LIK066) combination therapy, compared to each monotherapy, for 
treatment of adult patients with nonalcoholic steatohepatitis (NASH) and 
liver fibrosis (ELIVATE) 
 
To: 
 
A randomized, double-blind, parallel-group, multicenter study to assess 
efficacy, safety, and tolerability of oral tropifexor (LJN452) & licogliflozin 
(LIK066) combination therapy, and each monotherapy, compared with 
placebo for treatment of adult participants with nonalcoholic 
steatohepatitis (NASH) and liver fibrosis (ELIVATE) 
A Placebo 
treatment group 
has been added 
to the study and 
the title change 
reflects that all 
active treatment 
groups will be 
compared to 
placebo.  


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol 
Section 
Change 
Rationale for 
change 
List of 
abbreviations 
New abbreviations added or deleted   
Updated to align 
with the revised 
protocol 
Protocol 
Summary 
Updates made to all sections of the summary.  Details and rationale for 
each change in the summary can be found in the respective sections of 
this Amendment summary. 
To align with the 
changes made to 
the body of the 
protocol. 
Section 1.1.3 Updated text:  
CLJN452A2202 (FLIGHT-FXR) is an adaptive 3-part Phase 2 study of 
tropifexor in participants with phenotypic or biopsy-confirmed NASH, 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. In Parts A and B of 
study CLJN452A2202, one hundred fifty two participants received 
tropifexor at doses ranging from 10 to 90 μg daily for 12 weeks. 
 
ALT, hepatic fat fraction by MRI-PDFF, and 
body weight also improved in a dose dependent manner compared to 
placebo. These early changes were confirmed at Week 48 with a clinically 
meaningful dose response in reducing ALT, a sustained reduction of GGT, 
clinically meaningful reduction in Hepatic Fat Fraction, and dose 
dependent and continued reduction in body weight versus placebo for 
both 140 µg and 200 µg tropifexor.  
Tropifexor was generally well tolerated at all dose without safety signals of 
concern. Pruritus was reported in the 60 µg, 90 µg, 140 µg, 200 µg, and 
placebo arms and the frequency was dose dependent. The majority of 
pruritus events were Grade 1 (mild) in severity. Dose-related increases in 
LDL-C and decreases in HDL-C were observed by Week 12 with no 
subsequent worsening. Tropifexor did not affect triglyceride levels. 
Update summary 
of available 
FLIGHT-FXR data 
to align with 
tropifexor IB 
Edition 11 
Section 1.1.4 Updated text: 
CLIK066X2204 study tested licogliflozin at doses of 30 and 150 mg for 12 
weeks in NASH participants. Results from full study population confirmed 
that treatment with licogliflozin at 150 mg and 30 mg per day resulted in 
dose-dependent improvements in markers of liver injury (ALT, AST and 
GGT) and liver fat content. (LIK066 IB Edition 12) The study clinical report 
is currently in preparation. Both doses of licogliflozin led to significant 
placebo adjusted weight loss at the 150 mg and 30 mg doses respectively 
(LIK066 IB). Licogliflozin treatment also improved glycemic and insulin 
sensitivity markers; HbA1c and HOMA-IR at both doses. The most 
common AE was diarrhea, reported by similar number of participants in 
the placebo and 30 mg groups but at a higher rate in the 150 mg dose 
group. As in previous studies with licogliflozin, diarrhea was mostly mild in 
the participants who had it. Only one participant in the 150 mg dose group 
discontinued treatment as a result of diarrhea.  
In summary, in clinical studies, licogliflozin has been well tolerated to date, 
resulting in improvements in markers of liver injury, hepatic fat, and weight 
loss with doses tested up to 150 mg orally in the CLIK066X2204 study. 
Update summary 
of available 
CLIK066X2204 
data to align with  
licogliflozin IB 
Edition 12 


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Amended Protocol Version 02 (Clean) 
Protocol No. CLJN452D12201C 
Protocol 
Section 
Change 
Rationale for 
change 
Section 
1.1.6.1 
Text added: 
A clinical study (CLJN452A2103) assessing the effect of strong CYP3A4 
inhibitors and inducers on tropifexor PK has been completed after 
initiation of this trial and confirmed the expected interaction: the strong 
CYP3A4 inhibitor itraconazole increased the AUC of tropifexor by 47%; 
the strong CYP3A4 inducer rifampin decreased the AUC of tropifexor by 
77-79%. 
CYP3A4 
interaction study 
CLJN452A2103 
recently 
completed. 
Section 
1.1.6.3 
Text added:  
The pharmacokinetic drug interaction between tropifexor (140 ug) and 
licogliflozin (50 mg) was investigated in study CLJN452E12101. 
Preliminary data from this study confirm the absence of a clinically 
relevant pharmacokinetic drug interaction between these 2 drugs. In the 
presence of licogliflozin, mean peak plasma concentration (Cmax,ss) of 
tropifexor decreased by 15% and total exposure (AUCtau,ss) decreased 
by 13%. In the presence of tropifexor, mean peak plasma concentrations 
of licogliflozin increased by 8% and total exposure increased by 12%. The 
small observed changes are within the 0.8-1.25 range and therefore below 
the effect generally considered a weak drug interaction. 
DDI study 
CLJN452E12101 
recently 
completed. 
Section 2 
 
Table 2-1 
Primary 
Objective 
and Endpoint 
Primary Objective modified  
From: 
To demonstrate the efficacy of tropifexor + licogliflozin as assessed by 
histologic improvement after 48 weeks of combination treatment 
compared to each monotherapy treatment in patients with NASH and 
stage 2 or 3 fibrosis. 
 
To: 
 
To evaluate the efficacy of tropifexor + licogliflozin in combination therapy 
and each monotherapy treatment, as assessed by histologic improvement 
after 48 weeks compared to placebo in participants with NASH and stage 
2 or 3 fibrosis. 
 
Primary endpoint modified  
From:  
Proportion of participants with resolution of NASH and no worsening of 
fibrosis OR Improvement in fibrosis by at least one stage without 
worsening of NASH (no worsening of hepatocellular ballooning or lobular 
inflammation) at Week 48 compared with baseline 
 
 To:  
 
-Whether the participant has at least a one stage improvement in fibrosis 
without worsening of NASH (no worsening of hepatocellular ballooning or 
lobular inflammation) at Week 48 compared to baseline 
Aligned with 
guidance from 
Regulators. 


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- Whether the participant achieves resolution of steatohepatitis without 
worsening of fibrosis at Week 48 compared to baseline 
Section 2 
 
Table 2-1 
Key 
Secondary 
Objectives 
and 
Endpoints 
Two secondary Objectives were changed  
From: 
 
Improvement in fibrosis by at least one stage with no worsening of NASH 
after 48 weeks of treatment 
 
Resolution of NASH with no worsening of fibrosis after 48 weeks of 
treatment 
 
To 
 
To evaluate the efficacy of combination therapy and two monotherapies in 
NASH or fibrosis with a composite endpoint 
 
Two secondary Endpoints were changed  
From: 
Key secondary endpoint: Proportion of patients who have at least one 
stage improvement in fibrosis without worsening of NASH (no worsening 
of hepatocellular ballooning or lobular inflammation) at Week 48 
compared with baseline 
 
Key secondary endpoint: Proportion of patients with resolution of NASH 
and no worsening of fibrosis at Week 48 compared with baseline 
 
To: 
 
Key secondary endpoint: Whether the participant achieves resolution of 
NASH and no worsening of fibrosis OR improvement in fibrosis by at least 
one stage without worsening of NASH (no worsening of hepatocellular 
ballooning or lobular inflammation) at Week 48 compared with baseline. 
These objectives 
and associated 
endpoints were 
replaced with the 
original primary 
endpoint (the 
single composite 
endpoint). 
Section 2  
 
Preface Primary and Secondary Objective definitions with ‘to evaluate’ 
 
 
 
Added timeframe for objective evaluation for secondary and 
 
objectives to be assessed ‘after 48 weeks of treatment’ 
Harmonize 
language used in 
primary and 
secondary 
objective 
definitions. 
 
Clarification of 
timeframe for 
objective 
evaluation. 


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Section 2.1 
Primary estimands Section added 
To clearly define 
the primary 
estimand under 
the estimand 
framework 
described in ICH 
E9R1 
Section 3 
Updated first paragraph as follows: 
This is a randomized, double-blind, parallel-group, multiple-arm study to 
assess the efficacy, safety and tolerability of tropifexor and licogliflozin 
combination therapy, and each monotherapy compared with placebo as 
well as the combination therapy compared to each monotherapy, in 
participants with NASH and fibrosis. 
 
Study design updated as follows: 
Approximately 380 participants with NASH (NAS ≥4) and fibrosis stage 2 
or 3 will be randomly assigned to one of the following treatments: 
Arm A: Combination therapy Arm - (N=140): tropifexor 140 μg + 
licogliflozin 30 mg, once daily. 
Arm B: Tropifexor monotherapy Arm - (N=80): tropifexor 140 μg (+ 
placebo matching licogliflozin), once daily. 
Arm C: Licogliflozin monotherapy Arm - (N=80): licogliflozin 30 mg (+ 
placebo matching tropifexor), once daily.  
Arm D: Placebo Arm – (N=80): placebo matching tropifexor + placebo 
matching licogliflozin once daily. 
Include a placebo 
arm to minimize 
sources of bias 
and to ensure 
reliable inference 
with respect to the 
safety and 
effectiveness of 
the treatment as 
prompted by: 
1. Strong 
recommendati
on from DMC 
and HAs 
during the 
initial review 
of the protocol 
2. Recent trials 
which have 
shown 
unexpectedly 
high placebo 
response 
rates, raising 
concerns 
about the 
interpretability 
of 
outcomes in a 


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non-placebo 
controlled 
trial.  
 
Increase sample 
size to 
accommodate 
addition of 
placebo arm, 
change of 
hypothesis tests, 
update in 
response rate 
assumptions and 
to increase 
statistical power. 
Figure 3-
1Study 
Design 
New figure: 
 
Figure updated to 
reflect new 
sample size and 
study design, 
including addition 
of placebo 
treatment group, 
increase in 
sample size from 
210 to 380, and 
randomization 
ratio change from 
1:1:1 to 1.75 
(combination) : 1 
(tropifexor) : 1 
(licogliflozin) :1 
(placebo). 
Section 3 
Deleted the following text: “Additional monotherapy treatments, and 
potential combination arms may become available after the start of this 
study and may be considered to be added to this study via protocol 
amendments. This would only be proposed if situationally and scientifically 
justifiable, and with a full scientific biological rationale and supportive data 
packages. This is a theoretical consideration at this time. If additional 
arms are anticipated the appropriate guidance for platform studies will be 
considered.” 
Deletion 
requested by the 
United Kingdom’s 
Medicines and 
Healthcare 
Products 
Regulatory 
Agency (MHRA) 
during CTA 
review. 
Section 4.3  
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs 
Updated text: 
Currently there is no drug established as standard of care for participants 
with NASH. Combination of tropifexor and licogliflozin and each of these 
Rationale updated 
to reflect use of 
placebo as 
comparator. 


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compounds as monotherapy will be compared to placebo. Subsequently, 
the combination treatment will be compared to each of the monotherapies. 
A placebo treatment group was added to improve the assay sensitivity 
and interpretation of the treatment effect given the wide variability 
observed in histological response in recent studies for those participants 
receiving standard of care. 
Section 4.5 
Risks and 
Benefits 
New text added: 
When used as monotherapy, tropifexor and licogliflozin have been shown 
to have potential benefits in treating NASH. Based on the mechanisms of 
action of FXR agonists and SGLT1/2 inhibitors and the fact that the 
biologic pathways do not overlap, it is expected that they will complement 
each other and address the three main pathologic features of NASH, 
namely steatosis, inflammation and fibrosis. 
Appropriate eligibility criteria as well as specific stopping rules, are 
included in this protocol. Recommended guidelines for supportive 
management of study drug induced adverse events are provided in 
Section 10.2.  
The risk to participants in this trial is minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical 
monitoring, stopping rules and periodic review of safety data by an 
independent DMC.  
Toxicology of the combination is described in Section 1.1.9. All potential 
risks of each compound are described in the tropifexor and licogliflozin 
IBs. A brief summary of the benefits and risks of each compound follows: 
Section added to 
explain the 
anticipated risks 
and benefits of 
tropifexor and 
licogliflozin in 
combination. 
Sections 
4.5.1, 4.5.1.1 
and 4.5.1.2 
Tropifexor Benefits and Risks update to include emerging data. Updated 
to include additional details of hepatic effects of tropifexor in non-clinical 
(rats), healthy volunteers, and NASH participants studies. CYP3A4 
inhibitor and inducer data from Study CLJN452A2103 added. 
Non-clinical rat 
data requested by 
BfArM 
(Bundesinstitut für 
Arzneimittel und 
Medizinprodukte - 
The Federal 
Institute for Drugs 
and Medical 
Devices) and the 
German Ethics 
Committee during 
the Clinical Trial 
Application (CTA) 
review. Additional 
data available. 
Risks split by 
population tested 
for ease of review. 
Section 
4.5.2.1 
Added text: 
CLIK066X2204 study tested licogliflozin at doses of 30 and 150 mg for 12 
weeks in NASH participants. Results from full study population confirmed 
that treatment with licogliflozin at 150 mg and 30 mg per day resulted in 
dose-dependent improvements in markers of liver injury (ALT, AST and 
Aligned 
licogliflozin 
benefits section 
with data included 


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GGT) and liver fat content (LIK066 IB edition 12). The clinical study report 
is currently in preparation. Both doses of licogliflozin led to significant 
placebo adjusted weight loss at the 150 mg and 30 mg doses 
respectively. (LIK066 IB). Licogliflozin treatment also improved glycemic 
and insulin sensitivity markers; HbA1c and HOMA-IR at both doses. 
in other sections 
of the protocol. 
Section 
4.5.2.2 
Added text: 
In study CLIK066X2204, the most common AE was diarrhea, reported by 
similar number of participants in the placebo and 30 mg groups but at a 
higher rate in the 150 mg dose group. As in previous studies with 
licogliflozin, diarrhea was mostly mild in the participants who had it. Only 
one participant in the 150 mg dose group discontinued treatment as a 
result of diarrhea.  
 
Updated text: 
Appropriate exclusion criteria are applied in this study and guidance is 
provided to mitigate the risks as per Section 10.2.3. It is recommended 
that bilateral foot exams be performed at screening to assess the 
presence of any foot deformity (including amputation), disease, and/or the 
presence of clinically significant neuropathy that may increase the risk of 
amputation. 
Aligned 
licogliflozin risks 
section with data 
included in other 
sections of the 
protocol. 
 
 
 
 
 
 
Bilateral foot 
exams, which 
may not be 
routine for 
hepatologists, 
recommended to 
identify clinically 
significant 
neuropathy. 
Section 4.5.3 Removed the text ‘and sexually active males’ from the  following 
sentence: 
Women of child bearing potential and sexually active males must be 
informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. 
Updated in 
tropifexor IB 
edition 10, 
Release date 10-
Dec-2019,  
(IB Section 
7.2.1.4): 
“Based on the 
FDA guidance on 
reproductive and 
developmental 
toxicities 2011 
and after 
calculation of the 
safety margins 
based on potential 
amount of drug in 
semen   
(IB Section 4.3.7): 
there is no 
requirement for 
male tropifexor 


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study participants 
to use a condom 
during sexual 
intercourse and 
no requirement for 
contraception in 
their female 
partners (FDA 
2011)”. 
Section 5.1  
Inclusion Criterion 3 revised to specify that the NAFLD Activity Score 
(NAS) for eligible participants must be >= 4 with at least 1 point each in 
inflammation and ballooning on the screening histology assessment 
performed by the central reader. 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Section 5.2  
Exclusion Criterion 4: updated as follows: History of hypersensitivity to 
either of the study drugs or their excipients or to drugs of similar chemical 
classes, or participants with hereditary galactose intolerance, lactase 
deficiency or glucose-galactose malabsorption 
Requested by 
BfArM 
(Bundesinstitut für 
Arzneimittel und 
Medizinprodukte - 
The Federal 
Institute for Drugs 
and Medical 
Devices) and the 
German Ethics 
Committee during 
the Clinical Trial 
Application (CTA) 
review. 
Exclusion Criterion 5: Updated as follows: 
Taking a permitted medication listed in Table 6-2 but who is NOT on a 
stable dose (within 25% of baseline dose) from the start of the screening. 
period and 
a. for at least 3 months prior to the baseline visit for thyroid hormone, oral 
anti-diabetic medication, insulin, and GLP-1 agonists 
b. for at least 6 months prior to baseline for Vitamin E 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 6: revised to add “unit of alcohol”, commonly used in 
some participating countries as follows: 
Significant alcohol consumption is defined as more than 20 g/day (14 
units/week) in females, or more than 30 g/day (21 units/week) in males, 
on average. A “unit” of alcohol is equivalent to one (12-ounce; 355 ml) 
beer, one glass (4-ounce; 120 ml) of wine, or 1 shot (ounce; 30 ml) of hard 
liquor.  
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 7: definition of uncontrolled type 2 diabetes reduced 
from HbA1c >= 9.5% to HbA1c >= 9.0% 
Requested by the 
US Food and 
Drug 


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Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 8: exclusionary value for platelets is < LLN (lower limit 
of normal) and refers to central laboratory normal range and not a specific 
numeric value. 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 9: exclusionary values for albumin is < LLN, and total 
bilirubin and INR are > ULN (upper limit of normal) and refer to the central 
laboratory normal range and not a specific numeric value. Model For End-
Stage Liver Disease (MELD) score >12 added as exclusion. In addition, 
ALT, AST, ALP and total bilirubin will be evaluated 2 times during the 
screening period and both values must meet eligibility criteria prior to 
randomization. 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 10: added: presence of Immunoglobulin M (IgM) 
antibodies to Hepatitis A Virus (IgM anti-HAV). 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Exclusion Criterion 22: updated to: Diabetic complications, known 
peripheral vascular disease or clinically significant neuropathy that may 
increase the risk of amputation. 
Because many 
enrolled patients 
will be diabetic, 
and most 
diabetics 
experience at 
least some 
neuropathy, 
exclusion was 
updated to clarify 
that specifically 
patients with 
clinically 
significant 
neuropathy that 
may increase the 
risk of amputation 
are excluded. 
Exclusion Criterion 23: Updated to: Symptomatic genital or urinary tract 
infection within 4 weeks prior to randomization or participants with high 
risk as, determined by the investigator (including concomitant therapy with 
immunosuppressive potential), to be particularly susceptible to genital or 
urinary tract infection. 
In addition to 
patients with 
recent genital or 
urinary tract 
infections, those 
patients likely to 
be susceptible to 


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such infections 
are excluded. 
Exclusion Criterion 25: Updated to: Any history of and/or suspected 
Fournier’s gangrene, or participants with high risk as, determined by the 
investigator (including concomitant therapy with immunosuppressive 
potential), to be particularly susceptible to Fournier’s gangrene. 
In addition to 
patients with 
history of or 
suspected 
Fournier’s 
gangrene 
infections, those 
patients likely to 
be susceptible to 
such infection are 
also excluded. 
Exclusion Criterion 28: Updated to: Known positivity for Human 
Immunodeficiency Virus (HIV) infection. HIV antigen/antibody tests will be 
performed to determine HIV status if allowed and required according to 
local regulations. 
Requested by 
BfArM 
(Bundesinstitut für 
Arzneimittel und 
Medizinprodukte - 
The Federal 
Institute for Drugs 
and Medical 
Devices) and the 
German Ethics 
Committee during 
the Clinical Trial 
Application (CTA) 
review. 
Exclusion Criterion 33: Removed: Sexually active males must use a 
condom during intercourse while taking drug and for 5 days after stopping 
investigational 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 study drug via seminal fluid.  
Updated in 
tropifexor IB 
edition 10, 
Release date 10-
Dec-2019, 
Section 7.2.1.4: 
Based on the FDA 
guidance on 
reproductive and 
developmental 
toxicities 2011 
and after 
calculation of the 
safety margins 
based on potential 
amount of drug in 
semen (tropifexor 
IB Section 4.3.7), 
there is no 
requirement for 
male tropifexor 
study participants 


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to use a condom 
during sexual 
intercourse and 
no requirement for 
contraception in 
their female 
partners (FDA 
2011).’ 
Section 6.1.3 Text updated to: 
Participants (n = 380) will be assigned at Baseline visit to one of the 
following 4 treatment arms in a ratio of 1.75:1:1:1 in a blinded manner. 
Placebo capsules/tablets will be given in each treatment arm where 
necessary to maintain blinding. 
Arm A: Combination therapy Arm - (N=140): tropifexor 140 μg + 
licogliflozin 30 mg, once daily. 
Arm B: Tropifexor monotherapy Arm - (N=80): tropifexor 140 μg (+ 
placebo matching licogliflozin), once daily. 
Arm C: Licogliflozin monotherapy Arm - (N=80): licogliflozin 30 mg (+ 
placebo matching tropifexor),once daily.  
Arm D: Placebo Arm – (N=80): placebo matching tropifexor + placebo 
matching licogliflozin once daily. 
 
Text updated to 
reflect change to 
study design. 
Section 
6.2.1.1 
Table 6-2: updated to clarify duration of stability of permitted concomitant 
medications. Revised stability of permitted anti diabetes concomitant 
therapy to ‘Stable dose for at least 3 months prior to baseline’ and stability 
of Vitamin E ≤ 800 IU/day to ‘Stable dose for at least 6 months prior to the 
baseline visit’. Sliding scale insulin permitted. Stability for one month prior 
to qualifying biopsy has been removed. 
Revised stability 
of permitted anti 
diabetes 
concomitant 
therapy to ‘Stable 
dose for at least 3 
months prior to 
baseline’ and 
stability of Vitamin 
E ≤ 800 IU/day to 
‘Stable dose for at 
least 6 months 
prior to the 
baseline visit’ was 
requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Section 6.2.2 Table 6-3: updated to clarify when prohibited medications must be 
discontinued in participants who take them prior to study participation. 
Editorial 
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Table 6-3: Methotrexate and Alternative Liver Protection medications 
added to the prohibited medication table 
To eliminate 
confounders of 
response. 
Section 6.3.2 Text moved to introduce the section: 
The randomization numbers will be generated using the following 
procedure to ensure that treatment assignment is unbiased and concealed 
from participants and investigator staff. A participant randomization list will 
be produced by the IRT provider using a validated system that automates 
the random assignment of treatment arms to randomization numbers. 
These randomization numbers are linked to the different treatment arms. 
Clarification of 
randomization 
and IRT 
Section 6.6.2 Text added: 
Blinding codes may also be broken after a participant discontinues 
treatment due to disease progression if deemed essential to allow the 
investigator to select the participant’s next treatment regimen, and after 
discussion and agreement with Novartis. 
And: 
After the emergency break the participant must be discontinued from the 
study by the investigator. 
Additional reason 
for code break 
and next steps 
added as per 
Novartis template. 
Section 6.7.2 Updated text to ‘The participant will be dispensed 9 blister packs in a box 
and 3 bottles in a box for each 4 week period every 4 weeks from baseline 
through Week 20. At the Week 20, Week 32 and Week 40 visits 2 sets of 
4 week supplies of study medication will be distributed (Table 8-1). If the 
COVID-19 or other pandemic prevents on-site visits the site may arrange 
delivery of study medication to a participant’s home.  
 
 
 
 
 
 
Added to allow 
home delivery of 
study medication 
if necessary due 
to the COVID-19 
or other pandemic 
to avoid study 
medication 
interruption 
resulting from 
participants’ 
inability to obtain 
study medication 
from investigative 
site. 
 
 
 
 
 
 


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Section 8 
Added: 
“The date of each scheduled visit is calculated with the appropriate 
interval from the date of the baseline/randomization visit, not from the date 
of the previous visit. If a scheduled visit is late by more than half of the 
planned interval between it and the next scheduled visit, the visit should 
be skipped.” 
 
Added:  
“If the COVID-19 or any other pandemic limits or prevents on-site study 
visits, alternative methods of providing continuing care may be 
implemented. Phone calls, virtual contacts (e.g. teleconsulting) or visits by 
site staff/home nursing service at the participant´s home depending on 
local regulations and capabilities, may be considered. In-home visits 
would be conducted by the site staff (under the responsibility of the 
investigator), or by a health care provider (HCP) supporting this activity if 
this is in agreement with the investigator.” 
Text added to 
provide additional 
clarity on visit 
scheduling and 
visit windows. 
 
 
 
 
 
 
Added to allow 
home visits if 
necessary due to 
the COVID-19 or 
other pandemic to 
avoid study 
interruption of 
study 
assessments 
resulting from 
participants’ 
inability to attend 
study visits at the 
investigative site. 
Table 8-1 
Below updated 
 
• 
Visit numbers added 
• 
Screening visit changed from 8 to 10 weeks 
• 
HIV test at screening 
 
 
 
 
• 
Visit numbers 
added for 
clarity 
• 
Screening 
period 
increased to 
allow sufficient 
time for turn 
around of 
biopsy results 
• 
HIV testing 
Requested by 
BfArM 
(Bundesinstitut 
für Arzneimittel 
und 
Medizinprodukt
e - The 
Federal 
Institute for 
Drugs and 
Medical 
Devices) and 


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the German 
Ethics 
Committee 
during the 
Clinical Trial 
Application 
(CTA) review. 
• 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2 Statement added: “If the reason for screen failure is an inadequate biopsy 
sample taken during the screening period, a second liver biopsy cannot be 
performed for re-screening.  If the inadequate liver biopsy sample is 
historical, the investigator’s clinical judgment and local standard of care 
will determine if and when the liver biopsy can be repeated for re-
screening”. 
Requested by 
BfArM 
(Bundesinstitut für 
Arzneimittel und 
Medizinprodukte - 
The Federal 
Institute for Drugs 
and Medical 
Devices) and the 
German Ethics 
Committee during 
the Clinical Trial 
Application (CTA) 
review. 
Section 8.2.1 The second screening visit should only be conducted if participant 
remains eligible based on the assessments performed at screening visit 1. 
ALT, AST, total bilirubin and ALP will be tested at screening visits 1 and 2, 
and must meet the requirements in Section 5.2 at both screening visits to 
confirm eligibility. 
Qualifying ALT, 
AST, total bilirubin 
and ALP at both 
SV1 and SV2 
requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
Section 8.3.1 Section reorganized to reflect order of assessments performed 
Editorial 
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Section 
8.4.1.1 
Text updated to: 
A complete physical examination will be conducted at screening visit 1, 
baseline, Weeks 12, 24, and 48 which 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. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. At all other visits, a physical examination according to local 
guidelines, including bilateral foot exams, will be performed. 
To clarify at which 
visits a complete 
or modified 
physical 
examination is 
required.  
Section 9.1.1 Discontinuation of Study Treatment: ‘life-threatening events considered to 
be related to study medication’ added as a situation in which study 
participation might result in a safety risk to the participant.as follows: 
Any situation in which study participation might result in a safety risk to the 
participant (including life-threatening events considered to be related to 
study medication) 
 
Added text: 
Participants can discontinue from the study treatment or from the study 
without withdrawing consent. 
Requested by the 
US Food and 
Drug 
Administration 
(FDA) during the 
IND review. 
 
 
 
 
 
Text added to 
ensure site staff 
are clear that 
withdrawal of 
consent is not 
mandatory for, nor 
synonymous with, 
discontinuation. 
Section 
10.1.2 
Any AE of pancreatitis (acute, chronic or other), Fournier’s gangrene and 
ketoacidosis will be assessed as serious under “medically significant” 
even if other seriousness criteria are not met. 
AESI pancreatitis, 
Fournier’s 
gangrene and 
ketoacidosis are 
medically 
significant events. 
Section 
10.1.4 
Updated text: 
Clarification of 
duration of follow 
up of newborn in 


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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 at expected delivery date plus 12 
months. 
case of patient 
pregnancy. 
Section 
10.2.2 
Text updated to: 
Once a participant is exposed to study treatment, renal serum and urine 
laboratory values will be assessed routinely. Renal laboratory triggers and 
renal events are defined in Table 16-3 in Section 16.3. These laboratory 
abnormalities should be followed up as indicated in Table 16-3 by the 
investigator or designated personnel at the trial site. 
Details of 
laboratory values 
removed to avoid 
redundancy and 
risk of 
inconsistency with 
Table 16-3. 
Section 
10.2.3 
Adverse Events of Special Interest updated to include dyslipidemia, 
genital infections, ketoacidosis, and Fournier’s gangrene. 
Dyslipidemia 
added as potential 
risk with FXR 
agonism, and 
genital infections, 
ketoacidosis, and 
Fournier’s 
gangrene are 
potential side 
effects with 
SGLT2 inhibitors 
Section 11.1  Template language related to direct data entry removed  
Process not 
applicable to 
CLJN452D12201
C 
Section 12.2 
Demographics and baseline characteristics summary would only be 
provided for FAS. 
Limited difference 
was expected 
between SAF and 
FAS. 
Section 12.4 
A placebo arm was added to the trial. 
The addition of 
placebo was 
suggested by 
Health Authorities 
and DMC. 
Furthermore, the 
placebo response 
rates of recent 
studies in NASH 
are quite different 
from those of 
previous studies.  
The primary endpoint was changed from the single composite endpoint to 
two endpoints. 
The change was 
made to align with 
guidance from 


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Regulators. These 
two endpoints are 
used as primary 
endpoints in most 
Phase 3 NASH 
studies.  
The primary test of the study was changed to the comparisons between 
combination therapy and placebo for the two primary endpoints. 
 The primary 
objective of the 
study is to show 
the efficacy of the 
combination 
therapy compared 
with placebo. 
Comparisons between monotherapies and placebo were added. 
To evaluate the 
efficacy of 
monotherapies 
compared with 
placebo again 
(after the 
monotherapy 
studies).  
 
Moreover, these 
comparisons are 
now possible due 
to addition of the 
placebo treatment 
group. 
Section 
12.4.2 and  
Section 
12.5.1 
P-values would not be provided if formal hypothesis tests were not 
performed. 
This change was 
implemented to 
avoid potential 
confusions or 
misinterpretation 
of the results. 
Section 12.4 
Provided a better summary of the strategies to address intercurrent events 
and the methods to handle non-intercurrent event missing data. 
To clarify the two 
types of missing 
data and the 
strategies/method
s to handle them. 
Section 
12.4.1 
The primary endpoints were explained in more detail and were rephrased 
from sample level (proportion) to participant level (binary). 
To make use of 
the new estimand 
framework. 
Section 
12.4.2 
The overall Type I error rate was changed from one-sided 0.05 level to 
two-sided 0.05 level.  
To use a more 
strict alpha level 
for potential two-
sided 0.05 alpha 


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Protocol 
Section 
Change 
Rationale for 
change 
was  suggested 
by the health 
authorities.  
The hypothesis tests were arranged with hierarchical testing procedure.  
To control the 
overall Type I 
error rate. 
The test order was illustrated by an alpha recycling graph. 
To clarify the 
order of testing. 
The null and alternative hypotheses were updated  
Comparisons 
were changed 
from one-sided to 
two-sided. 
Section 
12.4.3  
Updated the list of intercurrent events. 
To take into 
account more 
potential events 
that have 
confounding 
effects to the 
primary 
estimands. 
Explained the strategies to handle intercurrent events. 
To provide a clear 
plan on how to 
address 
intercurrent 
events. This was 
suggested in ICH 
E9 R1 guidelines.  
Section 
12.4.4 
Created a separate subsection for non-intercurrent event missing data. 
Suggested by the 
new estimand 
framework 
explained in ICH 
E9 R1 guidelines 
The methods to manage non-intercurrent event missing data were 
updated. 
For clarity 
purpose. 
Multiple imputations would be performed based on fully conditional 
specification (FCS) with logistic regression instead of discriminant 
function. 
To handle 
arbitrary missing 
patterns. 
Section 
12.4.5 
Details of sensitivity analyses removed. 
Moved the details 
of sensitivity 
analysis from 
protocol to 
Statistical 
Analysis Plan. 


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Protocol 
Section 
Change 
Rationale for 
change 
Section 
12.5.1 
Replaced the two key secondary endpoints with the original primary 
composite endpoint  
 
The two previous 
key secondary 
endpoints are now 
the primary 
endpoints. 
Section 
12.5.1 
The secondary endpoints in Table 12-1 is re-described in the participant 
level. 
To follow the 
suggestions from 
ICH E9 R1 
guidelines 
Section 
12.5.1 
Added the analyses for ALT, AST, and GGT in Table 12-1. 
To align with the 
secondary 
objectives 
described in Table 
12-11. 
Section 
12.5.1 
Deleted the description of repeated measurements analysis of covariance 
(ANCOVA) model beneath Table 12-1. 
The analyses for 
repeated 
measurements 
are now described 
in Table 12-1 
Section 
12.5.2 
Statement removed:  
Data from the pre-treatment period and from the period after 30 days after 
last administration of study treatment will be listed but not summarized. 
 
Statement added to Section 12.5.2.1: 
Participants who died any time during the study will be listed with SAEs 
leading to such deaths. 
 
Clarification in  Section 12.5.2.4: 
The Fridericia QT correction formula (QTcF) will be used for clinical 
decisions and for analyses. Notable QTcF values and changes from 
baseline will be summarized by treatment and scheduled visit, where a 
notable value is defined as a QTcF ≥450 msec (male) or ≥460 msec 
(female) and the categories used for the change (increase) in QTcF are: ≤ 
30 ms, > 30 to ≤ 60 ms and > 60 ms. 
Off treatment data 
will be managed 
by listing and or 
summaries 
depending on the 
assessments. 
 
 
 
 
 
Updated to clarify 
the QTcF cutoff in 
females. 
Section 12.8 
including 
12.8.1 and 
12.8.2 
New text: 
Sample size and allocation are determined by three factors:  
1. Optimizing the power of passing at least one of the combination 
vs. placebo tests from the two primary endpoints;  
2. Optimizing the power of passing any monotherapy vs placebo test 
(given that at least one of the combination vs. placebo tests have 
succeeded);  
3. Restricting the size of placebo arm no larger than that of any 
treatment arm. 
 
Sample size and 
allocation were re-
calculated due to 
addition of 
placebo arm, 
change of primary 
endpoint(s), 
revision of 
hypothesis tests, 
update of 
response rate 


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Protocol 
Section 
Change 
Rationale for 
change 
assumptions and 
change in 
statistical power. 
Section 15  
Added below references: 
Bretz, F., Maurer, W., Brannath, W. and Posch, M. (2009). “A graphical 
approach to sequentially rejective multiple test procedures.” Statistics in 
Medicine 28: 586–604. 
He YL, Haynes W, Meyers CD, et al (2019) The effects of licogliflozin, a 
dual SGLT1/2 inhibitor, on body weight in obese patients with or without 
diabetes. Diabetes Obesity and Metabolism, 21: 1311-21. 
 
Rubin DB (1976). Inference and Missing Data. Biometrika, 63:581–92.  
 
Rubin DB (1987). Multiple Imputation for Nonresponse in Surveys. New 
York: John Wiley & Sons. 
Updated based on 
revised protocol 
Section 16 
Table 16-2 updated to reflect triggers and necessary actions by 
investigators, in context of clinical symptoms, when elevation of liver 
function tests is observed as compared to baseline. 
Updated to be 
aligned with 
recommendations 
received from 
Health Authorities 
(including FDA 
and BfArM) which 
have been 
implemented in 
other Novartis 
NASH studies. 
Table 16-3 updated for completeness to reflect renal laboratory triggers 
and necessary actions. 
To reflect alerts 
aligned with the 
patient population 
and study 
medication 
mechanism of 
action. 
Table 16-5 time for collection of ‘post previous evening dose’ samples 
updated to ‘Recommended  
18h (+/- 4h)’.  
Timing for sample 
collection is 
aligned with 
protocol 
Section 8.5.2. 
Editorial changes throughout the document for clarity. 
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 Informed 
Consent has been adapted accordingly to reflect the above changes. 


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No additional risks related to COVID-19 pandemic were identified, and therefore the benefit 
risk is unchanged. 
 


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Protocol No. CLJN452D12201C 
Protocol summary 
Table 1-1 
Protocol Summary 
Protocol number 
CLJN452D12201C 
Full Title 
A randomized, double-blind, parallel-group, multicenter study to assess 
efficacy, safety, and tolerability of oral tropifexor (LJN452) & licogliflozin 
(LIK066) combination therapy, and each monotherapy, compared with 
placebo for treatment of adult participants with nonalcoholic 
steatohepatitis (NASH) and liver fibrosis (ELIVATE) 
Brief title 
Study to assess efficacy, safety, and tolerability of oral tropifexor 
(LJN452) & licogliflozin (LIK066) combination therapy, and each 
monotherapy, compared with placebo (ELIVATE) 
Sponsor  
Novartis Pharma AG 
Investigation type 
Drug 
Clinical Phase 
Phase IIb 
Study type 
Interventional 
Purpose  
To compare tropifexor and licogliflozin in combination therapy and each 
monotherapy, to placebo for efficacy, safety, and tolerability in 
participants with NASH and liver fibrosis (stage 2 or 3) as per NASH CRN 
histological score. 
 Primary Objective(s)  
To evaluate the efficacy of tropifexor + licogliflozin in combination therapy 
and each monotherapy treatment, as assessed by histologic 
improvement after 48 weeks compared to placebo in participants with 
NASH and stage 2 or 3 fibrosis. 
Secondary Objectives 
• 
To evaluate the efficacy of combination therapy and two 
monotherapies in NASH or fibrosis with a composite endpoint after 
48 weeks of treatment. 
• 
To evaluate improvement in fibrosis by at least one stage after 48 
weeks of treatment. 
• 
To evaluate improvement in fibrosis by at least two stages with no 
worsening of NASH after 48 weeks of treatment. 
• 
To evaluate reduction in body weight from Baseline after 48 weeks 
of treatment. 
• 
To evaluate change in liver fat content after 48 weeks of treatment. 
• 
To evaluate the relationship of investigational treatment and markers 
of hepatic inflammation in NASH (ALT and AST) after 48 weeks of 
treatment. 
• 
To evaluate the relationship of investigational treatment and GGT, a 
marker of cholestasis and oxidative stress after 48 weeks of 
treatment. 
• 
To evaluate the safety and tolerability of tropifexor (LJN452) in 
combination with licogliflozin (LIK066), and each monotherapy 
treatment, compared to placebo, after 48 weeks of treatment 
Study design 
This is a randomized, double-blind, parallel-group, multiple-arm study to 
assess the efficacy, safety and tolerability of tropifexor and licogliflozin 


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combination therapy, and each monotherapy compared with placebo, 
as well as the combination therapy compared to each monotherapy, in 
participants with NASH and fibrosis. 
Rationale  
Tropifexor and licogliflozin each work through a different mechanism of 
action, thus allowing potential additive or complementary beneficial 
effects resulting in greater efficacy when used as a combination.  
Additive or complementary efficacy coupled with acceptable safety and 
tolerability would support further development of this combination for 
NASH. 
Study population 
Approximately 380 adult male and female participants with NASH and 
fibrosis stages 2–3 demonstrated on liver biopsy within 6 months prior to 
randomization. 
Key Inclusion criteria 
• 
Signed informed consent must be obtained prior to participation in 
the study. 
• 
Male and female participants 18 years or older (at the time of the 
screening visit). 
• 
Presence of NASH with fibrosis as confirmed by central reader's 
evaluation of liver biopsy obtained no more than 6 months before 
randomization demonstrated by the following:  
o 
NASH using NAFLD Activity Score (NAS) >= 4 with at least 
1 point each in inflammation and ballooning 
and 
o 
Fibrosis stage 2 or 3 using NASH CRN fibrosis criteria  
Key Exclusion criteria 
• 
Type 1 diabetes mellitus  
• 
Uncontrolled type 2 diabetes defined as glycated hemoglobin 
(HbA1c) ≥ 9.0% at screening  
• 
HbA1c < 6.5% at screening in Type 2 diabetics currently treated 
with insulin or sulfonylureas 
• 
Platelet count < LLN (see Central Laboratory Manual)  
• 
Clinical evidence of liver impairment as defined by the presence of 
any of the following abnormalities: 
o 
Serum albumin < LLN (see Central Laboratory Manual) 
o 
International Normalized Ratio (INR) > ULN (see Central 
Laboratory Manual) 
o 
ALT or AST >5x ULN (in either of the 2 values during 
screening). 
o 
Total bilirubin >ULN (see Central laboratory manual) (in 
either of the 2 values during screening) (including Gilbert‘s 
syndrome) 
o 
Alkaline phosphatase > 300 IU/L (in either of the 2 values 
during screening) 
o 
History 
of 
esophageal 
varices, 
ascites 
or 
hepatic 
encephalopathy 
o 
Splenomegaly 
o MELD score >12 


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Study treatment 
• 
Eligible participants will be randomized to 3 treatment arms and 1 
placebo arm in a ratio of 1.75:1:1:1 
• 
Arm A (N=140): tropifexor 140 µg + licogliflozin 30 mg, once 
daily 
• 
Arm B (N=80): tropifexor 140 µg (+ placebo matching 
licogliflozin), once daily 
• 
Arm C (N=80): licogliflozin 30 mg (+ placebo matching 
tropifexor), once daily 
• 
Arm D (N=80): placebo (placebo matching tropifexor + 
placebo matching licogliflozin) , once daily 
Efficacy assessments 
• 
Liver biopsy  
o 
NASH 
o 
fibrosis 
• 
MRI (PDFF) 
• 
Weight 
• 
Liver function tests (LFT) 
o 
ALT 
o 
AST 
o GGT 
Key safety assessment 
• 
Adverse events/serious adverse events (AE/SAE) 
• 
Adverse events of special interest (AESI) 
• 
Laboratory evaluations 
• 
Physical examination 
• 
Vital signs 
• 
Electrocardiogram (ECG) 
Other assessments 
 
 
• 
NAFLD fibrosis score 
 
 
• 
Pregnancy and assessment of fertility 
• 
Height  
• 
Waist and hip circumference 
 
 
 
 
 
 
  
 
 
 
Data analysis 
The study adopts two primary endpoints: 1. Whether the participant 
achieves at least one stage improvement in fibrosis without worsening of 
NASH at Week 48 compared with Baseline; 2. Whether the participant 
has resolution of NASH and no worsening of fibrosis at Week 48 
compared with Baseline. Five pairwise comparisons may be evaluated 
for each primary endpoint, rendering a total of ten potential comparisons. 
Family-wise Type I error rate is controlled at two-sided 5% (one-sided 
2.5%) level, and is split for the two primary endpoints. Each primary 


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endpoint will have its own branch of tests and may pass its alpha to the 
other branch from its last two tests.  
The main goal of the study is to demonstrate the combination efficacy of 
tropifexor + licogliflozin over placebo in participants with NASH and stage 
2 or 3 fibrosis, so the two combination therapy vs. placebo tests (one for 
each primary endpoint) will be performed first. Then, for each primary 
endpoint, the two monotherapies (LJN452 and LIK066) will be compared 
with placebo after the combination treatment reveals superiority over 
placebo with statistical significance. If one of the monotherapy vs. 
placebo tests succeeds, then it will pass its alpha to the corresponding 
combination vs. monotherapy test. An alpha recycling graph is made to 
illustrate the test hierarchy. 
Key words 
NASH, Tropifexor, Licogliflozin, LJN452, LIK066. 
 
 


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1 
Introduction 
1.1 
Background 
1.1.1 
Non Alcoholic Steatohepatitis (NASH) 
Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the 
Western world (Browning et al 2004, Ratziu et al 2010, Szczepaniak et al 2005). The clinical -
histologic phenotype of the disease extends from non alcoholic fatty liver to non alcoholic 
steatohepatitis (NASH). NASH includes not only fat in the liver but also inflammation and 
hepatocyte injury (ballooning) which over time can lead to increasing fibrosis, cirrhosis and end 
stage liver disease (Ekstedt et al 2015). 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% 
(Chalasani et al 2012, Vernon et al 2011). 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 
number 2 indication for liver transplantation in the US (Wong et al 2015). 
NASH is associated with obesity and Type 2 diabetes mellitus (Hossain et al 2009) and a 
NASH phenotype can be composed by the combination of several features of the metabolic 
syndrome (obesity, Type 2 diabetes mellitus, dyslipidemia) along with elevated ALT/AST 
and fatty infiltration of the liver. Patients with NASH have an increased risk of developing 
hepatocellular carcinoma (Starley et al 2010). NASH is also associated with an increased risk 
of 
cardiovascular 
mortality 
and 
type 
2 
diabetes 
mellitus 
(Targher et al 2005, 
Targher and Arcaro 2007). 
Several studies have been conducted with Vitamin E and thiazolidinediones in patients with 
NASH, but no long-term benefits have been demonstrated in prospective studies 
(Sanyal et al 2004). There are a number of agents currently in various stages of testing for the 
treatment of NASH but no therapy has been approved to date. 
Pharmacological activation of the farnesoid X nuclear receptor (FXR) has been proposed as a 
therapeutic target for NASH (Cariou 2008, Porez et al 2012). 
1.1.2 
Farnesoid X Nuclear Receptor (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 
gluconeogenesis and lipogenesis (Figure 1-1) (Pattni et al 2012, Walters et al 2015). In the liver, 
FXR activation 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 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 2003, Calkin and Tontonoz 2012). Furthermore, 
FXR agonists increase excretion of bile acids through the kidney, increase bile acid binding 
proteins in the ileum and stimulate FGF15 (in rodents) or FGF19 (in humans) expression (a key 
regulator of bile acid metabolism). 


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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. 
(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 phase 2b (FLINT) trial, it was shown that 45% of NASH patients receiving 25 mg OCA 
once daily for 72 weeks had improved liver histology compared to 21% of NASH patients 
receiving placebo in the same period (NeuschwanderTetri- et al 2015). In a phase 3 study 
(REGENERATE), at 72 weeks, treatment with OCA 25 mg improved liver fibrosis (≥1 stage) 
with no worsening of NASH (p=0.0002) and dose dependent reduction of ALT, AST and 
GGT was observed, demonstrating consistent efficacy with an overall AE profile similar to 
previous studies. (Youinossi 2019) 
1.1.3 
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 clinical studies. The investigator’s brochure 
(IB) provides a detailed review of the pre-clinical and clinical information on tropifexor 
available to date. 
As of 05-Aug-2020 (LJN452 investigator’s brochure Edition 11), 181 healthy volunteers, and 
17 participants with primary bile acid diarrhea in CLJN452X2202 received tropifexor. In 


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CLJN452X2201, 40 primary biliary cholangitis (PBC) participants were treated with tropifexor 
at doses ranging from 30 to 150 μg daily. In Parts A and B of the CLJN452A2202 study, 
152/198 NASH participants received tropifexor. Analysis of the Part C data of this trial, in 
which 101/152 participants received tropifexor, is ongoing.    
Human safety and tolerability, PK and pharmacodynamic data are available from the First-in-
Human study CLJN452X2101. In healthy volunteers the administration of tropifexor once daily 
for up to 14 days was generally well tolerated. Isolated asymptomatic and reversible elevations 
in ALT were observed at 100 μg dose and resolved after dose discontinuation. No significant 
findings in physical exam, vital signs or ECGs have been related to tropifexor; no adverse events 
related to itch were observed in CLJN452X2101. PK data were consistent with once daily 
dosing. Human PD data show that after single doses in healthy volunteers, there were dose-
dependent increases in FGF19 from 10 to 1000 µg tropifexor. After multiple doses, a maximal 
mean serum FGF19 was observed at 6 hours after administration of 60 µg tropifexor consistent 
with likely pharmacological effect. 
CLJN452A2202 (FLIGHT-FXR) is an adaptive 3-part Phase 2 study of tropifexor in 
participants with phenotypic or biopsy-confirmed NASH, 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. In 
Parts A and B of study CLJN452A2202, one hundred fifty two participants received tropifexor 
at doses ranging from 10 to 90 μg daily for 12 weeks.
 
 
 ALT, hepatic fat fraction by MRI-
PDFF, and body weight also improved in a dose dependent manner compared to placebo. 
Preliminary evaluation indicates that these early changes continued through Week 48 with a 
clinically meaningful dose response in reducing ALT, a sustained reduction of GGT, Clinically 
meaningful reduction in Hepatic Fat Fraction, and dose dependent and continued reduction in 
body weight versus placebo for both 140 µg and 200 µg tropifexor.  
Tropifexor was generally well tolerated at all doses without safety signals of concern. Pruritus 
was reported in the 60 µg, 90 µg, 140 µg, 200 µg, and placebo arms and the frequency was dose 
dependent. The majority of pruritus events were Grade 1 (mild) in severity. Dose-related 
increases in LDL-C and decreases in HDL-C were observed by Week 12 with no subsequent 
worsening. Tropifexor did not affect triglyceride levels. 
Based on Data Monitoring Committee (DMC) recommendation and PK/PD modeling, 140 μg 
and 200 μg daily doses are being tested in Part C (last participant/first treatment on 11 April 
2019) to complete the broad dose finding approach in this study. Study duration for Part C is 
48 weeks and paired liver biopsies, at Baseline and at Week 48 were performed. The Week 12 
analysis of the CLJN452A2202 part C data revealed clear and significant dose response in ALT, 
PDFF, GGT and body weight reduction which continued through Week 48. The overall rate of 
adverse events and SAEs was similar across treatment groups, with an increase in pruritus with 
high dose tropifexor compared to placebo. CLJN452A2202 data were reviewed by the DMC 
approximately every 6 months, without revealing any significant safety concern to date. 
In summary, in clinical studies tropifexor has been well tolerated to date, with doses currently 
being tested up to 200 μg orally in the ongoing Part C of CLJN452A2202 study. 
 


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During the course of this ongoing CLJN452D12201C study tropifexor (and its matching 
placebo) has been offered in two forms; a) initially as 3 hard gelatin capsules containing 10, 30 
and 100 μg tropifexor (or matching placebo) and b) to reduce the pill burden for the participants, 
as a single hard gelatin capsule containing 140 μg tropifexor (or matching placebo). This change 
in capsule number is not expected to alter the absorption of tropifexor since the same 
formulation principle is used for all dose strengths (10, 30, 100 and 140 µg): dry blend in hard 
gelatin capsule using the same excipients. As a result, and considering the cumulative tropifexor 
PK data to date including an approximately dose proportional increase in key PK parameters 
over a wide range of doses and dose strengths (CLJN452X2101). No effect on PK from this 
change in product form is expected.  
1.1.4 
Licogliflozin 
Licogliflozin is a selective and potent inhibitor of the sodium glucose co-transporters (SGLTs) 
1 and 2 that decreases absorption of glucose in the gut and reabsorption in the kidney 
(Chao and Henry 2010). In the normal state, 90% of the filtered glucose is reabsorbed by 
SGLT2 in the proximal convoluted tubule cells of the kidney, with the remaining 10% 
reabsorbed by the SGLT1. Inhibition of SGLT2 results in glucosuria, decreased blood glucose 
and modest weight loss in healthy participants and participants with T2DM (Bays 2013). In 
addition to expression in the kidney, SGLT1 is also expressed in the small intestine where it is 
required for glucose and galactose absorption. Thus, inhibition of enteric SGLT1 results in 
reduction of glucose and galactose absorption (Turk et al 1991) which results in calorie wasting 
and other potential endocrine-based weight loss mechanisms. Combined SGLT1 and SGLT2 
inhibition therefore offers the potential for improved efficacy over SGLT2 selective inhibitors 
in both lowering blood glucose and body weight.  
Licogliflozin was administered to 76 healthy participants in the US, 36 healthy participants in 
Japan. Single doses of up to 350 mg and repeated doses of up to 300 mg/day for 14 days in 
healthy participants were generally safe and tolerated. Licogliflozin was also administered to 
41 participants with T2DM and 127 obese participants in the US.  
In study CLIK066X2101, single and multiple doses of licogliflozin induced glucosuria in 
healthy volunteers (HVs) and participants with T2DM, and significantly lowered glucose area 
under the time-concentration curve (AUC) after an oral glucose tolerance test (OGTT) in 
participants with T2DM. Licogliflozin was found to be tolerated, had in both healthy 
participants and participants with T2DM.  
Treatment of normoglycemic and dysglycemic obese participants with 150 mg qd licogliflozin 
for 12 weeks in CLIK066X2201 was shown to be safe, and resulted in 5.7% reduction in body 
weight. Diarrhea was observed as a potential dose-limiting side effect in this study 
(He et al 2019). These studies are summarized in the LIK066 IB.  
Additionally, in the CLIK066B2201 dose finding study in obese or overweight adults in North 
America and Europe to evaluate weight loss after 24 weeks, 460 participants were randomized 
to either placebo, QD doses ranging from 2.5 to 150 mg, or BID doses ranging from 2.5 to 50 
mg. After 24 weeks of treatment, there was a dose dependent reduction in body weight, with 
change from baseline of -3.6% in the 50 mg qd group and -4.6% in the 150 mg QD group. In 
the CLIK066B1201 dose finding study to evaluate weight loss after 12 weeks in Japanese obese 
participants, 126 participants were randomized to either placebo or doses ranging from 2.5 to 


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50 mg QD. After 12 weeks, there was a dose dependent reduction in body weight, with change 
from baseline of -3.41% in the 25 mg group and -3.80% in the 50 mg group. 
CLIK066X2204 study tested licogliflozin at doses of 30 and 150 mg for 12 weeks in NASH 
participants. Results from full study population confirmed that treatment with licogliflozin at 
150 mg and 30 mg per day resulted in dose-dependent improvements in markers of liver injury 
(ALT, AST and GGT) and liver fat content. (LIK066 IB Edition 12) The study clinical report 
is currently in preparation. Both doses of licogliflozin led to significant placebo adjusted weight 
loss at the 150 mg and 30 mg doses respectively (LIK066 IB). Licogliflozin treatment also 
improved glycemic and insulin sensitivity markers; HbA1c and HOMA-IR at both doses. The 
most common AE was diarrhea, reported by similar number of participants in the placebo and 
30 mg groups but at a higher rate in the 150 mg dose group. As in previous studies with 
licogliflozin, diarrhea was mostly mild in the participants who had it. Only one participant in 
the 150 mg dose group discontinued treatment as a result of diarrhea.  
In summary, in clinical studies, licogliflozin has been well tolerated to date, resulting in 
improvements in markers of liver injury, hepatic fat, and weight loss with doses tested up to 
150  mg orally in the CLIK066X2204 study. 
1.1.5 
Biological rationale for the combination of tropifexor and licogliflozin 
Tropifexor and licogliflozin impact distinct targets affecting different nodes of NASH 
pathophysiology as evidenced by the following data in the tropifexor (LJN452) and licogliflozin 
(LIK066) Investigator’s Brochures: 
• Tropifexor activates a nuclear receptor (FXR) that has pleiotropic downstream effects in 
the liver. 
• Licogliflozin inhibits two closely related glucose cotransporters (SGLT1 and 2) in the 
gut and kidney. 
• Both compounds are potent and highly specific for their targets. 
• FXR is not associated with changes in SGLT1 or SGLT2 expression or activity, and there 
is no known downstream intersection of the two pathways. 
• Tropifexor specifically increases the enterocyte hormone fibroblast growth factor 19 
(FGF19) that has beneficial metabolic and anti-inflammatory effects. No such effect on 
FGF19 has been described for licogliflozin. 
1.1.6 
Drug interactions 
1.1.6.1 
Tropifexor 
Based upon in vitro investigations as well as a human absorption, distribution, metabolism, and 
excretion (ADME) study (CLJN452A2101), tropifexor metabolism in humans is catalyzed by 
multiple uridine 5'-diphosphoglucuronosyltransferases (UGTs), predominantly UGT1A1 and 
UGT1A3 as well as oxidative metabolism by cytochrome P450 CYP3A4 [DMPK 1809219-01, 
DMPK R1900333]. Recent clinical data with a UGT1A1 inhibitor indicate no clinically relevant 
effect of UGT1A1 inhibition on tropifexor pharmacokinetics (PK). Glucuronidation is likely 
still a relevant clearance pathway for tropifexor but it is typical for inhibition of glucuronidases 
to have small or negligible clinical effects (Williams et al 2004). Strong CYP3A4 inhibitors and 
inducers are prohibited in this study. A clinical study (CLJN452A2103) assessing the effect of 


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strong CYP3A4 inhibitors and inducers on tropifexor PK has been completed after initiation of 
this trial and confirmed the expected interaction: the strong CYP3A4 inhibitor itraconazole 
increased the AUC of tropifexor by 47%; the strong CYP3A4 inducer rifampin decreased the 
AUC of tropifexor by 77-79%.  
Tropifexor is not a substrate of any major transporter including organic anion transporting 
polypeptide OATP1B1, OATP1B3, OATP2B1, organic cation transporter OCT1, P-
glycoprotein (P-gp also known as multidrug resistance protein 1), breast cancer resistance 
protein (BCRP), and multidrug resistance-associated protein 2 (MRP2). Tropifexor at 140 µg 
QD is not anticipated to act as a perpetrator leading to classical drug-drug interaction (DDI) (i.e. 
via inhibition of drug metabolism enzymes or drug transporters). While in vitro inhibition of 
CYP3A4, UGT1A9 and UGT2B7 by tropifexor was observed, due to the low expected Cmax,ss 
(steady state) (0.01 μM at 140 μg QD) no effect on licogliflozin PK is expected see Section 
1.1.6.3. 
1.1.6.2 
Licogliflozin 
Based on the human absorption, distribution, metabolism, and excretion (ADME) study and in 
vitro investigations, licogliflozin is eliminated predominantly via metabolism including direct 
glucuronidation (UGT1A9, UGT2B4/2B7) and oxidation (mainly by CYP3A4). 
Strong CYP3A4 inhibitors and inducers as well as broad UGT inhibitors are prohibited in this 
study to exclude a potentially relevant effect on licogliflozin PK. Licogliflozin is not an 
inhibitor of CYP enzymes including CYP3A4 and is also unlikely to induce drug metabolizing 
enzymes via PXR activation. Licogliflozin inhibits UGT1A1 with IC50 values of 23 μM (total) 
and 19.7 μM (unbound). No clinically relevant effect on UGT1A1 is expected at 30 mg QD, 
the dose to be utilized in the proposed combination study with tropifexor, since Cmax,ss is at 
least 10 fold below IC50. Licogliflozin is a substrate of P-gp, but not of MRP2 and BCRP. 
Licogliflozin did not inhibit the transporters P-gp, BCRP, MRP2, organic anion transporter 1 
(OAT1) and OCT1 and was a poor inhibitor of OATP1B1, OATP1B3, OAT3, OCT2, the multi-
anion and toxin extrusion transporter 1 and multi-anion and toxin extrusion transporter 2-K. 
Overall, licogliflozin has a low potential to act as perpetrator of pharmacokinetic (PK) drug 
interactions and no effect on tropifexor PK is expected see Section 1.1.6.3. 
Due to the very low dose of tropifexor relative to licogliflozin, an impact of licogliflozin on 
tropifexor solubility could influence its absorption and PK. However, a theoretical assessment 
of physicochemical properties does not point to an interaction within the gastrointestinal tract, 
specifically a complex formation is not expected since the two molecules do not bear opposite 
charges over the intestinal pH range. 
1.1.6.3 
Drug interaction between tropifexor and licogliflozin 
The pharmacokinetic drug interaction between tropifexor (140 µg) and licogliflozin (50 mg) 
was investigated in study CLJN452E12101. (LJN452 IB Edition 11) Preliminary data from this 
study confirm the absence of a clinically relevant pharmacokinetic drug interaction between 
these 2 drugs. In the presence of licogliflozin, mean peak plasma concentration (Cmax,ss) of 
tropifexor decreased by 15% and total exposure (AUCtau,ss) decreased by 13%. In the presence 
of tropifexor, mean peak plasma concentrations of licogliflozin increased by 8% and total 
exposure increased by 12%. The small observed changes are within the 0.8-1.25 range and 
therefore below the effect generally considered a weak drug interaction.  


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1.1.7 
Toxicology of tropifexor 
Single oral administration of tropifexor did not cause severe acute toxicity. 
Tropifexor was also evaluated in oral gavage toxicology studies up to 1 month in mice, 26 
weeks in rats, and 39 weeks in dogs. 
Below is a summary of the major findings, their adversity and clinical relevance: 
• Pharmacological effects (direct and indirect) of clinical relevance:  
• Reversible and non-adverse alterations in serum chemistry parameters were noted at 
most dose levels in all species, including but not limited to decreases in bile acids, 
alterations in cholesterol and triglycerides and increases in fibrinogen, blood urea 
nitrogen (BUN) and alkaline phosphatase (ALP) (intestinal and hepatic isoforms). 
• Pharmacological effects (direct and indirect) of limited clinical relevance:  
• In the small and large intestine, reversible clinical signs (abnormal feces and 
emesis/vomiting) and microscopic findings occurred in rats and dogs at doses ≥0.1 
mg/kg/day, becoming dose-limiting at 0.5 mg/kg/day in rats and 0.1 mg/kg/day in 
dogs. Intestinal effects in animals likely resulted from pharmacological interferences 
with intestinal bile acid transporters leading to an increase in fecal bile acids, with 
the dog likely being the most sensitive species due to the higher percentage of 
intestinal taurocholic acid (a bile acid known to produce mucosal damage). 
• In the liver, hepatocellular hypertrophy occurred in mice at doses ≥0.1 mg/kg/day, 
rats at doses ≥0.03 mg/kg/day and dogs at doses ≥0.01 mg/kg/day. Hepatocellular 
hypertrophy was adverse in mice at doses ≥0.3 mg/kg/day and in rats and dogs at 
doses ≥0.1 mg/kg/day based on the consequential injury to the hepatobiliary tree 
(hepatocellular necrosis and/or bile duct hyperplasia and/or eosinophilic foci). This 
change was associated with a minimal hypertrophy/vacuolation of the gall bladder 
epithelium in male dogs at 0.1 mg/kg. Hepatocellular hypertrophy likely represents 
an adaptive response to high hepatic concentration of enzyme-inducing drugs (via 
FXR agonism, indirect nuclear receptor agonism) of limited clinical relevance. 
• In the kidney, vacuolation (at ≥ 100 mg/kg/day, consistent with lipid and likely 
reflecting pharmacological alteration in the lipid metabolism) and increased mitotic 
activity (at 1 mg/kg/day) were noted in the proximal convoluted tubules in short term 
studies in rats. Basophilic tubules were observed at doses ≥ 0.01 mg/kg/day at 13 
weeks but not at 26 weeks at similar doses. Reversible increases in creatinine (with 
or without tubular basophilia) also occurred at doses ≥ 0.1 mg/kg/day. Although 
adverse to the rat, renal tubular effects are monitorable, reversible and potentially of 
low clinical relevance given their absence in dogs at higher systemic exposures. 
• Pharmacological effects (direct and indirect) of no clinical relevance:  
• Reversible increases in total bilirubin (TBL) (primarily due to indirect/unconjugated 
bilirubin) occurred in rats at doses ≥ 1 mg/kg/day. Although adverse to rats by their 
severe magnitude, bilirubin increases are not relevant to humans based on the mode 
of action (i.e. interferences by high and clinically-irrelevant hepatic concentrations 
of tropifexor on bilirubin transport/metabolism via UGT-1A inhibition). 
• Reversible increases in calcium and inorganic phosphorus, occasionally 
accompanied by an increased incidence in renal mineralization, occurred in rats at 


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doses ≥0.1mg/kg/day. Renal mineralization is considered to reflect a 
pharmacological (increased Vitamin D receptor activity) exacerbation of a 
background finding unique to rats. 
The no observed adverse effect level (NOAEL) was 0.03 mg/kg/day in both the 26-week rat 
and the 39-week dog toxicity studies. The systemic exposure at the rat NOAEL was mean 
AUC0-24h 27.1 ng.hr/mL and at the dog NOAEL was mean AUC0-24h 274 ng.hr/mL. Based 
on the nature of the non-clinical findings, their monitorability and reversibility and the fact that 
the dog appears to be the most relevant species for risk assessment, the intended clinical trial 
design, using the selected dose of 140 μg tropifexor, is not considered to pose an undue risk to 
participants. 
1.1.8 
Toxicology of licogliflozin 
The principal target organs of toxicity identified in oral studies in rats (up to 26 weeks in 
duration) and/or dogs (up to 39 weeks in duration) were the gastrointestinal (GI) tract, kidney, 
urinary tract, bone, liver and adrenal gland; effects in these systems were considered related, if 
indirectly, to inhibition of SGLT1/2. In both species, reduced body weight gain was observed 
at almost all doses and weight loss occurred at the highest doses evaluated. 
Rats tolerated licogliflozin at doses up to 100 mg/kg for 4 weeks, with reversible weight loss 
and 1 death at the high dose; doses up to 30 mg/kg were tolerated for 26 weeks. 
Dogs did not tolerate doses ≥10 mg/kg for prolonged periods (i.e. ≥6 weeks) due to body weight 
loss, fecal changes and dehydration. The no observed adverse effect level (NOAEL) for 
licogliflozin was 5 mg/kg/day in the rat and 0.5 mg/kg/day in the dog. 
As expected, dose-dependent glucosuria was observed in non-clinical toxicology studies. Renal 
tubular dilatation was observed in mice (doses ≥ 10 mg/kg/day; 26-week study), rats (doses ≥ 
5 mg/kg/day; 13 and 26 week studies) and dogs (doses ≥ 5 mg/kg/day; 13 and 39 week studies) 
and accompanied by elevations in urinary renal injury biomarkers and urinary microalbumin 
and protein, which all showed evidence of reversibility following an extended 16-week 
recovery period. In the highest dose group of rats (100 mg/kg; 4 week study), renal 
inflammation was observed and was associated with micro-calcifications and elevation in 
urinary renal injury biomarkers. At higher non-tolerated doses in dogs, licogliflozin 
administration resulted in ascending pyelonephritis (doses ≥ 10 mg/kg/day but only in 4 week 
study where urine was collected by catheterization). Increases in urinary calcium, phosphate 
and magnesium, and decreased serum phosphorus and magnesium were present in both rats and 
dogs. 
Dose-dependent soft stool or diarrhea was observed in both rats and dogs (at doses ≥ 100 
mg/kg/day and ≥ 1.5 mg/kg/day, respectively), and cecum hyperplasia was observed in rats. 
Dose-dependent liver glycogen depletion (dogs) and liver cytoplasmic rarefaction attributed to 
glycogen accumulation (rats) were observed. Minimal increases (< 2 fold) in transaminase 
activity were present at high doses in the 4-week rat and dog studies and in the 13-week rat 
study. Dose-dependent, slight, reversible increases in trabecular bone were observed in rats in 
repeated dose studies up to 13 week in duration at doses ≥ 5 mg/kg/day, and were associated 
with increased bone ALP, and decreased serum osteocalcin, vitamin D and parathyroid 
hormone (PTH). No microscopic bone changes were present in the 26 week oral study in rats, 


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which examined similar dose levels, and microscopic bone changes were not observed in the 
dog. 
In vitro studies indicate that licogliflozin is not mutagenic or clastogenic. Licogliflozin is 
considered an aneugen based on in vitro and in vivo data. At the maximal dose for phase 2 
studies (150 mg), licogliflozin is not considered likely to pose an aneugenic risk for human 
participants. 
In embryo-fetal development studies conducted in rats and rabbits, no teratogenicity was 
observed in either species. Fertility was unaffected in studies conducted in rats. Results of a six 
months carcinogenicity study with licogliflozin in a transgenic mouse model indicates that oral 
administration of licogliflozin had no effect on survival and showed no evidence of 
carcinogenic potential. 
Based on the nature of the non-clinical findings, their monitorability and reversibility, the 
intended clinical trial design, using the selected dose of 30 mg licogliflozin, is not considered 
to pose an undue risk to participants. 
1.1.9 
Toxicology of the combination 
Licogliflozin and tropifexor were administered in combination daily via oral gavage to rats for 
at least 13 weeks to assess the reversibility, persistence, or delayed occurrence of any effects 
after an 8 week recovery phase (Study 1770788). 
Licogliflozin / tropifexor-related clinical observations included mucoid feces and yellow 
discoloration of the perineal skin and hair coat on Day 2 of the dosing phase for females 
administered 30/0.1 mg/kg/day licogliflozin / tropifexor. This was transient and, thus, 
considered tolerated. 
Most changes in hematology and serum chemistry were consistent with what was previously 
observed with either licogliflozin or tropifexor and mostly related to the pharmacology of either 
compound, with the exception of 2 males administered 30/0.1 mg/kg/day, who had slightly 
decreased blood pH and slightly elevated ALP. 
At the terminal sacrifice, all the microscopic changes were consistent with the ones previously 
observed with tropifexor and licogliflozin. The primary target organs observed microscopically 
were the liver, kidney, bone, spleen and gastrointestinal tract and were similar in the 
combination study compared to the single agent studies. However, there was a slight increase 
incidence of mucosal hyperplasia in the cecum and colon of animals at 30/0.1 mg/kg/day 
licogliflozin /tropifexor. 
In conclusion, daily oral (gavage) administration of licogliflozin alone or in combination with 
tropifexor for 13 weeks was tolerated up to 30 mg/kg/day (licogliflozin) and 30/0.1 mg/kg/day 
(licogliflozin / tropifexor). The potential combination effects seem to be consistent with the 
pharmacological effect of each of the components. 
1.1.10 
Rationale for testing the combination of tropifexor and licogliflozin 
The rationale for evaluating the combination of tropifexor 140 μg and licogliflozin 30 mg daily 
is based on the following: 
1. 
Each of the drugs used as monotherapy has been shown to have potential benefits 
in treating NASH based on the data available from non-clinical studies, 


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preliminary data in NASH participants for both tropifexor and licogliflozin, and 
a general knowledge about the mechanisms of action of FXR agonists and 
SGLT1/2 inhibitors. The biologic pathways, not overlapping, are therefore 
expected to complement each other and address the three main pathologic 
features of NASH, namely steatosis, inflammation and fibrosis. 
2. 
Based on all preclinical and clinical data for tropifexor and licogliflozin available 
to date, there are no anticipated safety, tolerability or pharmacokinetic concerns 
combining these two drugs at the doses tested in this study. 
3. 
The risk to participants in this trial will be minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical monitoring. 
1.2 
Purpose 
The purpose of this study is to compare tropifexor and licogliflozin in combination therapy and 
each monotherapy to placebo for efficacy, safety, and tolerability in participants with NASH 
and liver fibrosis (stage 2 or 3) as per NASH clinical research network (CRN) histological score. 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of tropifexor 
+ licogliflozin in combination therapy 
and each monotherapy treatment, as 
assessed by histologic improvement 
after 48 weeks compared to placebo 
in participants with NASH and stage 2 
or 3 fibrosis. 
• 
Whether the participant achieves at least one 
stage of improvement in fibrosis without worsening 
of NASH at Week 48 compared to Baseline 
• 
Whether the participant has resolution of NASH 
without worsening of fibrosis at Week 48 compared 
to Baseline 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the efficacy of 
combination therapy and two 
monotherapies in NASH or fibrosis 
with a composite endpoint after 48 
weeks of treatment. 
• 
Key secondary endpoint: Whether the participant 
achieves resolution of NASH and no worsening of 
fibrosis OR improvement in fibrosis by at least one 
stage without worsening of NASH at Week 48 
compared with Baseline. 
• 
To evaluate improvement in fibrosis 
by at least one stage after 48 weeks 
of treatment. 
• 
Whether the participant has at least one stage 
improvement in fibrosis at Week 48 compared with 
Baseline 
• 
To evaluate improvement in fibrosis 
by at least two stages with no 
worsening of NASH after 48 weeks of 
treatment 
• 
Whether the participant has at least two stage 
improvement in fibrosis without worsening of 
NASH at Week 48 compared with Baseline 
• 
To evaluate reduction in body weight 
from Baseline after 48 weeks of 
treatment  
• 
Whether the participant has 5% or more reduction 
in body weight at Week 48 compared to Baseline  
• 
To evaluate change in liver fat content 
after 48 weeks of treatment 
• 
Change in liver fat content based on MRI - PDFF 
(in 40% of participants) over time up to Week 48 
compared with Baseline 


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Objective(s) 
Endpoint(s) 
• 
To evaluate the relationship of 
investigational treatment and markers 
of hepatic inflammation in NASH (ALT 
and AST) after 48 weeks of treatment 
• 
Change in ALT and AST over time up to Week 48 
compared with Baseline 
• 
To evaluate the relationship of 
investigational treatment and GGT, a 
marker of cholestasis and oxidative 
stress after 48 weeks of treatment 
• 
Change in GGT over time up to Week 48 
compared with Baseline 
• 
To evaluate the safety and tolerability 
of tropifexor (LJN452) in combination 
with licogliflozin (LIK066), and each 
monotherapy treatment, compared to 
placebo, after 48 weeks of treatment 
• 
Occurrence of adverse events, serious adverse 
events, adverse events resulting in discontinuation 
of study treatment, adverse events of special 
interest and changes in vital signs and laboratory 
parameters  


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2.1 
Primary estimands 
The primary question of interest to be answered in the trial using liver histology is:  
Does the combination therapy (tropifexor + licogliflozin), administered once per day in 
participants with NASH and stage 2 or 3 fibrosis over 48 weeks, lead to histologic improvement 
compared with placebo treatment? 
This question gives rise to 2 primary estimands, due to 2 different endpoints of interest. 
The first primary estimand has the following attributes with respect to the primary question: 
• Treatment: The randomized treatment (the investigational combination therapy <tropifexor 
140 μg + licogliflozin 30 mg> or the placebo) taken for 48 weeks, irrespective of 
administration or dose changes in anti-diabetic and lipid-lowering concomitant medication 
according to medical need. More details about the treatment are provided in Section 6 
• Population: Participants with NASH (using NAFLD Activity Score (NAS) ≥ 4 with at least 
1 point each in inflammation and ballooning on the screening histology assessment 
performed by the central reader) and stage 2 or 3 fibrosis (using NASH CRN fibrosis 
criteria), as defined by the inclusion and exclusion criteria of the study Section 5. 
• Endpoint: Whether the participant achieves at least one stage improvement in fibrosis 
without worsening of NASH at Week 48 compared with Baseline. 
• Summary measure: Odds ratio of the participants achieving at least one stage improvement 
in fibrosis without worsening of NASH, at Week 48 compared with Baseline, of the two 
treatments for each pairwise comparison. 
The second primary estimand has the subsequent characteristics with respect to the primary 
question: 
• Treatment: The randomized treatment (the investigational combination therapy <tropifexor 
140 μg + licogliflozin 30 mg> or the placebo) taken for 48 weeks, irrespective of 
administration or dose changes in anti-diabetic and lipid-lowering concomitant medication 
according to medical need. 
• Population: Participants with NASH and stage 2 or 3 fibrosis confirmed by biopsy, as 
defined by the inclusion and exclusion criteria of the study. 


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• Endpoint: Whether the participant has resolution of NASH and no worsening of fibrosis at 
Week 48 compared with Baseline. 
• Summary measure: Odds ratio of the participants obtaining resolution of NASH and no 
worsening of fibrosis, at Week 48 compared with Baseline, of the two treatments for each 
pairwise comparison. 
If the answer to the primary question is yes, additional questions may be assessed: 
Does the monotherapy (tropifexor OR licogliflozin) alone, taken once per day by participants 
with NASH and stage 2 or 3 fibrosis over 48 weeks, result in histologic improvement compared 
with placebo? 
If the answer to this question is yes as well, then another question will be evaluated: 
Does the combination therapy lead to more histological improvement than monotherapies? 
For each primary estimand, the population, endpoint, and summary measure for the additional 
questions are the same as those for the primary question.  Only the treatment will change 
accordingly. For the first additional question, the treatment of interest would be monotherapy 
and the control would be placebo, whereas for the second additional question, the treatment of 
interest would be combination therapy and the control would be monotherapy. 
Intercurrent events of primary estimand will be addressed with various strategies (considering 
that these events occur before the histological assessments at Week 48): 
1. Bariatric surgery: participants who have undergone bariatric surgeries during trial 
participation are considered as non-responders (composite variable strategy).  
2. Use of alcohol above protocol permitted amount: the intercurrent events (overuse of alcohol) 
will be ignored for estimation (treatment policy strategy). 
3. Addition or removal of any medication that may have a confounding effect on the endpoints: 
the treatment effect will be assessed with the intercurrent event ignored (treatment policy 
strategy); in the supplementary analysis, the treatment effect will be imputed as if the 
intercurrent event doesn’t occur (hypothetical strategy) 
4. Premature discontinuation of study treatment due to tolerability, efficacy, adherence, or 
adverse event: participants who discontinue the treatment after Week 24 will be asked to 
have their biopsies assessed at Week 48 regardless of the intercurrent event (treatment 
policy strategy), participants who discontinue the treatment before Week 24 will be 
considered as non-responders (composite variable strategy), and participants who have no 
biopsy extracted at Week 48 will be considered as non-responders (composite variable 
strategy). 
5. Death, transplantation and other clinical outcomes: participants will be considered as non-
responder (composite endpoint strategy). 
6. Acute medical condition not related to the study treatment affecting the liver: participants 
will have their Week 48 biopsies assessed regardless of the intercurrent events (treatment 
policy strategy). 
7. Acute medical condition related to the study treatment affecting the liver: participants are 
considered as non-responder (composite endpoint strategy). 


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3 
Study design 
This is a randomized, double-blind, parallel-group, multiple-arm study to assess the efficacy, 
safety and tolerability of tropifexor and licogliflozin combination therapy, and each 
monotherapy compared with placebo as well as the combination therapy compared to each 
monotherapy, in participants with NASH and fibrosis. 
The study consists of 1) a screening period, 2) a treatment period starting from randomization 
on Day 0 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of 
study treatment. Optional pre-screening should also be considered (Section 8.1.1). The 
screening period starts from the time of the first assessment after signing of informed consent 
and continues for up to 10 weeks when all inclusion/exclusion criteria have been evaluated and 
all Baseline assessments have been performed. The study duration from first dose of study 
medication is 52 weeks. The total duration of participation may be up to 62 weeks. 
 
Approximately 380 participants with NASH (NAS ≥4) and fibrosis stage 2 or 3 will be 
randomly assigned to one of the following treatments: 
Arm A: Combination therapy Arm - (N=140): tropifexor 140 μg + licogliflozin 30 mg, 
once daily. 
Arm B: Tropifexor monotherapy Arm - (N=80): tropifexor 140 μg (+ placebo matching 
licogliflozin), once daily. 
Arm C: Licogliflozin monotherapy Arm - (N=80): licogliflozin 30 mg (+ placebo 
matching tropifexor), once daily.  
Arm D: Placebo Arm – (N=80): placebo matching tropifexor + placebo matching licogliflozin 
once daily. 
 


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Figure 3-1 
Study Design  
 
 
 
4 
Rationale 
4.1 
Rationale for study design 
NASH is a complex disease with the involvement of multiple pathways. Combination therapy 
with tropifexor (multimodal effect with anti-steatotic, anti-inflammatory and anti-fibrotic 
properties) and licogliflozin (weight loss through calorie wasting from gut and kidney, better 
glycemic control, decrease in de novo liver lipogenesis) is expected to result in greater efficacy 
and higher number of responders than monotherapy. Each drug works through a different 
mechanism of action, thus allowing potential additive or complementary beneficial effects.  
This study is designed as a randomized, double-blind, parallel-group, multi-center, fixed-dose, 
phase 2 study to assess the efficacy, safety and tolerability of the combination of tropifexor and 
licogliflozin and each compound as monotherapy compared to placebo as well as the 
combination therapy compared to each monotherapy, in participants with NASH F2-F3. The 
primary endpoint is histology-based (whether the participant achieves resolution of NASH and 
no worsening of fibrosis, OR improvement in fibrosis by at least one stage with no worsening 
of NASH at Week 48 compared to Baseline). With supportive key secondary histology 
endpoints and with acceptable safety and tolerability, this study will inform further development 
of the combination in NASH participants (i.e. this is a Phase 3 enabling study). 
 


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4.2 
Rationale for dose/regimen and duration of treatment 
The doses and dosing regimens of licogliflozin and tropifexor are chosen in this study to reflect 
doses and dosing regimens currently under consideration or evaluation in monotherapy NASH 
studies. (See Section 6.7.2 for instructions on taking study treatment). 
Tropifexor is currently being studied in NASH as monotherapy in study CLJN452A2202. The 
doses of 10 to 90 µg tropifexor have been tested and were well tolerated in CLJN452A2202 
Parts A and B, with an observed dose dependent elevation of FGF19, and reduction in liver fat 
content, ALT and GGT. CLJN452A2202 Part A biomarker data, suggested that exposures of 
AUC > 40 ng.hr/mL should be explored. At a dose of 140 µg tropifexor 80% of NASH 
participants are expected to achieve this threshold and it is therefore chosen as the reference 
dose for the monotherapy and the combination arms in this study. CLJN452A2202 is ongoing 
with doses of 140 µg and 200 µg once daily being tested in Part C. The Week 12 analysis of the 
CLJN452A2202 part C data revealed clear and significant dose response in ALT, PDFF, GGT 
and body weight reduction. The overall rate of adverse events and SAEs was similar across 
treatment groups, with an increase in pruritus with tropifexor compared to placebo. 
Licogliflozin is currently being tested as 30 mg and 150 mg QD monotherapy in NASH 
(CLIK066X2204). An interim analysis showed promising reduction of ALT, AST, GGT, body 
weight, waist circumference, hemoglobin A1c and liver fat. The majority of AEs reported were 
GI in nature, specifically mild diarrhea. The incidence of diarrhea was similar between the 
placebo and 30 mg treatment groups. One participants in each treatment group discontinued 
study medication due to an AE. No SAEs have been reported in participants treated with 
licogliflozin in this study.  
A range of doses from 2.5 to 150 mg licogliflozin have been tested in obese participants (both 
Japanese and non-Japanese). In obese Japanese participants over 12 weeks of treatment with 
placebo, 2.5, 10, 25 or 50 mg once daily licogliflozin, 30 mg appeared to be at the plateau of 
the observed dose-body weight loss curve. However, the rate of diarrhea events increased 
largely between 25 mg and 50 mg from about 14% to about 39% [CLIK066B1201]. In obese 
non-Japanese participants over 24 weeks of treatment with placebo, 2.5, 10, 50 or 150 mg once 
daily licogliflozin, 30 mg appeared to be near the plateau of the observed dose-body weight loss 
curve, and the  incidence of diarrhea increased from about 16% to about 55%  in the  10 mg and 
50 mg treatment groups, respectively [CLIK066B2201]. Thus 30 mg is expected to have a 
similar body weight loss while considerably lower diarrhea incidence compared to 50 mg and 
is therefore preferred. Assuming that data from obese participants are indicative of NASH 
participants for both body weight loss and diarrhea events, as suggested by the 150 mg dose 
(with diarrhea events of 18/22 vs 52/77 for NASH vs obese participants), 30 mg is selected for 
this combination. 
In summary, the doses for this study were selected based on the expectation of achieving 
increased efficacy with the combination therapy, compared to individual monotherapies, while 
maintaining tolerability and safety of the participants. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Currently there is no drug established as standard of care for participants with NASH. 
Combination of tropifexor and licogliflozin and each of these compounds as monotherapy will 


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be compared to placebo. Subsequently, the combination treatment will be compared to each of 
the monotherapies. 
A placebo treatment group was added to improve the assay sensitivity and interpretation of the 
treatment effect given the wide variability observed in histological response in recent studies 
for those participants receiving standard of care. 
4.4 
Purpose and timing of interim analyses/design adaptations 
No interim analysis is planned for this study. 
4.5 
Risks and benefits 
When used as monotherapy, tropifexor and licogliflozin have been shown to have potential 
benefits in treating NASH. Based on the mechanisms of action of FXR agonists and SGLT1/2 
inhibitors and the fact that the biologic pathways do not overlap, it is expected that they will 
complement each other and address the three main pathologic features of NASH, namely 
steatosis, inflammation and fibrosis. 
Appropriate eligibility criteria as well as specific stopping rules, are included in this protocol. 
Recommended guidelines for supportive management of study drug induced adverse events are 
provided in Section 10.2.  
The risk to participants in this trial is minimized by compliance with the eligibility criteria and 
study procedures, as well as close clinical monitoring, stopping rules and periodic review of 
safety data by an independent DMC.  
Toxicology of the combination is described in Section 1.1.9. All potential risks of each 
compound are described in the tropifexor and licogliflozin IBs. A brief summary of the benefits 
and risks of each compound follows: 
4.5.1 
Tropifexor 
Based on the mechanism of action of tropifexor as a highly potent and specific agonist of the 
Farnesoid X Receptor (FXR) and data acquired in nonclinical toxicology studies, the First-in-
Human study CLJN452X2101, and the ongoing Phase 2b CLJN452A2202 study, the risk-
benefit assessment of tropifexor is as follows: 
4.5.1.1 
Benefits 
Due to its multimodal mechanism of action, tropifexor treatment may have the anticipated 
benefits on biliary metabolism (reduced synthesis and increased detoxification), lipid 
distribution (lowering hepatic triglycerides accumulation) as well as anti-inflammatory and 
anti-fibrotic properties, leading to reduction of hepatic fibrosis and improvement of participant 
outcomes over longer term treatment. In study CLJN452A2202 in NASH, marked decreases in 
transaminases and in GGT, liver fat content and body weight were observed in a dose dependent 
manner, in participants receiving tropifexor compared to placebo.  


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4.5.1.2 
Risks 
Non-clinical 
Liver effects: In rats, hepatic effects (hepatocellular vacuolation periportal hepatocellular 
hypertrophy, and bile duct hyperplasia as well as increases in FXR target gene for alkaline 
phosphatase expression) occurred at tropifexor doses ≥ 0.03 mg/kg/day in toxicity studies 
ranging from 2 weeks to 26 weeks in duration. All hepatic effects were either absent or 
decreased in incidence and severity by the end of the tropifexor-free recovery period indicating 
that full recovery would likely have been achieved with a longer recovery period. In addition, 
tropifexor was protective in various rodent models of liver disease/impairment including a 
model of drug-induced cholangiohepatitis and Alpha-naphthylisothiocyanate (ANIT) induced 
cholestasis. 
Normal healthy human volunteers 
Transient and asymptomatic increases in ALT were observed in healthy volunteers. This ALT 
increase was rapid in onset and resolved despite continued dosing, indicative of adaptation in 
humans.  
NASH Participants  
Of note, increases in transaminases similar to those observed in healthy volunteers were not 
seen in NASH participants in CLJN452A2202. Participants with impaired liver function and 
liver diseases other than NASH are excluded from the ELIVATE study (see exclusion criteria 
#9 and #10) and liver function tests including transaminases are monitored closely throughout 
study participation.  Guidelines for the evaluation and detection of potential toxicities and for 
their management and for minimization of risk are discussed in the tropifexor IB and in 
Appendix 2 of this protocol. 
Pruritus and lipid alterations (LDL-C elevation and HDL-C reduction) have been noted in 
clinical trials with FXR agonists (including tropifexor) and may be dose dependent. Both will 
be closely monitored in this study (please see the tropifexor IB for details). 
Study CLJN452A2103 confirmed that the strong CYP3A4 inhibitor itraconazole increased the 
AUC of tropifexor by 47% and the strong CYP3A4 inducer rifampin decreased the AUC of 
tropifexor by 77-79% (Section 1.1.6.1). Therefore strong CYP3A4 inhibitors and inducers are 
prohibited during study participation (Section 6.2.2) 
The Data Monitoring Committee (DMC) will review safety data at regular intervals throughout 
the study. 
4.5.2 
Licogliflozin 
4.5.2.1 
Benefits 
Numerous lines of evidence, including data from a licogliflozin First–in-Human (FIH) clinical 
study CLIK066X2101, indicate that combining the effects of both SGLT1 and SGLT2 
inhibition may offer more effective and safe treatment for obesity and diabetes via numerous 
mechanisms (Zambrowicz et al 2012). For example, SGLT2 inhibition increases urinary 


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glucose excretion in both healthy participants and participants with T2DM, and lower glucose 
levels occur without hypoglycemia due to an insulin independent mechanism of action 
(Komoroski et al 2009a). Clinical validation of SGLT2 inhibitors as therapeutic targets for 
T2DM has been firmly demonstrated, and these compounds are now in wide use for T2DM 
(Wilding et al 2009, Komoroski et al 2009b). Agents such as dapagliflozin and canagliflozin 
also have additional beneficial effects on blood pressure and body weight (decrease ~2-3% 
compared to placebo; Scheen and Paquot 2014). In support of the link between obesity and 
hepatic injury related to excess accumulation of fat in the liver, weight loss leads to 
improvement in histologic NASH. This suggests that targeting obesity in NASH participants is 
likely a therapeutic opportunity to limit or reverse liver disease progression (Lassailly et al 2015, 
Vilar-Gomez  et al 2015). 
Inhibition of SGLT1 in the gut results in additional numerous weight-lowering mechanisms 
including calorie wasting from the gut, lower postprandial insulin levels, and an increase in 
incretin hormone (GLP-1, PYY) release as a consequence of distal, unabsorbed glucose in the 
gut (Sadry  and Drucker 2013). When dosed close to a meal, licogliflozin has more marked 
efficacy in lowering postprandial glucose, lowering insulin levels, and increasing incretin 
hormones than when administered 6 hours or more prior to a meal, suggesting that gut luminal 
exposure to licogliflozin is required for SGLT1 inhibition. The additional benefit of SGLT1 
inhibition also carries the risk of diarrhea due to glucose malabsorption. The orally administered, 
dual SGLT1/2 inhibitor licogliflozin has demonstrated safety, tolerability and efficacy in 
obesity and diabetes (LIK066 IB, Edition 10). 
CLIK066X2204 study tested licogliflozin at doses of 30 and 150 mg for 12 weeks in NASH 
participants. Results from full study population confirmed that treatment with licogliflozin at 
150 mg and 30 mg per day resulted in dose-dependent improvements in markers of liver injury 
(ALT, AST and GGT) and liver fat content(LIK066 IB edition 12).The clinical study report is 
currently in preparation.  Both doses of licogliflozin led to significant placebo adjusted weight 
loss at the 150 mg and 30 mg doses respectively. (LIK066 IB). Licogliflozin treatment also 
improved glycemic and insulin sensitivity markers; HbA1c and HOMA-IR at both doses. 
4.5.2.2 
Risks 
Risks of SGLT1/2 inhibition in human participants may include the development of diarrhea 
and genital and urinary tract infection (secondary to glucosuria). In study CLIK066X2204, the 
most common AE was diarrhea, reported by similar number of participants in the placebo and 
30 mg groups but at a higher rate in the 150 mg dose group. As in previous studies with 
licogliflozin, diarrhea was mostly mild in the participants who had it. Only one participant in 
the 150 mg dose group discontinued treatment as a result of diarrhea (LIK066 IB Edition 12). 
Other potential risks based on reports with marketed SGLT2 inhibitors include hypoglycemia, 
Fournier’s gangrene (necrotizing fasciitis of the genitalia and perineum), intravascular volume 
depletion, ketoacidosis, electrolyte disturbance and lower limb (toe) amputation. Appropriate 
exclusion criteria are applied in this study and guidance is provided to mitigate the risks as per 
Section 10.2.3. It is recommended that bilateral foot exams be performed at screening to assess 
the presence of any foot deformity (including amputation), disease, and/or the presence of 
clinically significant neuropathy that may increase the risk of amputation. Guidelines for the 
evaluation and detection of potential toxicities, their management and minimization of risk are 
discussed in detail in the LIK066 IB. The relatively low exposure associated with the dose of 


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licogliflozin proposed in this study has been tested and is deemed safe in healthy participants, 
T2DM participants, and obese participants. 
4.5.3 
Study conduct 
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 must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
Participants participating in this study might have reductions in hepatic fat and liver fibrosis; it 
is possible that this is a clinical benefit. For this reason, paired liver biopsies (Screening and 
Week 48) have been included in this study. Screening biopsies will confirm the diagnosis of 
NASH (steatosis, lobular inflammation, hepatocyte ballooning) and presence of fibrosis. The 
primary risks of liver biopsy are pain and bleeding from the site of needle entry into the liver, 
although the latter occurs in less than one percent of participants. Other possible major 
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 participants 
prior to a biopsy. 
There may be participant benefit in the ancillary dietary and exercise counseling accompanying 
the pharmacologic intervention. 
MRI makes use of powerful magnetic fields and radio waves, which are believed to cause no 
direct adverse consequences when used within approved specifications. No MRI-contrast will 
be administered in this study. Thus in principle, MRI scans can be repeated in the same 
participants 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. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a public health emergency as declared by Local or Regional authorities, i.e,. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and should be 
permitted/approved by Local or Regional Health authorities and Ethics Committees as 
appropriate. 
5 
Study Population 
The study population will consist of approximately 380 adult male and female participants with 
histologic evidence of NASH and fibrosis stage 2 or 3 as per NASH CRN histological score; 
see Inclusion and Exclusion criteria for details. 
The study will be conducted in approximately 155 centers worldwide. Since a screening failure 
rate is expected to be around 70%, approximately 1267 participants may be screened. 


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The Investigator will ensure that all participants being considered for the study have met the 
eligibility criteria. No additional criteria should be applied by the investigator so that the study 
population will be representative of all eligible participants. 
Participant selection will be established by checking through all inclusion/exclusion criteria at 
screening and Baseline. A relevant record of the eligibility criteria must be stored with the 
source documentation at the study center. 
Deviation from any entry criterion excludes a participant from enrollment into the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male and female participants 18 years or older (at the time of the screening visit) 
3. Presence of NASH with fibrosis confirmed by central reader's evaluation of liver biopsy 
obtained no more than 6 months before randomization as demonstrated by the 
following:  
a. NASH using NAFLD Activity Score (NAS) ≥ 4 with at least 1 point each in 
inflammation and ballooning on the screening histology assessment 
performed by the central reader 
and 
b. Fibrosis stage 2 or 3  using NASH CRN fibrosis criteria (see Table 8-2 & 
Table 8-3) 
4. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Taking medications prohibited by the protocol. (see Section 6.2.2, Table 6-3) 
2. Pregnant or nursing (lactating) women. 
3. Weight at Baseline changed by > 5% since qualifying liver biopsy. 
4. History of hypersensitivity to either of the study drugs or their excipients or to drugs of 
similar chemical classes, or participants with hereditary galactose intolerance, lactase 
deficiency or glucose-galactose malabsorption. 
5. Taking a permitted medication listed in Table 6-2 but who is NOT on a stable dose 
(within 25% of Baseline dose) from the start of the screening period and 
a. for at least 3 months prior to the Baseline visit for thyroid hormone, oral anti-
diabetic medication, insulin, GLP-1 agonists, and estrogen or estrogen 
containing birth control 
b. for at least 6 months prior to Baseline for Vitamin E 
6. Current, or history of, significant alcohol consumption for a period of more than 3 
consecutive months within 1 year prior to screening.  
a. Significant alcohol consumption is defined as more than 20 g/day (14 
units/week) in females, or more than 30 g/day (21 units/week) in males, on 


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average. A “unit” of alcohol is equivalent to one (12-ounce; 355 ml) beer, 
one glass (4-ounce; 120 ml) of wine, or 1 shot (ounce; 30 ml) of hard liquor.  
or  
b. A score on the alcohol use disorders identification test (AUDIT) questionnaire 
≥ 8.  
7. Diabetes related: 
a. Type 1 diabetes mellitus. 
b. Uncontrolled type 2 diabetes defined as HbA1c ≥ 9.0% at screening.  
c. HbA1c < 6.5% at screening in Type 2 diabetics currently treated with insulin 
or sulfonylureas. 
8. Platelet count < LLN (see Central laboratory manual).  
9. Clinical evidence of liver impairment as defined by the presence of any of the following 
abnormalities: 
a. Serum albumin < LLN (see Central laboratory manual). 
b. International Normalized Ratio (INR) > ULN (see Central laboratory 
manual). 
c. ALT or AST > 5× ULN (in either of the 2 values during screening).  
d. Total bilirubin > ULN (see Central laboratory manual) (in either of the 2 
values during screening), including Gilbert’s syndrome. 
e. Alkaline phosphatase > 300 IU/L (in either of the 2 values during screening). 
f. History of esophageal varices, ascites or hepatic encephalopathy. 
g. Splenomegaly. 
h. MELD score >12. 
10. Other forms of chronic liver disease: 
a. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg). 
b. Hepatitis C as defined by presence of detectable hepatitis C virus (HCV) 
RNA. 
c. Autoimmune liver disease. 
d. Primary biliary cholangitis. 
e. Primary sclerosing cholangitis 
f. Wilson's disease. 
g. Alpha-1-antitrypsin (A1AT) deficiency. 
h. Hemochromatosis or iron overload. 
i. Drug-induced liver disease as defined on the basis of typical exposure and 
history. 
j. Bile duct obstruction. 
k. Suspected or proven liver cancer. 
l. Any other type of liver disease other than NASH. 
m. Hepatitis A as defined by presence of Immunoglobulin M (IgM) antibodies 
to HAV (IgM anti-HAV). 
11. History of liver transplantation or planned liver transplant. 
12. History of biliary diversion. 


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13. History or current diagnosis of ECG abnormalities based on Central ECG report 
indicating significant risk of safety for participants participating in the study such as: 
a. Concomitant clinically significant cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker. 
b. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment 
screening.    
c. History of familial long QT syndrome or known family history of Torsade de 
Pointes. 
14. Medical history of pancreatitis (acute or chronic). 
15. Amylase and/or lipase >3 X ULN. 
16. Prior or planned (during study period) bariatric surgery. 
17. Calculated eGFR < 60 mL/min/1.73m2 (using the MDRD formula).  
18. Hyperkalemia defined as potassium level > 5.2 millimoles per liter (mmol/L) 
19. Chronic (> 3 months) use of excessive doses of Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs) as evaluated by investigator. 
20. Ketoacidosis, lactic acidosis, or hyperosmolar coma within six months of 
randomization. 
21. History of lower limb amputation (including toe amputation) unless due to trauma. 
22. Diabetic complications, known peripheral vascular disease or clinically significant 
neuropathy that may increase the risk of amputation. 
23. Symptomatic genital or urinary tract infection within 4 weeks prior to randomization or 
participants with high risk as, determined by the investigator (including concomitant 
therapy with immunosuppressive potential), to be particularly susceptible to genital or 
urinary tract infection. 
24. Recent history of gastrointestinal disorder associated with chronic diarrhea. 
25. Any history of and/or suspected Fournier’s gangrene, or participants with high risk as, 
determined by the investigator (including concomitant therapy with 
immunosuppressive potential), to be particularly susceptible to Fournier’s gangrene. 
26. Diabetic foot ulcer within 4 weeks prior to randomization. 
27. History of inflammatory bowel disease (ulcerative colitis, Crohn’s disease).  
28. Known positivity for Human Immunodeficiency Virus (HIV) infection. HIV 
antigen/antibody tests will be performed to determine HIV status if allowed and required 
according to local regulations. 
29. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. 
30. History or evidence of ongoing drug abuse, within the last 6 months prior to 
randomization.  
31. Use of other investigational drugs within 5 half-lives of randomization, or within 30 
days, whichever is longer. 


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32. Previous exposure to any other investigational or recently (2019 onwards) approved 
NASH treatment within 6 months prior to qualifying biopsy (participants known to have 
only received placebo may be included). 
33. Sexually active males must use a condom during intercourse while taking drug and for 5 
days after stopping investigational 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 study drug via seminal fluid. (With amendment version 01, this exclusion 
criterion is no longer applicable).  
34. 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) after stopping of 
investigational medication. Highly effective contraception methods include: 
a. Total abstinence (when this is in line with the preferred and usual lifestyle of 
the participant). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
b. Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) total hysterectomy or bilateral tubal ligation at least 
six weeks before taking investigational drug. In case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 
c. Male sterilization (at least 6 months prior to screening). For female 
participants on the study, the vasectomized male partner should be the sole 
partner for that participant. 
d. Use of oral, (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS) or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms).Women are considered not of child 
bearing potential if they are post-menopausal or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral 
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. 
If local regulations deviate from the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF. 
 
35. Any other condition which, in the opinion of the investigator, would impede 
compliance or hinder completion of the study. 


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Exclusionary laboratory tests can be repeated for eligibility during the screening period if the 
sample is compromised or otherwise reasonably suspected of being inaccurate. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
The 140 μg dose of tropifexor and its matching placebo are each now available as a single hard 
gelatin capsule. Participating at the time of availability of the single tropifexor/placebo capsule, 
may continue on the 3-capsule tropifexor (100 μg + 30 μg + 10 μg) or matching placebo regimen 
described in protocol v01 until the available 3-capsule supply is depleted. After the 3-capsule 
supply is depleted, participants will take one 140 μg tropifexor or matching placebo capsule 
daily as described in Table 6-1. See Sections 6.1.3 and Section 6.7.2 for additional information 
regarding tropifexor dosing utilizing the 3 capsule and single capsule regimens.  No change has 
been made to licogliflozin dosing.   
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administratio
n 
Presentation 
Type  
 
Sponsor 
(global or 
local) 
Tropifexor 
(LJN452) 140 μg 
 
140 μg hard gelatin 
capsule  
 
 
Oral 
Double blind 
Novartis 
(global) 
Placebo 
Tropifexor 
(LJN452) 140 μg 
 
Hard gelatin capsule 
matching to 
tropifexor (LJN452) 
140 μg  
 
 
Oral 
Double blind 
Novartis 
(global) 
Licogliflozin 
(LIK066) 30 mg 
10 mg film coated 
tablets 
Oral 
Double blind 
Novartis 
(global) 
Placebo 
Licogliflozin 
(LIK066) 30 mg 
Film coated tablets 
matching to 
licogliflozin (LIK066) 
10 mg 
Oral 
Double blind 
Novartis 
(global) 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
An overview of the prohibited medication is given in Table 6-3, and the summary of permitted 
medication if on stable dose is in Table 6-2. 


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6.1.3 
Treatment arms/group 
Participants (n = 380) will be assigned at Baseline visit to one of the following 4 treatment arms 
in a ratio of 1.75:1:1:1 in a blinded manner. Placebo capsules/tablets will be given in each 
treatment arm where necessary to maintain blinding. 
Arm A: Combination therapy Arm - (N=140): tropifexor 140 μg + licogliflozin 30 mg, once 
daily. 
Arm B: Tropifexor monotherapy Arm - (N=80): tropifexor 140 μg (+ placebo matching 
licogliflozin), once daily. 
Arm C: Licogliflozin monotherapy Arm - (N=80): licogliflozin 30 mg (+ placebo matching 
tropifexor), once daily.  
Arm D: Placebo Arm – (N=80): placebo matching tropifexor + placebo matching licogliflozin, 
once daily. 
The 140 μg dose of tropifexor and its matching placebo are each now available as a single hard 
gelatin capsule. Participants participating at the time of availability of the single 
tropifexor/placebo capsule, may continue on the 3-capsule tropifexor (100 μg + 30 μg + 10 μg) 
or matching placebo regimen until the available 3- capsule supply is depleted. After the 3-
capsule tropifexor or matching placebo supply is depleted, participants will take one 140 μg 
tropifexor or matching placebo capsule daily. No change is made to licogliflozin dosing. Further 
details can be found below and in Section 6.7.2. 
6.1.3.1 
Dosing with 3 capsule (10 + 30 + 100 μg) tropifexor supply 
Until 3-capsule tropifexor (100 μg + 30 μg + 10 μg) and matching placebo is replaced by the 
140 μg hard gelatin single capsule, in order to maintain the blind, placebo capsules matching 
tropifexor (LJN452) 10, 30 and 100 µg and placebo tablets matching licogliflozin (LIK066) 10 
mg will be given to participants as indicated in Table 6-5, so that all participants will receive 3 
capsules and 3 tablets per day. One capsule from each of the 3 bottles, and 3 tablets from the 
blister pack should be taken close to the evening meal; either just prior to (within 5 minutes) 
consuming the evening meal, or no more than 30 minutes after consuming the evening meal 
and at about the same time each day.  
6.1.3.2 
Dosing with single capsule (140 μg) tropifexor supply 
After tropifexor and matching placebo is replaced by the 140 μg hard gelatin single capsule, in 
order to maintain the blind, placebo capsules matching tropifexor 140 µg and placebo tablets 
matching licogliflozin (LIK066) 10 mg will be given to participants as indicated in Table 6-6, 
so that all participants will receive 1 capsule and 3 tablets per day. One capsule from the bottle, 
and 3 tablets from the blister pack should be taken close to the evening meal; either just prior 
to (within 5 minutes) consuming the evening meal, or no more than 30 minutes after consuming 
the evening meal and at about the same time each day. 
6.1.4 
Treatment duration 
The planned duration of treatment is 48 weeks. Participants may be discontinued from treatment 
earlier due to unacceptable tolerability, disease progression and/or at the discretion of the 
investigator or the participant. 


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If discontinuation of study treatment occurs, the participant should NOT be considered 
withdrawn from the study. The participant should return to the clinic as soon as possible, after 
discontinuation of study drug. In this case, if the participant and study investigator agree, 
participant may continue in the study without treatment.
 
 Alternatively, a study treatment discontinuation visit 
will be conducted. 
6.2 
Other treatment(s) 
No other treatment beyond investigational drug and control drug are included in this trial. 
An overview of the prohibited medication is given in Table 6-3, and the summary of permitted 
medication if on stable dose is in Table 6-2. 
6.2.1 
Concomitant therapy 
The investigator must instruct the participant to notify the study site about any new medications 
he/she takes after the participant is enrolled into the study.  
All medications, vaccines, procedures, and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the participant was enrolled into the study 
must be recorded on the appropriate case report forms (CRF).   
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. There are no restrictions related to COVID-19 vaccines, and these are allowed 
throughout study participation as permitted by local regulations. 
Drugs to control medically significant lipid abnormalities (which have been confirmed upon 
repeat testing) can be prescribed according to local standard of care. Participants on medications 
specified in Table 6-2 can be included if these medications are medically necessary, and the 
investigator feels the dose will remain stable for the duration of the double-blind treatment 
period. In addition, doses of oral anti-diabetic medication, insulin, GLP-1 agonists, thyroid 
hormone, and estrogen or estrogen containing birth control, must be stable for at least 3 months 
prior to the Baseline visit. Sliding scale insulin therapy is allowed if this approach has been 
implemented for at least 3 months prior to the Baseline visit. Insulin dose adjustment is 
permitted during the study if required. Doses of vitamin E ≤ 800 IU/day must be stable for at 
least 6 months prior to the Baseline visit. A stable dose is defined as a dose within 25% of the 
Baseline dose. New use or dose adjustments > 25% of the Baseline dose of these medications 
is not allowed after entering the study. 
 
 


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6.2.1.1 Permitted concomitant therapy requiring caution and/or action 
Table 6-2 
Medications permitted only if dose is stable (within 25 percent of 
Baseline dose) and expected to remain stable through the double-
blind treatment period 
Medication 
Stable dose start 
Oral anti-diabetic medications 
At least 3 months prior to the Baseline visit 
Insulin 
At least 3 months prior to the Baseline visit 
GLP-1 agonists such as liraglutide, exenatide, 
lixisenatide, albiglutide or dulaglutide 
At least 3 months prior to the Baseline visit 
Beta-blockers and thiazide diuretics 
At or before Screening Visit 1 
Vitamin E < 800 IU/day 
At least 6 months prior to the Baseline visit 
Thyroid hormone 
At least 3 months prior to the Baseline visit 
Phenothiazines  
At or before Screening Visit 1 
Estrogen or estrogen containing birth control 
At least 3 months prior to the Baseline visit 
 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below Table 6-3 is NOT allowed after the start of 
investigational drug, and should be discontinued as soon as screening is considered so that 
participants medications and conditions are stable and the screening assessments reflect the 
participant’s Baseline condition.   
Alcohol consumption is to be strongly discouraged, and if consumed should not exceed 20 g/day 
(14 units/week) in females and 30 g/day (21 units/week) in males. A “unit” of alcohol is 
equivalent to 12-ounce, 355 ml beer, 4-ounce, 120 ml glass of wine, or 1 ounce, 30 ml shot of 
hard liquor. 
Use of methotrexate is prohibited as liver fibrosis has been reported with its chronic use.  
A study in healthy volunteers was conducted to investigate the effect of UDP 
glucuronosyltransferase (UGT) inhibition on the pharmacokinetics (PK) of tropifexor by co-
administration with the UGT1A1 inhibitor, atazanavir (ATZ) (CLJN452A2110). The inhibition 
of UGT1A1 by ATZ did not lead to increased exposure of tropifexor, suggesting that inhibition 
of the UGT1A1 pathway has no clinically relevant impact on tropifexor PK. Therefore, no 
Drug-Drug Interactions are expected between tropifexor and UGT1A1 inhibitors based on 
UGT1A1 activity / genotype, and therefore use of these compounds is not prohibited in this 
study. Non-selective UGT inhibitors are prohibited. 
 
 


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Table 6-3 
Prohibited medications 
Medication 
Timing 
SGLT2 Inhibitors or combined SGLT1/2 
inhibitors 
Such as: canagliflozin, dapagliflozin, 
empagliflozin 
Stop at least 3 months prior to Baseline 
Pharmacologically active weight-loss 
medications 
Such as: lorcaserin, phentermine/topiramate, 
bupropion-naltrexone HCL, orlistat) 
Stop at least 3 months prior to Baseline 
Treatment with drugs that have a high incidence 
of diarrhea 
Such as: Orlistat, Acarbose. 
Stop at or before Screening Visit 1 
Treatment with drugs that alter intestinal motility 
Such as: e.g. erythromycin, metoclopramide, 
tegaserod, methylnaltrexone, alvimopan, 
loperamide, diphenoxylate and atropine 
(Lomotil) and difenoxin and atropine (Motofen)) 
Stop at or before Screening Visit 1 
Non-selective UGT inhibitors: 
Such as: diclofenac, probenecid, valproic acid 
Stop at or before Baseline 
Strong CYP3A4 inhibitors: 
Such as: viekira Pak, indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat (GS-
9350) ,indinavir, ketoconazole, troleandomycin, 
telaprevir, danoprevir/ritonavir, 
elvitegravir/ritonavir, saquinavir/ritonavir, 
lopinavir/ritonavir, itraconazole, 
voriconazole,mibefradil, LCL161, clarithromycin, 
posaconazole, telithromycin, grapefruit juice, 
conivaptan, nefazodone, nelfinavir, saquinavir, 
idelalisib, boceprevir, darunavir/ritonavir. 
Stop at or before Baseline 
Strong CYP3A4 inducers: 
Such as: avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort (Hypericum 
perforatum), rifabutin, phenobarbital, mitotane, 
enzalutamide. 
Stop at or before Baseline 
Methotrexate 
Stop at least 3 months prior to Baseline 
Vitamin E doses > 800 IU/day 
Stop (or reduce dose) at least 6 months prior 
to Baseline 
Drugs approved in any market for treatment of 
NASH 
Stop at least 6 months prior to Baseline 
Alternative Liver Protection medication: 
Silymarin; Bicyclol; Polyene Phosphatidylcholine 
(Essentiale); Diammonium Glycyrrhizinate; 
Reduced glutathione (GSH); S-
adenosylmethionine–methionine; 
Ursodeoxycholic Acid (UDCA) 
Stop at or before Screening Visit 1 


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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is uniquely identified in the study by a Participant Number (Participant No.) 
assigned by Novartis when the participant is first enrolled for screening and is retained as the 
primary identifier for the participant throughout his/her entire participation in the trial. 
The participant number, assigned by Novartis, is composed of a Site Number (Site No.) and a 
sequential participant number suffixed to it, so that each participant is numbered uniquely across 
the entire database. Once assigned to a participant, the participant number will not be reused. 
Upon signing the informed consent form, the participant is assigned the next sequential number 
available in electronic data capture (EDC) system. The investigator or his/her staff will contact 
the IRT and provide the requested identifying information for the participant to register them 
into the IRT. The site must select the case report form (CRF) book with a matching Participant 
Number in the EDC system to enter data. 
If a participant fails screening and rescreens for the study, THEN the participant must sign a 
new ICF and be issued a new participant number prior to any screening assessment being 
conducted for the participant under the new screening participant number. If the participant fails 
to be treated for any reason, the IRT must be notified within 2 days that the participant was not 
treated. The reason for not being treated will be entered on the appropriate CRF. 
6.3.2 
Treatment assignment, randomization 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of treatment arms to randomization numbers. These 
randomization numbers are linked to the different treatment arms. 
At Baseline visit, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the participants fulfills all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the participant, which will be used to link the 
participants to a treatment arm and will specify a unique medication number for the first 
package of study drug to be dispensed to the participant. The randomization number will not be 
communicated to the caller. 
Japanese participants will be assigned to treatment arms with randomization blocking for Japan 
that is separate from the randomization for all other countries.  
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). 
This will allow a balanced assignment of participants to each treatment arm. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Group. 


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6.3.3 
Stratification 
There will be no stratification for Japanese participants. They will be included in a separate 
randomization list as described in Section 6.3.2. 
To ensure balance of participants among the 4 treatment groups, the following stratum levels 
will be implemented: 
• T2DM yes 
• T2DM no 
6.4 
Treatment blinding 
This is a double-blind study: participants, 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: 
 
 
2. Randomization data will be kept strictly confidential until the time of final database 
lock and will not be accessible by anyone else involved in the study with the 
exceptions in Table 6-4.  
a. The randomization codes will be disclosed to an independent analysis team 
to prepare safety and efficacy reports for the DMC. The independent 
analysts will keep randomization data confidential until data base lock. Data 
will be shared with the study team under blinded conditions. 
 
 
 
3. The identity of the treatments will be concealed by the use of placebo that are each 
identical in packaging, labeling, schedule of administration, appearance, taste and 
odor to the respective active treatment. Placebo capsules/tablet will be given in 
active treatment groups when needed to maintain blinding as described in 
Section 6.1.3.  
A double-dummy design is used because the identity of the study treatment cannot be disguised, 
as the drug products are visibly different. 
Unblinding will only occur in the case of participant emergencies (see Section 6.6.2) and at the 
conclusion of the study. Unblinding a single participant’s treatment at a site for safety reasons 
(necessary for participant management) will occur via an emergency system in place at the site. 
As a result the participant should be discontinued from the study treatment. 
 
 
At the time of safety review, the DMC will review unblinded reports created by an independent 
analysis team. More details will be provided in the DMC charter. 


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Table 6-4 
Blinding and unblinding plan 
 
Time or Event 
 
Role 
Randomizatio
n list 
generated 
Treatment 
allocation 
& dosing 
Safety 
event 
(single 
participant 
unblinded) 
Safety 
review 
Participants 
B 
B 
B 
B 
Site staff 
B 
B 
UI 
B 
Novartis CTT 
B 
B 
UI 
B 
Global Clinical Supply  
UG 
B 
UI 
B 
Randomization Office 
UI 
UI 
UI 
UI 
Unblinded Pharmacovigilance sponsor 
staff 
B 
UI 
UI 
B 
Statistician/statistical programmer 
B 
B 
UI 
B 
Data Monitoring Committee(DMC) and 
independent statistician/programmer 
supporting DMC 
UI 
UI 
UI 
UI 
All other sponsor staff not identified 
above (i.e. trial team, project team, 
management & decision boards, 
support functions) 
B 
B 
B 
B 
Key: 
UG: Unblinded at the group level (i.e has access to unblinded group level summary results, but not to 
the individual participant treatment codes) 
UI: Unblinded to individual participant treatment codes 
B: Completely blinded 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose escalation guidelines 
There is no provision for dose escalation of study medication doses in the protocol 
6.5.1.1 
Starting dose 
Not applicable 
6.5.2 
Definitions of dose limiting toxicities (DLTs) 
Not applicable as this is not a dose ranging study. 
6.5.3 
Dose modifications 
Temporary interruptions of study medication are permitted. Study medication should be 
reintroduced under careful monitoring if the investigator feels it is in the best interest of the 
participant.  


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For participants who do not tolerate the protocol-specified dosing schedule, dose interruption 
is recommended in order to allow participants to continue the study treatment, based on 
investigator’s discretion. 
These dose interruptions must be recorded on the appropriate CRF. 
6.5.4 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4 week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists, etc., should be consulted as deemed necessary. Further guidelines 
and recommendations for the management of specific study treatment combination-induced 
toxicities (i.e. renal, liver) are provided in Section 10.2 and Section 16. All participants must be 
followed up for adverse events and serious adverse events for 30 days following the last study 
dose. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed, and to 
complete the participant diary. Compliance will be assessed by the investigator and/or study 
personnel at each visit using pill counts and information provided by the participant. This 
information should be captured in the source document at each visit.
 
 
 
 
 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’
s next treatment regimen, and after discussion and agreement with Novartis. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant 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 participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 


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participant 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/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name 
• participant number 
In addition, oral and written information to the participant 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. 
After the emergency break the participant must be discontinued from the study by the 
investigator. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs Section 6.1.1. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to a certain treatment. Investigator staff will identify the 
study drug package(s) to dispense to the participant by contacting the IRT and obtaining the 
medication number(s). Immediately before dispensing the package to the participant, 
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 participant’s unique participant number. 
As per Section 4.6, during a public health emergency as declared by Local or Regional 
authorities, i.e; pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of IMP directly to a participant's home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant's health to administer the study treatment 
even without performing an on-site visit. The dispatch of IMP from the site to the participant’s 
home remains under the accountability of the Investigator. Each shipment/provisioning will be 
for a maximum of 8-weeks supply. In this case, regular phone calls or virtual contacts (aligned 
with the protocol visit schedule in Table 8-1) will occur between the site and the participant for 
instructional purposes, safety monitoring, investigation of any adverse events, ensuring 
participants continue to benefit from treatment, and discussion of the participant's health status 
until the participants can resume visits at the study site. Where assessment of suitability for 
continued IMP administration is required (e.g. a protocol required negative urine pregnancy test 
in WOCBP) the participant will be instructed by site on their requirements to perform these 
procedures remotely and the communication process with site prior to participant self-
administration. 


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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
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 designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the IB.  
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) 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 participant 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. Participants will be 
asked to return all unused study treatment and used/unused packaging at the end of the study or 
at the time of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, at the conclusion of the study, and as appropriate during the 
course of the study, the investigator will return all unused study treatment, packaging, drug 
labels, and a copy of the completed drug accountability log to the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
Participants should be instructed to take the dose of study medication daily, close to the evening 
meal; either just prior to (within 5 minutes) consuming the evening meal, or no more than 30 
minutes after consuming the evening meal and at about the same time each day. Only at 
Baseline and week 4 visit, the participants should take their doses at the clinic following a meal 
instead of in the evening. 
Once the protocol amendment v02 is approved and after the tropifexor (LJN452) 10, 30 and 
100 µg and matching placebo hard gelatin capsule supply is depleted, the participant will 
receive 9 blister packs in a box (10 mg licogliflozin or matching placebo tablets) and 1 bottle 
of 140 µg hard gelatin capsules (replacing the 10, 30 and 100 µg tropifexor or matching placebo 
capsules) for each 4 week period every 4 weeks through Week 20. At the Week 24, Week 32 
and Week 40 visits 2 sets of 4 week supplies of study medication will be distributed to 
accommodate the 8 weekly visit schedule (Table 8-1).  The participants will take 3 tablets from 
the blister pack and 1 capsule from the bottle daily as described above.  
If the COVID-19 or other pandemic prevents on-site visits the site may arrange delivery of 
study medication to a participant’s home.  


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6.7.2.1 
Overview of treatment - type and number of capsules and tablets 
taken per day 
The 140 μg dose of tropifexor and its matching placebo are each available as a single hard 
gelatin capsule.  Participants on the study at the time of availability of the single 
tropifexor/placebo capsule, may continue on the 3-capsule tropifexor (100 μg + 30 μg + 10 μg) 
or matching placebo regimen, as shown in Table 6-5, until the available 3 capsule supply is 
depleted.  
Table 6-5 
Dosing with 3 capsule (10 + 30 + 100 μg) tropifexor supply  
Treatme
nt Arm  
Tropifexor 
(LJN452) 
10μg capsu
le 
Tropifexor 
(LJN452) 
30μg capsu
le 
Tropifexor 
(LJN452) 
100μg  
capsule 
Tropifexor 
(LJN452) 
Placebo  
capsule 
Licogliflozi
n (LIK066) 
10mg  table
t 
Licogliflozi
n (LIK066) 
Placebo   
tablet 
Frequency 
Arm A 
Combo 
Tropifexor (L
JN452) 
140 μg 
 & 
Licogliflozin 
(LIK066)  
30 mg 
1 
1 
1 
0 
3 
0 
Daily  
Arm B 
Mono 
Tropifexor (L
JN452) 
140 μg 
1 
1 
1 
0 
0 
3 
Daily 
Arm C 
Mono 
Licogliflozin 
(LIK066) 
30 mg 
0 
0 
0 
3 
3 
0 
Daily 
Arm D 
Placebo 
0 
0 
0 
3 
0 
3 
Daily 
After the 3-capsule supply is depleted, participants will take 1-capsule of 140 μg tropifexor or 
matching placebo daily as described in Table 6-6. No change is made to licogliflozin dosing.  


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Table 6-6 
Dosing with single capsule (140 μg) tropifexor supply 
Treatment 
Arm  
Tropifexor 
(LJN452) 
140μg capsule 
Tropifexor 
(LJN452) 
Placebo capsul
e 
Licogliflozin 
(LIK066) 
10mg  tablet 
Licogliflozin 
(LIK066) 
Placebo  tablet 
Frequency 
Arm A 
Combo 
Tropifexor (LJN45
2) 140 μg 
 & 
Licogliflozin (LIK06
6)  
30 mg 
1 
0 
3 
0 
Daily  
Arm B 
Mono 
Tropifexor (LJN45
2) 140 μg 
1 
0 
0 
3 
Daily 
Arm C 
Mono 
Licogliflozin (LIK06
6) 30 mg 
0 
3 
3 
0 
Daily 
Arm D 
Placebo 
0 
3 
0 
3 
Daily 
 
IMPORTANT: Please ensure that the date of the change, and the number of capsules (from 3 
capsule to 1 capsule) is accurately captured in the eCRF Change in Dosing log for each 
participant. 
  
 


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Dosing recommendations: 
1. Participants should take 3 Tablets from the blister pack (licogliflozin or matching 
placebo) & 1 or 3 Capsules (tropifexor or matching placebo ) depending on current 
supply close to the evening meal; either just prior to (within 5 minutes) consuming the 
evening meal, or no more than 30 minutes after consuming the evening meal, at about 
the same time each day. Participants directed to take 3 capsules must be reminded that 
one capsule is to be taken from each of the 3 tropifexor/placebo bottles provided. At 
Baseline and week 4 the dose will be taken in the morning at the clinic close to a meal 
instead of in the evening. 
 
 
 
4. Participants should be instructed to swallow the capsules and tablets whole and not to 
chew them. 
5. If vomiting or diarrhea occurs during the course of treatment, no re-dosing of the 
participant is allowed before the next scheduled dose. 
6. If a dose is missed and not remembered the same day, it should not be made up on a 
subsequent day. 
 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT system. 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. It should be emphasized to the participant that the 
contents of the study medication bottles are not identical; the participant must take one 
capsule from EACH bottle and 3 tablets from the blister pack each day. The participant 
must also be instructed to contact the investigator if for any reason he/she has not taken the 
study treatment as prescribed. 
 
 
 
 
At site dosing – Baseline and Week 4:  
• Participants should take study drug either just prior to (within 5 minutes) consuming 
the morning meal, or no more than 30 minutes after consuming the morning meal. 
• Participants should be instructed to swallow whole capsules and not to chew or open 
them. 
• If vomiting occurs during the course of treatment, participants should not take the 
study treatment again before the next scheduled dose. 
• No evening dose should be taken on the days of the Baseline and Week 4 visits as the 
daily dose is taken at the site on those 2 days. 


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6.7.2.2 
Dietary restrictions 
No food or alcohol should be consumed for 8 hours before each study visit where blood samples 
will be collected to ensure these laboratory assessments to be taken in a fasted state. 
In case of development of diarrhea, a low carbohydrate meal (i.e. < 50%) close to taking study 
medication may help to improve the symptom. 
To keep the fat intake as constant as possible, participants participating in this study will be 
instructed to carefully adhere to American Heart Association (AHA) diet or local equivalent if 
there is a country specific recommended diet, see Section 16.5. Participants will be asked about 
dietary compliance to the AHA diet (or local equivalent) as outlined in Table 8-1. Participants 
should also be counseled regarding appropriate exercise as per local standards. Any significant 
changes to diet or exercise habits should be reported to the investigator. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institution Review Board (IRB)/Independent Ethics Committee 
(IEC) approved informed consent. 
If applicable, in cases where the participant’s representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 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 participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council of Harmonization Good Clinical Practice (ICH –
E6 GCP) guidelines and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/ IEC. 
Information about common side effects already known about the investigational treatments can 
be found in the IBs for tropifexor and licogliflozin. This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Optional study specific pre-screening consent for pre-screening assessments  
• Main study consent, which also includes: 
 
 
 
 
 
 


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• As applicable, Pregnancy Outcomes Reporting Consent for female participants or 
the female partners of any male participants who took study treatment.  
 
 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements for the duration 
of the study.  
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted by site to request her 
consent to collect pregnancy outcome information. 
 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
 
 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. The date of each scheduled visit is calculated with 
the appropriate interval from the date of the Baseline/randomization visit, not from the date of 
the previous visit. If a scheduled visit is late by more than half of the planned interval between 
it and the next scheduled visit, the visit should be skipped. 
If the COVID-19 or any other pandemic limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented. Phone calls, virtual contacts (e.g. 
teleconsulting) or visits by site staff/home nursing service at the participants home depending 
on local regulations and capabilities, may be considered. In-home visits would be conducted by 
the site staff (under the responsibility of the investigator), or by a health care provider (HCP) 
supporting this activity if this is in agreement with the investigator. 
Participants who discontinue from study treatment for any reason (see Section 9.1 for more 
details) should be scheduled for an end of treatment visit as soon as possible, and attend the 
follow-up visits as indicated in the Assessment Schedule. 


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Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and any adverse event 
and concomitant medications not previously reported must be recorded on the electronic case 
report form (eCRF). 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
 
 
As per Section 4.6, during a public health emergency as declared by Local or Regional 
authorities, i.e; pandemic, epidemic or natural disaster that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the investigator 
as the situation dictates. If permitted  by a Local Health authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 
 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol solicited 
medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Waist 
circumference 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Hip circumference 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Prior and ongoing / 
concomitant 
medications and 
non-drug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol history / 
compliance with 
protocol 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECG)2 
X 
 
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
Liver Biopsy5 
 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
Hepatitis serology6 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV 
antigen/antibody 
tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver function tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Hematology 
X  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry7 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid panel 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase & lipase9 
X 
 
X 
X 
Serum 
BUN,creatinine 
and eGFR 
(MDRD) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
(central)10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy and 
assessments of 
fertility 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Pregnancy Urine 
dipstick test 
(local)11 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Pregnancy serum 
test (central lab)12 
X 
X 
X 


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Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Follicle stimulating 
hormone (FSH) 
 X 
 
 
  
  
  
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Urine screening for 
drug abuse 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Drug dispensation 
  
  
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
 
Drug 
administration 
record 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Compliance 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Participant 
diary review 
  
  
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
S 
Adverse Events18 
X 
Serious Adverse 
Events19 
X 
Diet Compliance 
and exercise 
counseling 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


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Period 
Screening 
Treatment 
Unscheduled  
EOS/PSW  
Follow-Up 
W52 
 
Visit Name Screening 
1 
Screening 
2 
Baseline 
W2 
W4 
W8 
W12 
W16 W20 
W24 
W32 
W40 
 
W48 
Visit  Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
- 
14 
Days -70 to -42 
-42 to -1 
0 
14 
28 
56 
84 
112 
140 
168 
224 
280 
336 
- 
364 
Weeks -10 to -6 
-6 to 0 
0 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
0 
52 
Study treatment 
completion 
information21 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
Study completion 
information 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
X Assessment to be carried out at respective visit and data for assessment to be recorded in the source, clinical database or received electronically from a vendor 
S Assessment to be carried out and data for assessment to be recorded in the source documentation at the site only 
1 Vital signs (including blood pressure and pulse measurements)  
2 For any ECGs with safety concerns, two additional ECG must be performed to confirm the safety finding. 
 
 
 
 
 
 


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5 Biopsy 
a).The liver biopsy can be performed any time during the 10 week screening period, and should only be performed in participants who fulfill Screening visit 1 
eligibility criteria refer Section 8.3.1.8 for details.  
b) Screening biopsy results confirming eligibility are required prior randomization. Plan for the biopsy visit accordingly. The Screening visit 2 assessment can 
be performed before the biopsy results are obtained. 
c). Read by a central pathologist.  
d). Week 48 biopsy optional if participant discontinues before 24 weeks treatment period. 
6 Hepatitis B surface antigen (HBsAg); HCV antibody (Ab) – if detected, reflex to Hepatitis C RNA by PCR; Immunoglobulin M (IgM) Hepatitis A antibodies (IgM 
anti-HAV) see Section 8.4.2.6. 
7 At screening visit 1 this also includes ferritin, transferrin saturation, iron, and if not historically available also Anti-nuclear antibodies (ANA), Anti-smooth muscle 
antibodies (ASMA) and Anti-mitochondrial antibodies (AMA), see Section 8.4.2.2 
8 Coagulation parameters including APTT, PT, INR and TT and fibrinogen. 
9. Amylase & lipase to be analyzed at screening & Baseline and subsequently if pancreatitis is suspected. 
10 Dipstick measurements for color, clarity, specific gravity, pH, bilirubin, nitrite, ketones, protein, glucose, blood, urobilinogen and leukocyte esterase will be 
performed. If dipstick measurement results are positive (abnormal), microscopy would be assessed.  
11 Women Of Child Bearing potential (WOCBP) must have a urine dipstick pregnancy test every 4 weeks, including at week 28, 36 and 44 (when there are no study 
visits), up to and including the follow up visit.  
12 After Baseline visit onwards serum sample to be collected for serum pregnancy test only if urine dipstick test is positive – During the study if test is positive, the 
participant must be discontinued from study drug.  
 
 
  
 
 
 
  
 
 
 
17 At Baseline and week 4, to be collected at least 1-2 hours post dose at clinic. 
18 Update as necessary 
19 Update as necessary - SAEs must be reported & recorded until 30 days after the participant has stopped study participation; see appropriate protocol Section 10.1.2.  
 
  
21 For participants who discontinue study treatment prematurely before the end of the treatment period for any reason other than withdrawal of informed consent, the 
Week 48, End of Treatment (EOT) and Week 52 End of Study (EOS) visits must be performed. 
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8.1 
Screening 
8.1.1 
Pre-screening 
For participants who do not have a qualifying historical liver biopsy, it is recommended that 
available ultrasound based elastography (e.g. transient elastography – Fibroscan, Acoustic 
Radiation Force Impulse (ARFI), 2D-Shear Wave Elastography, where available) be reviewed 
prior to performing the liver biopsy. Fibroscan may be a useful pre-screening tool prior to liver 
biopsy. 
Prior to screening visit 1 optional study specific pre-screening assessments may be carried out, 
including Fibroscan and/or local laboratory tests (HbA1c, platelets, INR, total bilirubin, ALT, 
AST, ALP and serum albumin) to assess participant eligibility for inclusion. Prior to any study 
specific pre-screening assessments being carried out the pre-screening informed consent form 
must be signed by the participant. 
Only data related to SAEs causally related to pre-screening study procedures blood sampling 
or Fibroscan will be recorded (Section 10.1.3). All other data related to pre-screening will be 
recorded only in the source documentation. 
If Fibroscan is performed at pre-screening it is not required to be repeated later in the screening 
period; if the participant is randomized this data will be recorded on the eCRF. 
8.1.2 
Information to be collected on screening failures 
All participants who have signed informed consent and subsequently found to be ineligible prior 
to randomization into the study at Baseline Visit are considered screening failures. If a 
participant discontinues before entering the treatment period, IRT must be notified within 2 
days and the reason for not entering the study will be recorded on the appropriate eCRF. In 
addition, the following eCRFs should be completed: Visit Date, Informed Consent, 
Demography, Inclusion/Exclusion Criteria, Participant Re-Screening (if applicable), Protocol 
Deviation, Disposition, Withdrawal of Consent (if applicable) and SAEs that occurred during 
the screening period. No other data will be entered into the clinical database for participants 
who are screen failures (see Section 10.1.3 for SAE reporting details). Data available from third 
party vendors for screen failed participants will be electronically transferred to the clinical 
database. 
If for any reason the participant is a screen failure, the participant may be rescreened. There is 
no restriction on the number of times a potential participant may be rescreened or on how much 
time must pass from the date of screen failure and the date of rescreening. If the reason for 
screen failure is an inadequate biopsy sample taken during the screening period, a second liver 
biopsy cannot be performed for re-screening. If the inadequate liver biopsy sample is historical, 
the investigator’s clinical judgment and local standard of care will determine if and when the 
liver biopsy can be repeated for re-screening. If a participant is a screening failure, but is 
rescreened and subsequently enrolled, the reason for the original screening failure must be 
documented in the source documents.  
If a participant is rescreened for the study, the participant must sign a new ICF and be issued a 
new participant number prior to any study related assessment or collecting any data for new 
screening visit being conducted. For all participants, the investigator/qualified site staff will 


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record if the participant was rescreened on the rescreening eCRF and any applicable screening 
numbers the participant was issued prior to the current screening number. 
The date of the new informed consent signature must be entered on the Informed Consent eCRF 
to correspond to the new screening participant number. For rescreening, all screening 
assessments must be performed as per protocol. 
Investigators will have the discretion to record on the medical history eCRF any abnormal test 
finding that occurred prior to the informed consent signature. 
8.2 
Participant demographics/other Baseline characteristics 
Baseline characteristic data to be collected on all participants include (all labs are central) (see 
also Table 8-1): 
12-lead ECG, vital signs, drug testing, hematology, clinical chemistry, urinalysis, physical 
examination, anthropometric assessments, HIV antigen/antibody tests, Hepatitis A, B or C 
serology, anti-nuclear antibodies (ANA), anti-smooth muscle antibody (ASMA), anti-
mitochondrial antibody (AMA), iron, ferritin, 
 
 
 A serum pregnancy test will be performed for women of child-bearing 
potential,
 
 
 
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 
 
, depending on the assessment as listed in Table 8-1. 
Country-specific regulations should be considered for the collection of demographic and 
Baseline characteristics in alignment with eCRF. 
8.2.1 
Screening visit 2 – additional assessments 
The second screening visit should only be conducted if participant remains eligible based on 
the assessments performed at screening visit 1. ALT, AST, total bilirubin and ALP will be tested 
at screening visits 1 and 2, and must meet the requirements in Section 5.2 at both screening 
visits to confirm eligibility. 
The period between screening visit 1 and the anticipated randomization / Baseline visit is a 
maximum of 10 weeks. If the liver biopsy is performed at screening visit 2, this visit should be 
done at least three weeks prior to the Baseline visit to allow sufficient time for liver biopsy 
central reading. The Baseline visit should occur as soon as all eligibility criteria are met. 
8.2.2 
Demographic Information 
Participant demographic data to be collected at screening on all participants include: year of 
birth or age, gender, race, ethnicity, source of referral and child-bearing potential (for females 
only). 
8.2.3 
Medical History 
Any relevant medical history including surgical/medical procedures, protocol solicited medical 
history, and/or current medical conditions before obtaining informed consent will be recorded 
in the Medical History eCRF. Significant findings that are observed after the participant has 


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signed the informed consent form and that meet the definition of an AE must also be recorded 
in the AE eCRF. 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. 
8.2.4 
Alcohol history and assessments 
Any history of alcohol use will be recorded in the eCRF. At screening visit 2 the 10-item 
questionnaire Alcohol Use Disorders Identification Test (AUDIT) will be used. Further, for all 
the other visits the 3-item questionnaire, modified AUDIT will be administered to the 
participants as indicated in Table 8-1.  
Optional: If the investigator requires additional data to evaluate the current alcohol use of the 
participant at the screening visit, the carbohydrate deficient transferrin (CDT) test can be 
assessed using the central lab. 
8.2.5 
Smoking history 
The current and/or previous use of tobacco products will be recorded, as well as the estimated 
number of pack-years. Non-smokers will be advised not to start smoking during the study. 
8.2.6 
Prior and concomitant medications 
Concomitant medications and prior medications taken will be captured at the screening visit, 
and updated at the Baseline visit. Any change to the ongoing or any new concomitant 
medication will be recorded in eCRF on an ongoing basis throughout study participation. 
8.2.7 
Treatment exposure and compliance 
All doses of study treatment administration will be recorded on the appropriate eCRF page. 
Compliance will be assessed by means of site and participant-specific drug accountability by 
Novartis study personnel during the site monitoring visits using medication pack numbers, Drug 
Label Form information and information collected by IRT. 
8.3 
Efficacy 
All efficacy assessments should be performed prior to the administration of study treatment. 
The recommended order for the efficacy assessments is described below. 
8.3.1 
Efficacy assessments 
The efficacy assessments should be completed in the following recommended order. 
• Weight 
 
 
• Blood samples collection for: 
1. 
Liver function test (LFT)  
 
  
 
  


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• Liver biopsy  
 
 
  
All remaining study visits procedures (e.g. laboratory samples collection, vital signs 
measurement, 
 etc.) must be completed prior to administration of study 
treatment. 
8.3.1.1 
Weight 
Weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes), and waist and 
hip circumference in centimeters (cm) will be measured as indicated in Table 8-1. 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
8.3.1.3 
Liver function tests 
ALT, AST, GGT, total ALP (and isoenzymes if total alkaline phosphatase is >ULN), and 
5’nucleotidase (if either GGT or total ALP is > ULN during study participation), TBL, direct 
and indirect bilirubin and albumin will be assessed as indicated in Table 8-1. 
After Baseline visit onwards if the TBL concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect bilirubin will be quantified. 
The methods for assessment and recording are specified in the central laboratory manual. Some 
of the liver function tests may be completed as part of the blood chemistry panel. 


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8.3.2 
Appropriateness of efficacy assessments 
The primary and secondary efficacy variables selected for this protocol will detect clinically 
meaningful changes in liver histology including steatohepatitis and fibrosis, liver fat content, 
liver enzymes and body weight and indirect markers of NASH. Liver histology assessments 
determined by the Central Reader’s provide the data for the primary endpoint and remain the 
assessments required by regulatory authorities for diagnosis of NASH and evaluation of 
treatment effect. Improvement in steatosis as determined by magnetic resonance along with 
sustained improvement in alanine aminotransferase (ALT) are recommended as valid endpoints 
of efficacy and are assessments for secondary endpoints in this phase 2 trial (Sanyal et al 2011). 
8.4 
Safety and Tolerability 
Safety assessments are specified below with the assessment schedule Table 8-1 detailing when 
each assessment is to be performed.  
Standard safety parameters and measures will be collected including adverse events and serious 
adverse events according to definitions and process detailed in the protocol. 
For details on AE collection and reporting, refer to AE Section 10.1.1 
As per Section 4.6, during a public health emergency as declared by Local or Regional 
authorities, i.e, pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 2 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
8.4.1 
Assessments & Specifications  
8.4.1.1 
Physical examination 
A physical examination will be performed on participants according to the schedule defined in 
Table 8-1. 
A complete physical examination will be conducted at screening visit 1, baseline, Weeks 12, 
24, and 48 which 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. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. At all other visits, a 
physical examination according to local guidelines, including bilateral foot exams, will be 
performed. 
Information for all physical examinations must be included in the source documentation at the 
study site. 
Clinically relevant findings that are present prior to signing informed consent form must be 
recorded on the appropriate CRF that captures medical history screen on the participant eCRF. 
Significant findings that occur after signing informed consent form which meet the definition 
of an Adverse Event must be recorded as an adverse event. 
8.4.1.2 
Vital signs 
Clinically notable vital signs are defined in Section 16.1. 


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Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 8-1. After the participant 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 participants. If blood pressure is high (i.e., SBP ≥140 mmHg and/or DBP 
≥100 mmHg, or ≥130/80 for participants with diabetes or chronic renal insufficiency), blood 
pressure measurement will be repeated after a 5 minutes rest and confirmed in the same arm. 
All measurements should be recorded in source documents and the lowest reading entered in 
the CRF. 
As intravascular volume depletion is a potential risk, if a participant reports symptoms 
suggesting postural hypotension, erect and supine SBP and DBP should be measured, recorded 
in source documents and used in guiding AE reporting. 
If possible, assessments should be performed using the same equipment and by the same 
qualified study site staff member throughout the study. 
8.4.1.3 
Anthropometric assessments 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes), and waist and hip circumference in centimeters (cm) will be measured as 
indicated in Table 8-1. 
For the assessment of the waist and hip circumference, the participant should be standing 
upright during the measurements, with arms relaxed at the side, feet evenly spread apart and 
body weight evenly distributed. 
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 participant, but not to the point that the tape is constricting 
(World Health Organization 2011). 
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 
8.4.2 
Laboratory evaluations 
Laboratory evaluations will be assessed as indicated in Table 8-1. 
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 central laboratory manual. 
Clinically notable laboratory findings are defined in Section 16.1. 


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One sample of serum will be frozen and stored. This sample will be used to repeat study lab 
tests when needed. It may also be used for additional testing. These stored samples will be 
destroyed 3 years after end of study at the latest. 
Local lab collection may be used during a public health emergency as declared by Local or 
Regional authorities, i.e;. pandemic, epidemic or natural disaster that limits or prevents on-site 
study visits. 
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
local lab, collection site or relevant clinical facility that are certified for lab diagnostics may be 
used. 
Safety samples (specifically hematology, clinical chemistry and coagulation panels) that can be 
collected locally will be collected and analyzed in line with the study laboratory manual. Where 
samples are collected and analyzed at a local laboratory instead of the central laboratory.  
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) AE, if central laboratory results are unevaluable, inconclusive or cannot 
be obtained due to public health emergencies, or when the treating physician cannot wait for 
central laboratory results for decision making.  
The results of the local laboratory will be recorded in the eCRF  
8.4.2.1 
Hematology 
Hematocrit (Hct), Hemoglobin (Hb), mean corpuscular volume (MCV), Red blood cells (RBC), 
Platelets, White blood cells (WBC), absolute differential WBC count, (Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils), RBC Morphology will be measured as 
indicated in Table 8-1. 
8.4.2.2 
Clinical Chemistry 
Sodium, potassium, chloride, bicarbonate, calcium, blood urea nitrogen (BUN)/urea, 
 
 albumin, ALP, ALT, AST, gamma-glutamyl-transferase (GGT), lactate 
dehydrogenase (LDH), magnesium, phosphorus, TBL (if > 1.5 x ULN, direct and indirect 
bilirubin will be quantified), serum creatinine (sCR), uric acid, creatine kinase (CK), total 
protein, high sensitivity C-reactive protein (hsCRP), haptoglobin; will be measured as indicated 
in Table 8-1. 
At screening visit 1, the following assessments will be included: ferritin, transferrin saturation, 
total iron, and if not historically available also anti-nuclear antibodies (ANA), anti-smooth 
muscle antibodies (ASMA), and anti-mitochondrial antibodies (AMA). 
Amylase and lipase will be tested at screening and baseline and thereafter if pancreatitis is 
suspected. 
The estimated glomerular filtration rate (eGFR) will be calculated corresponding to each 
creatinine measurement using the MDRD formula based on the participant’s age at the time of 
measurement, gender and race. 
Optional: If the investigator requires additional data to evaluate the current alcohol use of the 
participant 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 8.3.1.3 
 
8.4.2.3 
Coagulation tests 
Coagulation parameters including Fibrinogen, Activated Partial Thromboplastin Time (APTT), 
Prothrombin Time (PT), International Normalized Ratio) (INR) and Thrombin Time (TT) will 
be assessed as indicated in Table 8-1. 
8.4.2.4 
Fasting lipids profile 
Blood samples will be collected for a fasting lipid panel, including total cholesterol, HDL-
cholesterol (high-density lipoprotein) and LDL-cholesterol (low-density lipoprotein), VLDL-
cholesterol (very low-density lipoprotein), triglycerides, free glycerol, apolipoprotein A1, 
apolipoprotein B, lipoprotein (a), NMR lipid Subclass Particle Analysis and free fatty acids as 
per the assessment schedule Table 8-1.  
Lipid measurements should be collected after an 8-hour (overnight) fast. Detailed information 
will be provided in the central laboratory manual. 
8.4.2.5 
Urinalysis 
A clean-catch midstream urine sample will be obtained, in order to avoid contamination with 
epithelial cells and sediments, and allow proper assessments, as indicated in Table 8-1. 
Parameters to be evaluated by urine dipstick test will include color, clarity, specific gravity, pH, 
glucose, protein, bilirubin, ketones, nitrite, leukocyte esterase, urobilinogen and blood. Standard 
microscopic evaluation of urinary sediments will be performed if the urine dipstick test shows 
abnormalities. 
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial 
cells). 
Urine for calculation of protein to creatinine ratio (PCR) or albumin to creatinine ratio (ACR) 
can be aliquoted from the clean-catch. (see Table 16-3). 
8.4.2.6 
Hepatitis markers 
At screening, the presence of hepatitis C virus (HCV) will be by detection of HCV antibody 
(Ab). If HCV antibody (Ab) is not detected, participant can continue through the screening 
process. If HCV antibody (Ab) is detected, reflex test to the polymerase chain reaction (PCR) 
test for hepatitis C virus RNA will be performed. If HCV RNA is not detected in PCR, 
participant can continue through the screening process. Presence of HCV RNA is exclusionary.  
At Screening, assay for presence of Immunoglobulin M (IgM) Hepatitis A antibodies (IgM anti-
HAV) will be performed. Presence of IgM anti-HAV is exclusionary. No further testing is 
needed.  
At Screening, assay for presence of hepatitis B surface antigen (HBsAg) will be performed. 
Presence of HBsAg is exclusionary. No further testing is needed.  


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Hepatitis A, B or C serology will be assessed as indicated in Table 8-1 and if deemed 
appropriate, hepatitis serology will be assessed for liver safety monitoring as indicated in 
Section 10.2.1. 
8.4.2.7 
Screening for drug abuse 
Urine samples will be collected for a testing for Amphetamines/MDMA Screen, 
Antidepressants Screen, Barbiturates Screen, Benzodiazepines Screen, Cannabinoids Screen, 
Cocaine Screen, Opiates Screen, Methadone Screen, Propoxyphene, Phencyclidine (PCP), as 
per the assessment schedule Table 8-1. Participants will be excluded by exclusion criterion 30 
if the treating physician determines the presence of ongoing drug abuse. Participants testing 
positive (e.g. for prescription medications) are not automatically excluded. 
8.4.3 
Pregnancy and assessments of fertility 
Pregnancy 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
Women of child-bearing potential (WOCBP) are defined as all females physiologically capable 
of becoming pregnant. 
A serum β-hCG test will be performed at the Screening and Baseline Visits for all WOCBP.  A 
positive test at either visit is an exclusion criterion for participating in the study. 
From baseline onwards the urine pregnancy dipstick test will be repeated every four weeks up 
to and including the follow up visit (see Table 8-1) including at weeks 28, 36, and 44, when 
there are no scheduled site visits. The tests will be performed at the clinical center or at 
participant’s home. In case of home pregnancy test, the women of child-bearing potential will 
be provided with urine pregnancy test kits. The result will be documented in the participant 
diary and must be provided to the investigator at next scheduled visit. In case of positive urine 
pregnancy dipstick test the participant must contact investigator immediately. A positive urine 
pregnancy test after start of study drug requires its immediate interruption until serum β-hCG 
is performed and found to be negative. If positive, the participant will enter the post-treatment 
follow up period. See also Section 10.1.4 
Additional pregnancy testing might be performed if requested by local requirements. 
After Baseline a serum β-hCG test will be performed when there is positive urine pregnancy 
dipstick test.  
Female participants of child-bearing potential, who are or might become sexually active, must 
be informed of the need to prevent pregnancy during the study and for 5 days after study 
completion. 
The decision on the contraceptive method should be reviewed at least every 3 months to 
evaluate the individual need and compatibility of the method chosen and the need for additional 
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Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
Surgical bilateral oophorectomy without a hysterectomy 
Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.4 
Other safety evaluations 
8.4.4.1 
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 8-1. Determination of 
eligibility will be based on the ECG report from the central ECG review, not on the ECG 
machine-generated report. 
All ECGs must be performed on the ECG machines provided by vendor assigned for the study 
by Novartis. 
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, HR, PR, QRS, and QT) are to be assessed. Each ECG tracing 
should be labeled with the study number, participant initials, participant number, date and time, 
and kept in the source documents at the study site. Additional, unscheduled, safety ECGs may 
be repeated at the discretion of the investigator at any time during the study as clinically 
indicated. For any ECGs with participant safety concerns, two additional ECGs must be 
performed to confirm the safety finding. Clinically significant ECG findings at baseline must 
be discussed with the Novartis before administration of study treatment. Clinically significant 
abnormalities must be recorded on the relevant section of the medical history/Current medical 
conditions/AE eCRF page as appropriate. 
Local ECG collection may be used during a public health emergency as declared by Local or 
Regional authorities, i.e, pandemic, epidemic or natural disaster that limits or prevents on-site 
study visits. 
If participants cannot visit the site for protocol specified safety ECG assessments, an alternative 
local facility, collection site or relevant clinical facility that are certified for ECG collection 
may be used. 
 


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8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population and have 
been used in previous trials in this indication or deemed appropriate based on non-clinical and 
early clinical experience. Participants are seen frequently during treatment and will be assessed 
for safety parameters, including AE of special interest for the study medications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration) and can 
be decided by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• participant/guardian decision 
• Pregnancy (see Section 8.4.3 and Section 10.1.4) 
• Any situation in which continued study participation might result in a safety risk to 
the participant (including life-threatening events considered to be related to study 
medication) 
• Following emergency unblinding 
• Emergence of the following adverse events: 


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• For ALT, AST, TBL and/or alkaline phosphatase elevations mandating study 
treatment discontinuations (see Sections 10.2.1 and Section 16.2 for further 
instructions and monitoring). 
• Any evidence of liver decompensation as defined by ascites, bleeding esophageal 
varices, hepatic encephalopathy, jaundice.  
• Serious COVID-19 infection requiring hospitalization 
If the decision of discontinuing the study medication comes from the participant, the 
investigator should make a reasonable effort to understand the primary reason for the 
participant’s discontinuation from study treatment and record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow up visits indicated in the assessment schedule (Table 8-1).  
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, the following data should be 
collected at clinic abbreviated visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code see Section 6.6.2. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow up  
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 


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9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/opposition to use data/biological samples occurs only when a 
participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
• No longer wishes to receive study treatment 
• 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 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, all efforts should be made to complete a final evaluation at the time of 
the participant’s withdrawal of consent/opposition to use data/biological samples should be 
made as detailed in the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
A participant will be considered to have completed the study when the participant has completed 
the last visit planned in the protocol. 
Continuing care should be provided by investigator and/or referring physician based on 
participant availability for follow-up.  


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The investigator must provide follow-up medical care for all participants who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
For all participants who discontinue treatment early or who complete treatment, a safety follow-
up visit (EOS, Week 52) should be conducted 4 weeks after last treatment (EOT, Week 48). 
The information to be collected at this follow up visit includes concomitant medications, 
adverse events, and laboratory samples, as detailed on Table 8-1. 
All SAEs reported during this time period must be reported as described in Section 10.1.3.  
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time.  
This may include reasons related to the  
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Practical reasons (including slow enrollment), or  
• For regulatory or medical reasons.  
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a participant who discontinued from study treatment. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The investigator or sponsor depending 
on the local regulation will be responsible for informing IRBs/IECs of the early termination of 
the trial. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in clinical 
investigation participant after providing written informed consent for participation in the study. 
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 investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events  
An AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 


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For participants whose NASH status is unknown and who sign the pre-screening ICF, AEs 
which occur after signature of this consent will only be captured if they meet the definition of 
serious as outlined in Section 10.1.2 and are reported to be causally related with pre screening 
procedures (e.g. lab testing). The occurrence of adverse events must be sought by non-directive 
questioning of the participant at each visit during the study. Adverse events also may be detected 
when they are volunteered by the participant during or between visits or through physical 
examination findings, laboratory test findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual participant and identifying adverse events. Alert ranges for laboratory and other test 
abnormalities are defined in Section 16.1. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
1. 
The severity grade: 
 1=mild: usually transient in nature and generally not interfering with normal 
activities 
 2=moderate: sufficiently discomforting to interfere with normal activities 
 3=severe: prevents normal activities 
 
2. 
Its relationship to the study treatment  
 Yes 
 No 
If the event is due to lack of efficacy or progression of underlying illness (i.e. progression of 
the study indication) the assessment of causality will usually be ‘Not suspected.’ The rationale 
for this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack of 
efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of cohorts, not on a single participant. 
3. 
Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
4. 
Whether it constitutes a serious adverse event (see Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met 
5. 
Action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 


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• no action taken (e.g. further observation only) 
• study treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• participant hospitalized/participant’s hospitalization prolonged 
6. 
Its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved 
with sequelae; fatal; or unknown) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
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 drugs can be 
found in the IBs. Summary information will be included in the participant informed consent 
and should be discussed with the participant during the study as needed. Any new information 
regarding the safety profile of the 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 participant.  
The investigator must also instruct each participant to report any new adverse event (beyond 
the protocol observation period) that the participant, or the participant’s personal physician, 
believes might reasonably be related to study treatment. This information must be recorded in 
the participant’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
All adverse events will be collected after ICF is signed and monitored until 30 days after last 
dose of study treatment. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of an SAE refers to a reaction in which the participant was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 


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• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
• social reasons and respite care in the absence of any deterioration in the 
participant’s general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any AE of pancreatitis (acute, chronic or other), Fournier’s gangrene and ketoacidosis will be 
assessed as serious under “medically significant” even if other seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last dose of study treatment must be 
reported to Novartis safety immediately, without undue delay, under no circumstances later 
than 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site.  
Any SAEs experienced more than 30 days after the last dose of study treatment should only be 
reported to Novartis safety if the investigator suspects a causal relationship to study treatment, 
unless otherwise specified by local law/regulations. 
SAE reporting requirements in different scenarios are summarized below: 


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Table 10-1 
SAE reporting requirements in different scenarios 
Scenario 
Reporting requirements  
Pre-screening 
participant 
SAEs causally related to pre-screening study procedure (e.g. blood 
sampling or FibroScan) occurring after the participant has provided pre-
screening informed consent until the time the participant is deemed not 
eligible for the study must be reported to Novartis safety using a paper 
SAE form. 
Screening participant 
SAEs occurring after the participant has provided study informed 
consent until the time the participant is either deemed a screen failure or 
is randomized must be reported to Novartis safety, only if they are 
considered potentially related to study procedure, using the electronic 
serious adverse event eSAE module of the eCRF. 
Randomized OR 
Treated participant 
SAEs occurring after the participant has been randomized  until 30 days 
after the last dose of study treatment must be reported to Novartis 
safety, regardless of suspected causality using the electronic serious 
adverse event eSAE module of the eCRF. 
More than 30 days after 
the last dose of study 
treatment 
SAEs occurring more than 30 days after the last dose of study treatment 
and for which the investigator suspects a causal relationship to study 
treatment must be reported to Novartis safety using a paper SAE form. 
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. 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 participant continued or withdrew 
from study participation. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one must be reported separately as a new event. 
Information about all SAEs during the study period is collected and recorded on the electronic 
serious adverse event (eSAE) module of the CRF. For SAEs experienced during pre-screening 
or after the last study visit, a paper SAE Form will be used. 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 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. 
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 CMO & PS 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 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. 


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10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form, This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. After consent is provided, 
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 at expected delivery date plus 12 
months. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. 
Any SAE experienced during pregnancy 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. 
If participants cannot visit the site to have serum pregnancy tests during a public health 
emergency as declared by Local or Regional authorities, i.e; pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
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 recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 


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safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-2 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drugs, a standardized process for identification, monitoring and evaluation of 
liver events has to 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 AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Section 16.2 for complete definitions of liver laboratory triggers and liver events. 
Elevations in ALT and AST during study conduct must be reviewed in the context of 
participant’s baseline value, prior to study medication initiation. Participants with baseline 
values of ALT or AST > 5× ULN are excluded. 
Participants who develop elevations in liver-related laboratory parameters and/or clinical 
symptoms suggestive of liver disease should be managed according to Table 16-2. If ALP, ALT, 
AST, or bilirubin elevations reach the specified thresholds outlined in Table 16-2, the 
participant must return to the study site for re-evaluation within 48 to 72 hours after the 
laboratory results becoming available, at which time central confirmatory laboratory testing 
will be performed. This includes ALP, ALT, AST, total and direct bilirubin and INR.
 
 
 
 If prompt evaluation is not 
possible within 48 to 72 hours following receipt of abnormal laboratory results, study drug 
should be interrupted immediately (date of last study drug dose must be recorded in the eCRF) 
and the participant must return to the study site as soon as possible for re-evaluation. The 
sponsor should be notified of laboratory abnormalities and any clinical symptoms within 48 
hours of available laboratory results and/or assessment of clinical symptoms. 


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If the elevation is confirmed, close observation of the participant will be initiated, including 
consideration of treatment interruption or discontinuation (as described in Table 16-2) if 
deemed appropriate and close monitoring, causality and clinical evaluation should be performed 
as below; 
• Repeating the liver tests to confirm elevation as described in Table 16-2  
• Discontinuation of the investigational drug if appropriate. Note that discontinuation is 
mandatory in the case of decompensated cirrhosis as defined by ascites, bleeding esophageal 
varices, hepatic encephalopathy, jaundice or any other liver decompensation related 
symptom 
• Hospitalization of the participant if appropriate 
• An investigation of the liver event which needs to be followed until resolution 
• Obtain a more detailed history of symptoms and prior or concomitant diseases 
• Obtain a history of concomitant drug use (including nonprescription or over‑the‑counter 
medications and herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
• Rule out acute viral hepatitis types A, B, C, D, E and alcoholic hepatitis; hypoxic/ischemic 
hepatopathy; autoimmune hepatitis and biliary tract disease and other liver diseases. 
• Obtain a history of exposure to environmental chemical agents 
These investigations can include serology tests, liver biopsy, imaging and pathology 
assessments, hepatologist’s consultancy, based on investigator’s discretion. 
Participants who permanently discontinue study drug due to potential liver toxicity must be 
followed for close monitoring until abnormalities stabilize to baseline levels or baseline grade 
of abnormality and the participant is asymptomatic. All follow-up information, and the 
procedures performed must be recorded on the appropriate CRFs. 
10.2.2 
Renal safety monitoring 
Once a participant is exposed to study treatment, renal serum and urine laboratory values will 
be assessed routinely. Renal laboratory triggers and renal events are defined in Table 16-3 in 
Section 16.3. These laboratory abnormalities should be followed up as indicated in Table 16-3 
by the investigator or designated personnel at the trial site. 
10.2.3 
Adverse events of special interest 
10.2.3.1 Pruritus 
Pruritus is a common adverse event for the FXR-agonist class of drugs. Events will be captured 
during the study. Pruritus should be managed according to normal standard of care. If a 
participant experiences pruritus, an interruption in dosing of study medication can be considered. 
Although not specific to NASH, guidance for pruritus management can be found in the 
guidelines of the American Association for the Study of Liver Diseases (AASLD) and the 
European Association for the Study of the Liver (EASL) for the management of cholestatic 
pruritus. (Lindor KD, Gershwin ME, Poupon R et al 2009, J Hepatol 2009). Protocol rules 
outlined in Section 6.2 for Other Treatments must be followed. 


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10.2.3.2 Dyslipidemia 
Management of dyslipidemia is critical in participants with NASH. Increases in LDL-C and 
decreases in HDL-C are observed with experimental treatments for NASH including the FXR-
agonist class of drugs, such as tropifexor. The participant’s cardiovascular risk should be 
assessed by the investigator. Lipids are monitored by regular laboratory testing during the study. 
Dyslipidemia should be aggressively managed to achieve appropriate target levels, as 
recommended by local/ regional guidelines. Interventions, such as diet, exercise, and especially 
early introduction of lipid-lowering agents (e.g. statins) should be considered. Doses of lipid 
lowering agents should be adjusted as required to reach appropriate lipid levels.  
Laboratory abnormalities related to lipids should be reported as an adverse event only if the 
criteria in Section 10.1 are met. Cardiovascular events would be closely monitored and captured 
during the study.  
10.2.3.3 Diarrhea 
Osmotic diarrhea has been observed in participants treated with licogliflozin (inhibition of 
absorption of glucose and fructose in the gut). Events will be closely monitored and captured 
during the study. Participants with gastrointestinal disorders associated with chronic diarrhea 
are not included in the study. If a participant experiences diarrhea, an adjustment of the diet, or 
interruption or discontinuation in dosing of study medication can be considered. Events of 
diarrhea should be recorded in the participant diary and on the AE eCRF. 
10.2.3.4 Genital infections  
In clinical studies with licogliflozin, a small number of participants experienced non-serious, 
mild genital infections (mainly mycotic) with AEs including balanitis and vulvovaginal 
infections. This is observed due to dose dependent glucosuria as a consequence of SGLT2 
inhibition. All genital infections reported in licogliflozin clinical trials were non-serious with 
the overall frequency similar to published reports for marketed SGLT2 inhibitors (dapagliflozin, 
canagliflozin). 
Participants with symptomatic genital infection in the 4 weeks before randomization should be 
excluded. The possibility of genital infections (mainly mycotic like thrush) is described in the 
clinical study informed consent forms. Participants will be instructed to pay attention to genital 
hygiene and have appropriate hydration and be warned that severe genital infection may require 
urgent medical attention (see Section 10.2.3.8, Fournier’s gangrene). 
10.2.3.5 Hypoglycemia 
Participants with T2DM treated with antidiabetic medications (especially insulin and 
sulfonylureas) are at risk of hypoglycemia. Licogliflozin is effective in reducing glucose level 
and may lead to hypoglycemia in participants receiving other antidiabetic medications 
(especially insulin and insulin secretagogue). Diabetic participants must continue their routine 
self-monitoring of glucose levels and be educated regarding hypoglycemic symptoms 
(dizziness, lightheadedness; palpitations, heart racing/pounding, shaking, sweating, hunger, 
blurred vision, impairment of motor function, confusion), explanation of possible triggers 
(strenuous exercise, delayed meals, changes in meal composition, illness, periods of prolonged 
fasting) and treatment by the physician managing the participant’s diabetes. 


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During the course of the study, if a participant experiences clinically symptomatic 
hypoglycemia, an immediate medical evaluation should be conducted. Glucose levels will be 
measured. If a confirmed glucose level is <56 mg/dL by repeated measurement, background 
anti-diabetic medication may require dose adjustment, or study treatment may be interrupted 
and the participant treated according to standard of care for hypoglycemia.  
Events consistent with or suspected to be hypoglycemia, should be recorded in the participant 
diary and on the AE eCRF. 
Furthermore, this study outlines inclusion and exclusion criteria to minimize this risk and 
exclude participants at risk of this adverse event (please refer to Section 5 for details). 
10.2.3.6 Pancreatitis 
In the 2012 update to the diagnosis Atlanta classification of acute pancreatitis, 2 of the following 
3 features are required for diagnosis: (1) abdominal pain consistent with acute pancreatitis 
(acute onset of a persistent, severe, epigastric pain often radiating to the back), (2) serum lipase 
(or amylase) activity at least 3 times greater than the upper limit of normal (ULN), and (3) 
characteristic findings of acute pancreatitis on contrast-enhanced computed tomography, 
magnetic resonance imaging or transabdominal ultrasonography. (Banks et al 2012) Therefore, 
in the event of AE of significant abdominal pain or other suggestive features, consider whether 
the participant may have pancreatitis; amylase and lipase should be checked and the need for 
diagnostic imaging considered. If pancreatitis is confirmed by this definition, the event must be 
reported as an SAE even if hospitalization is not required. All tests and procedures related to 
the diagnosis and treatment of the event should be recorded in the appropriate eCRFs.  The 
acute episode should be managed as in normal clinical practice. Study medication may be 
interrupted during investigation of the event. If pancreatitis is confirmed, licogliflozin and other 
potentially suspect medicinal products should be discontinued. 
10.2.3.7 Ketoacidosis 
Euglycemic ketoacidosis is a rare adverse event reported with SGLT-2 inhibitor class of drugs. 
Participants are advised to maintain hydration and avoid excessive alcohol consumption. 
Participants should seek medical attention immediately in case they develop any of the 
following symptoms: vomiting, dehydration, labored breathing, unusual fruity smell in breath, 
tachycardia, confusion or disorientation and/or coma. Please note that blood glucose levels may 
be normal in this condition. Laboratory investigations for ketones, electrolytes and anion gap 
must be performed immediately. The participant must be hospitalized and managed for 
ketoacidosis as in normal clinical practice. Study medication should be interrupted and 
precipitating factors must be identified. Participants are advised to interrupt study medication 
in situations which can predispose ketoacidosis such as during prolonged fasting due to illness 
or surgery. If ketoacidosis is confirmed, the event must be reported as an SAE. All tests and 
procedures related to the diagnosis and treatment of the event should be recorded in the 
appropriate eCRFs. 
10.2.3.8 Fournier’s Gangrene 
Fournier’s gangrene is a rare adverse event reported with SGLT-2 inhibitor class of drugs. 
Participants are advised to pay attention to genital hygiene. Participants developing fever with 
pain or swelling in genital or anal region or any other signs/symptoms of infection of genitalia 


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or perineum must seek medical advice immediately. Prompt treatment (including antibiotics 
and consideration of surgical debridement) should be instituted. Study medication should be 
discontinued. If the diagnosis of Fournier’s gangrene is confirmed, the event must be reported 
as an SAE. All tests and procedures related to the diagnosis and treatment of the event should 
be recorded in the appropriate eCRFs. 
10.3 
Committees 
10.3.1 
Data Monitoring Committee 
This study will include an external Data Monitoring Committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. 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, metabolic disorders or 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. 
The 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 participants develop similar SAEs, or otherwise if found 
necessary by the sponsor, the DMC chairman will be alerted. Further details regarding relevant 
data and actions will be specified in the separate DMC charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (eCRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel or designated contract research organization (CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 


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the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant 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 data will be sent 
electronically to Novartis or a designated CRO at specific timelines. 
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. 
Once all the necessary 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. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to 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/delegated CRO/CRA organization. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 


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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 eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
A final analysis will be conducted after all participants finish the end of study or premature 
study discontinuation visit. No interim analysis for earlier statistical inference is planned for the 
study. Analyses for DMC review will be outlined in a separate DMC charter. 
Unless if specified differently, descriptive analysis for categorical data will be summarized as 
frequencies and percentages and continuous data will be summarized with the mean, standard 
deviation, median, minimum, and maximum. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
Following analysis populations will be defined for the statistical analysis: 
Screened analysis set (SCR) comprises of all participants who signed the informed consent. 
Randomized Analysis set (RAN) comprises of all participants who received a randomization 
number, regardless of whether participants received study medication. 
Full Analysis Set (FAS) comprises of all participants to whom study treatment has been 
assigned by randomization. Participants who were mis-randomized (not qualified for 
randomization but randomized inadvertently) and did not receive investigational medication, 
however, are excluded from the FAS. Efficacy analysis will be conducted on FAS. Following 
the intent-to-treat (ITT) principle, participants are analyzed according to the treatment they have 
been assigned during the randomization procedure regardless of actual treatment received and 
the true stratum the participant belongs to if a participant is assigned to wrong stratum during 
randomization. 
Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
treatment. Participants will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized/assigned treatment if the participant took at 
least one dose of that treatment or the first treatment received if the randomized/assigned 
treatment was never received. 
The number of participants in each analysis set will be presented by treatment group and overall 
for the screen set. 
The number and percentage of participants 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 participants. The frequency (%) of participants with protocol deviations and 
criteria leading to their exclusion from each analysis set will be presented for randomized set. 


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12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, the 
mean, standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline, including NASH specific 
co-morbidities, will be summarized separately by system organ class and preferred term and by 
treatment group.  
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.  
The duration of exposure (days) to investigational treatment, the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized for the safety set. The proportion of participants with dose reduction will also be 
presented by treatment groups.  
Proportion of participants non-compliance with the planned study treatment, which is defined 
as relative dose intensity >1.25 or <0.75, will be summarized descriptively for the double-blind 
treatment period.  
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized by treatment group according to the World Health 
Organization (WHO), Anatomical Therapeutic Chemical (ATC) classification system.  
12.4 
Analysis of the primary endpoint(s)/estimand(s)  
The two primary endpoints to be analyzed are:  
1. Whether the participant has at least one stage improvement in fibrosis without worsening of 
NASH at Week 48 compared with baseline;  
2. Whether the participant achieves resolution of NASH and no worsening of fibrosis at Week 
48 compared with baseline.  
 
Five pairwise comparisons may be evaluated for each primary endpoint, rendering a total of ten 
potential comparisons. Family-wise Type I error rate is controlled at two-sided 5% (one-sided 
2.5%) level, and is split for the two primary endpoints. Each primary endpoint will have its own 
branch of tests and may pass its alpha to the other branch from its last two tests.  
The main objective of the study is to demonstrate the combination efficacy of tropifexor + 
licogliflozin over placebo in participants with NASH and stage 2 or 3 fibrosis, so the two 
combination therapy vs. placebo tests (one for each primary endpoint) will be performed first. 
Then, for each primary endpoint, the two monotherapies (LJN452 and LIK066) will be 
compared with placebo after the combination treatment reveals superiority over placebo with 


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significant evidence. If one of the monotherapy vs. placebo tests succeeds, then it will pass its 
alpha to the corresponding combination vs. monotherapy test. An alpha recycling graph is 
presented in Section 12.4.2 to illustrate the test hierarchy.   
The following estimand framework is adopted to meet the objective. 
1. Population: Participants with NASH (using NAFLD Activity Score (NAS) ≥ 4 with at least 
1 point each in inflammation and ballooning on the screening histology assessment 
performed by the central reader) and stage 2 or 3 fibrosis (using NASH CRN fibrosis 
criteria), as defined by the inclusion and exclusion criteria of the study Section 5. 
2. Treatment of interest: the combination therapy (tropifexor 140 μg + licogliflozin 30 mg, 
once daily) is the treatment of interest in the comparisons of combination vs. placebo, 
combination vs. tropifexor, and combination vs. licogliflozin, whereas the monotherapy 
(tropifexor 140 μg once per day or licogliflozin 30 mg once per day) is the treatment of 
interest in the comparisons of tropifexor vs. placebo and licogliflozin vs. placebo. 
3. Variables of interest: histological response defined as: 
a. Whether the participant achieves improvement in fibrosis by at least one stage without 
worsening of NASH at week 48 compared with baseline. 
b. Whether the participant has resolution of NASH (absence of ballooning with no or 
minimal inflammation by histology) and no worsening of fibrosis at week 48 compared 
with baseline.  
4. Summary measure: Odds ratio of participants achieving histological response at Week 48 
for the following comparisons for each primary endpoint: combination vs. placebo, 
monotherapies vs. placebo, and combination vs. monotherapies. 
5. Intercurrent events include  
 Early discontinuation of study treatment before week 48 visit. 
 Non-histologic clinical event suggesting treatment failures (e.g bariatric surgery, liver 
transplant and death due to disease). 
 Study treatment incompliance defined as relative dose intensity >1.25 or <0.75. 
 More than four weeks of cumulative exposure to any prohibited medications 
Section 6.2.2, alcohol usage more than what is permitted in the protocol, initiation of 
other T2DM or lipid lowering medication (e.g. GLP-1 modulator, statins), initiation of 
other treatment being evaluated or approved for NASH, or new concomitant 
interventions for weight control before the assessment for primary endpoint. The 
identification of relevant medications will be based on ATC3 and/or ATC5 codes, which 
will be included in analysis data set specifications. The list of concomitant interventions 
with significant effect for general weight loss will be determined based on blinded review 
of the study data. 
For the intercurrent events related to the primary estimand, various strategies (such as treatment 
policy and composite variable) defined in ICH E9 (R1) will be utilized for the analyses. For 
instance, participants who discontinue the treatment after Week 24 will be asked to have their 
biopsies assessed at Week 48 regardless of the intercurrent event (treatment policy strategy), 
participants who discontinue the treatment before Week 24 will be considered as non-
responders (composite variable strategy), and participants who have no biopsies extracted at 
Week 48 will be considered as non-responders (composite variable strategy). 


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For non-intercurrent event missing data, certain multiple imputation methods will be applied to 
estimate the endpoints. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
Section 2.1 describes the primary estimands that contain the primary endpoints. This section 
defines the primary endpoints in detail. 
The study uses two primary endpoints.  
The first primary endpoint is: Whether (yes or no) the participant achieves improvement in 
fibrosis by at least one stage without worsening of NASH at week 48 compared with baseline. 
One stage fibrosis improvement is defined as the decrease by one point on the NASH CRN 
fibrosis score, i.e. “from 3 to 2” or “from 2 to 1” (considering that the randomized participants 
either has stage 2 or stage 3 fibrosis at baseline). Worsening of NASH is determined if any of 
three components of the NAS score (Steatosis, Lobular inflammation or Hepatocyte ballooning) 
at Week 48 is greater than that at baseline (FDA definition). 
The second primary endpoint is: Whether (yes or no) the participant has resolution of NASH 
and no worsening of fibrosis at week 48 compared with baseline. 
Resolution of NASH is satisfied if the NAS score for lobular inflammation ≤ 1 AND the NAS 
score for Hepatocyte ballooning = 0, regardless of the value for steatosis (FDA definition). 
Worsening of fibrosis is defined as an increase in the NASH CRN fibrosis score from baseline 
to Week 48, i.e. “from 2 to 3”, “from 2 to 4”, or “from 3 to 4”. 
The two binary primary endpoints will be summarized as odds ratios for pairwise comparisons 
between treatments. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The main goal of the study is to reveal the efficacy of the combination therapy (tropifexor + 
licogliflozin) compared with placebo in the two primary endpoints, so the two tests of 
combination therapy vs. placebo (one for each endpoint) will be conducted first. The study will 
be considered successful if at least one of these two tests passes with statistical significance. An 
overall two-sided 5% (one-sided 2.5%) alpha is adopted to the study and is splitted evenly to 
the two primary endpoints. In addition to the comparison between combination therapy and 
placebo, another four pairwise comparisons may be evaluated for each primary endpoint, 
rendering a total of ten ([1+4]*2=10) potential comparisons.  Each primary endpoint will have 
its own branch of tests and may pass its alpha to the other branch from its last two tests. Under 
each branch, the two monotherapies (LJN452 and LIK066) will be compared with placebo after 
the combination treatment shows superiority over placebo with significant evidence. If one of 
the monotherapy vs. placebo tests succeeds, then it will pass its alpha to the corresponding 
combination vs. monotherapy test. An alpha recycling graph (Bretz et al 2009) is presented in 
Figure 12-1 below to illustrate the test relationship. 
 
 
 


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Figure 12-1 
An alpha recycling graph 
 
 
 
 
Within each primary endpoint branch, five comparisons may be evaluated in the following 
levels:  
• Combination vs. placebo 
• Tropifexor (LJN452) vs. placebo; licogliflozin (LIK066) vs. placebo 
• Combination vs. tropifexor (LJN452);  
• Combination vs. licogliflozin (LIK066); 
Since there are two primary endpoints, a total of ten comparisons may be tested. 
The comparisons are based on the four arms of the study: one combination therapy arm, two 
monotherapy arms and one placebo arm. The proportions of histological responders in these 
four arms are assumed following binomial distributions (𝑛𝑛, 𝑝𝑝). The sampling distribution of the 
difference 𝑝𝑝̂𝑚𝑚_𝑖𝑖−𝑝𝑝̂𝑚𝑚_𝑗𝑗 will be asymptotically normal with mean  𝑝𝑝𝑚𝑚_𝑖𝑖−𝑝𝑝𝑚𝑚_𝑗𝑗and variance 
𝑝𝑝𝑚𝑚_𝑖𝑖൫1−𝑝𝑝𝑚𝑚_𝑖𝑖൯
𝑛𝑛𝑚𝑚_𝑖𝑖
+
𝑝𝑝𝑚𝑚_𝑗𝑗൫1−𝑝𝑝𝑚𝑚_𝑗𝑗൯
𝑛𝑛𝑚𝑚_𝑗𝑗
, where 𝑚𝑚 is the index of the primary endpoint (𝑚𝑚= 𝐴𝐴 if the 


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endpoint is “at least one stage improvement in fibrosis without worsening of NASH”. 𝑚𝑚= 𝐵𝐵 
if the endpoint is “NASH resolution without worsening of fibrosis”.), and 𝑖𝑖 & 𝑗𝑗 are the indices 
of the two treatments in the comparison. For example, in the first level tests, 𝑖𝑖 represents the 
combination treatment and 𝑗𝑗 denotes the placebo. The information of proportion difference is 
later used for sample size calculation. 
Some additional notations: 
𝑝𝑝𝐴𝐴= (𝑝𝑝𝐴𝐴_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑝𝑝𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝𝐴𝐴_𝑃𝑃𝑃𝑃𝑃𝑃)~ True (population-wise) response rates of combination, 
licogliflozin, tropifexor and placebo with respect to at least one stage improvement in fibrosis 
without worsening of NASH at Week 48. 
𝑝𝑝𝐵𝐵= (𝑝𝑝𝐵𝐵_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑝𝑝𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝𝐵𝐵_𝑃𝑃𝑃𝑃𝑃𝑃)~ True (population-wise) response rates of combination, 
licogliflozin, tropifexor and placebo with respect to NASH resolution without worsening of 
fibrosis at Week 48. 
𝑛𝑛𝐴𝐴= (𝑛𝑛𝐴𝐴_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑛𝑛𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑛𝑛𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑛𝑛𝐴𝐴_𝑃𝑃𝑃𝑃𝑃𝑃)~  Numbers of participants in the combination, 
licogliflozin, tropifexor and placebo arms to be analyzed for primary endpoint A. 
𝑛𝑛𝐵𝐵= (𝑛𝑛𝐵𝐵_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑛𝑛𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑛𝑛𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑛𝑛𝐵𝐵_𝑃𝑃𝑃𝑃𝑃𝑃)~ Numbers of participants in the combination, 
licogliflozin, tropifexor and placebo arms to be analyzed for primary endpoint B. 
𝑝𝑝̂𝐴𝐴= (𝑝𝑝̂𝐴𝐴_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑝𝑝̂𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝̂𝐴𝐴_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝̂𝐴𝐴_𝑃𝑃𝑃𝑃𝑃𝑃)~  Observed response rates of the combination, 
licogliflozin, tropifexor and placebo arms with respect to at least one stage improvement in 
fibrosis without worsening of NASH at Week 48. 
𝑝𝑝̂𝐵𝐵= (𝑝𝑝̂𝐵𝐵_𝐶𝐶𝐶𝐶𝐶𝐶, 𝑝𝑝̂𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝̂𝐵𝐵_𝐿𝐿𝐿𝐿𝐿𝐿, 𝑝𝑝̂𝐵𝐵_𝑃𝑃𝑃𝑃𝑃𝑃)~  Observed response rates of the combination, 
licogliflozin, tropifexor and placebo arms with respect to NASH resolution without worsening 
of fibrosis at Week 48. 
The null and alternative hypotheses of the ten comparison tests can be represented in the 
following form of odds ratio: 
𝐻𝐻𝑚𝑚_𝑘𝑘_0: 
𝑝𝑝𝑚𝑚_𝑖𝑖 (1−𝑝𝑝𝑚𝑚_𝑖𝑖)
𝑝𝑝𝑚𝑚_𝑗𝑗 (1−𝑝𝑝𝑚𝑚_𝑗𝑗) = 1  vs. 𝐻𝐻𝑚𝑚_𝑘𝑘_1: 
𝑝𝑝𝑚𝑚_𝑖𝑖 (1−𝑝𝑝𝑚𝑚_𝑖𝑖)
𝑝𝑝𝑚𝑚_𝑗𝑗 (1−𝑝𝑝𝑚𝑚_𝑗𝑗) ≠1  , 
where 𝑚𝑚, 𝑘𝑘, and 𝑖𝑖&𝑗𝑗 are the indices of the endpoint, the test, and the compared populations, 
respectively. For instance, if the endpoint to be analyzed is “whether the participant achieves 
improvement in fibrosis by at least one stage without worsening of NASH at week 48 compared 
with baseline”, then 𝑚𝑚= 𝐴𝐴 and the five relevant comparisons are:   
Combination vs. placebo (test 1, 𝑘𝑘= 1, 𝑖𝑖= 𝐶𝐶𝐶𝐶𝐶𝐶, 𝑗𝑗= 𝑃𝑃𝑃𝑃𝑃𝑃) 
Tropifexor (LJN452) vs. placebo (test 2,𝑘𝑘= 2, 𝑖𝑖= 𝐿𝐿𝐿𝐿𝐿𝐿, 𝑗𝑗= 𝑃𝑃𝑃𝑃𝑃𝑃); licogliflozin (LIK066) vs. 
placebo (test3, 𝑘𝑘= 3, 𝑖𝑖= 𝐿𝐿𝐿𝐿𝐿𝐿, 𝑗𝑗= 𝑃𝑃𝑃𝑃𝑃𝑃) 
Combination vs. tropifexor (LJN452) (test 4, 𝑘𝑘= 4, 𝑖𝑖= 𝐶𝐶𝐶𝐶𝐶𝐶, 𝑗𝑗= 𝐿𝐿𝐿𝐿𝐿𝐿); combination vs. 
licogliflozin (LIK066) (test 5, 𝑘𝑘= 5, 𝑖𝑖= 𝐶𝐶𝐶𝐶𝐶𝐶, 𝑗𝑗= 𝐿𝐿𝐿𝐿𝐿𝐿) 
There are ten potential tests to be performed for the two primary endpoints (five for each 
primary endpoint), and it is important to control the overall Type I error rate for these tests. The 
alpha recycling graph presented in Figure 12-1 shows how alpha transfers among them. If the 
data fails to reject the null hypothesis of a test, then the alpha of that test will not be passed to 
others. This restriction ensures the control of overall Type I error rate. Again, for the primary 


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endpoints, the overall alpha is set at two-sided 5%. A logistic regression model with the logit 
of probability for histological response as the dependent variable, treatment groups as the main 
effect, baseline fibrosis stage and T2DM (No/Yes) as explanatory variables, and the baseline 
BMI as a covariate will be utilized to test the hypotheses at each step. While this model will be 
the typical logistic regression in most cases, it should be set as the Firth logistic regression if 
some arm (such as the placebo) has a low response rate, as the Firth method returns less biased 
results for data with rare events. The null hypothesis of kth test, if executed, will be rejected if 
the p-value for the coefficient of treatment effect in the kth comparison is less than or equals to 
its corresponding alpha. If no alpha is passed to a specific comparison, then its corresponding 
test will not be performed and p-value will not be calculated. More statistical specifications of 
the model will be described in the statistical analysis plan (SAP). 
The number and percentages of histological responders at week 48 in FAS will be summarized 
by treatment groups. The difference between the treatment of interest and the alternative 
treatment will be presented along with 95% confidence interval calculated based on the normal 
approximation for distribution of the difference between two binomial random variables.  
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Intercurrent events of primary estimand will be addressed with various strategies (given that 
these events occur before the histological assessments at Week 48): 
1. Bariatric surgery: participants who have undergone bariatric surgeries during trial 
participation are considered as non-responders (composite variable strategy).  
2. Use of alcohol above protocol permitted amount: the intercurrent events (overuse of 
alcohol) will be ignored for estimation (treatment policy strategy). 
3. Addition or removal of any medication that may have a confounding effect on the 
endpoints: the treatment effect will be assessed with the intercurrent event ignored 
(treatment policy strategy). The treatment policy strategy may not be ideal if the 
confounding medications highly affect the endpoints. Consequently, a supplementary 
analysis will be conducted where the treatment effect is imputed as if the intercurrent 
event doesn’t occur (hypothetical strategy) 
4. Premature discontinuation of study treatment due to tolerability, efficacy, adherence, or 
adverse event: participants who discontinue the treatment after Week 24 will be asked to 
have their biopsies assessed at Week 48 regardless of the intercurrent event (treatment 
policy strategy), participants who discontinue the treatment before Week 24 will be 
considered as non-responders (composite variable strategy), and participants who have no 
biopsy extracted at Week 48 will be considered as non-responders (composite variable 
strategy). 
5. Death, transplantation and other clinical outcomes: participants will be considered as non-
responder (composite endpoint strategy). 
6. Acute medical condition not related to the study treatment affecting the liver: participants 
will have their Week 48 biopsies assessed regardless of the intercurrent events (treatment 
policy strategy). 
7. Acute medical condition related to the study treatment affecting the liver: participants are 
considered as non-responder (composite endpoint strategy). 


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12.4.4 
Handling of missing values not related to intercurrent events 
While not possible to confirm missing completely at random (MCAR), the histological response 
status from the early termination visit after at least 24 weeks of study treatment will be used for 
the primary analysis in case of missing primary endpoint at week 48. Participants otherwise 
with primary endpoint missing or any primary endpoint after intercurrent events will have the 
values imputed using multiple imputation (MI) methods (Rubin 1976, Rubin 1987) under a 
missing at random (MAR) assumption.  
For multiple imputation: an arbitrary missing pattern will be assumed and a fully conditional 
specification (FCS) method with logistic regression will be applied. The logistic model will be 
used to analyze the multiple imputed datasets, and pooled results will be obtained based on 
Rubin’s combination rules. More implementation details of the multiple imputation (MI) will 
be specified in the SAP. 
The proportion of participants with missing primary endpoints at week 48 will be compared 
among the combination therapy, monotherapies and the placebo.  
12.4.5 
Sensitivity analyses for primary endpoint(s)/estimand(s) 
Any sensitivity analysis of the primary efficacy estimands will be described in the SAP. 
12.5 
Analysis of secondary endpoints 
Summary tables of descriptive statistics will be presented by treatment group, and by scheduled 
visit where applicable, for secondary endpoints. Counts and percentages will be presented for 
categorical variables and the arithmetic mean, standard deviation, minimum, maximum, median 
and first and third quartile will be presented for continuous variables. 
12.5.1 
Efficacy 
 endpoint(s) 
Secondary efficacy endpoints will be analyzed in the FAS and planned analyses are outlined in 
Table 12-1 below:  
 
 


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Table 12-1 
Planned Analyses 
Endpoints 
Analysis 
Key secondary endpoint: whether the participant 
achieves resolution of NASH and no worsening 
of fibrosis OR Improvement in fibrosis by at least 
one stage without worsening of NASH at Week 
48 compared with baseline. 
Same statistical methods as for one branch of 
the primary analysis with overall Type I error 
rate controlled at two sided 0.05 level. 
Whether (yes or no) the participant has at least 
one stage improvement in fibrosis at week 48 
compared with baseline 
Same statistical methods as for the key 
secondary endpoint analysis with neither 
hypothesis tests nor p-values. 
Whether (yes or no) the participant has at least 
two stage improvement in fibrosis stage and no 
worsening of NASH at week 48 compared with 
baseline 
Same statistical methods as for the primary 
analysis with neither hypothesis tests nor p-
values. 
Change in liver fat content based on MRI - PDFF 
(in 40% of participants) over time up to Week 48 
compared with baseline 
Descriptive statistics, adjusted mean and mean 
differences of treatment of interest vs. 
alternative treatment with 95% CI by scheduled 
visits based on repeated measurement analysis 
of covariance (ANCOVA) model will be 
presented. 
Whether (yes or no) the participant has 5% or 
more reduction in body weight at Week 48 
compared to baseline  
Number and percentage of participants with 5% 
or more reduction in body weight. Difference in 
percentages between treatment of interest and 
alternative treatment along with 95% CI 
calculated based asymptotic normal distribution 
of difference in proportions will be presented. 
CMH test stratified with baseline T2DM status 
will be performed to estimate odds ratio (95% 
CI) between treatment of interest and alternative 
treatment. 
Change in ALT and AST over time up to Week 
48 compared with Baseline 
The mixed model of repeated measurement will 
be fitted to changes from baseline in these 
endpoints over time. The point estimate and the 
associated 95% CI of the change from each 
treatment at each visit will be presented. 
Change in GGT over time up to Week 48 
compared with Baseline 
The mixed model of repeated measurement will 
be fitted to changes from baseline in GGT over 
time. The point estimate and the associated 
95% CI of the change from each treatment at 
each visit will be presented. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used and will be presented by actual investigational 
treatment as participant first received after randomization. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). The on-treatment period lasts from the date of first administration of study 
treatment to 30 days after the date of the last actual administration of any study treatment.  
A separate summary for death including on treatment and post treatment deaths will be provided. 


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12.5.2.1 Adverse Events 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Separate summaries will be provided for study medication related adverse events, serious 
adverse events, other significant adverse events and adverse events leading to study drug 
discontinuation. 
Participants who died any time during the study will be listed with SAEs leading to such deaths.  
12.5.2.2 Clinical laboratory evaluation 
Summary statistics for standard laboratory test results will be provided by treatment and 
visit/time. Shift tables using the low/normal/high/ (low and high) classification will be used to 
compare baseline to the worst on-treatment value.  
Number (percent) of participants with post-treatment changes in lab parameters related to 
hepatotoxicity (ALP, ALT, AST, or bilirubin elevations as outlined in Section 10.2.1 and Table 
16-2) will also be summarized. 
12.5.2.3 Vital signs 
The change from baseline in vital sign parameters, including Anthropometric measurements, 
will be summarized at scheduled post-baseline visits by treatment group. Change from baseline 
will only be summarized for participants with both baseline and post-baseline values.  
Participants with clinically notable vital signs as defined in Section 16.1 will be listed.  
12.5.2.4 ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally. 
Number of participants changing in normal or abnormal ECG will be summarized by treatment 
and scheduled visit. 
The Fridericia QT correction formula (QTcF) will be used for clinical decisions and for analyses. 
Notable QTcF values and changes from baseline will be summarized by treatment and 
scheduled visit, where a notable value is defined as a QTcF ≥450 msec (male) or ≥460 msec 
(female) and the categories used for the change (increase) in QTcF are: ≤ 30 ms, > 30 to ≤ 60 
ms and > 60 ms.  


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12.7 
Interim analyses 
No interim analysis is planned for the study. Analysis needed for safety review by DMC will 
be defined in a separate DMC charter. 
12.8 
Sample size calculation 
Sample size and allocation are determined by three factors:  
1. Optimizing the power of passing at least one of the combination vs. placebo tests from 
the two primary endpoints;  
2. Optimizing the power of passing any monotherapy vs placebo test (given that at least 
one of the combination vs. placebo tests have succeeded);  
3. Restricting the size of placebo arm no larger than that of any treatment arm. 
12.8.1 
Primary endpoint(s) 
Assumptions about true histological response rates for various treatments and placebo are made 
for sample size calculation. Published studies so far (Table 12-2) suggest unignorable placebo 
effect ranging from 8% to 18% for different populations and endpoints, but unpublished studies 
indicate some even higher placebo rates. For each primary endpoint, the response rates of the 
two monotherapies are assumed to be similar to each other and higher than that of placebo, and 
the response rate of the combination therapy is deemed to be the highest. 


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Table 12-2 
Placebo effects on histological responses 
Histological 
Response 
definition 
Time point 
Histological 
study 
NASH 
population with 
Fibrosis stages 
Placebo 
response rate 
Fibrosis 
improvement of 1 
stage and no 
worsening in 
NASH 
 
Month 18 
REGENERATE 
(2019) 
Obeticholic acid 
F1 + F2 + F3 
10.6% 
F2 + F3 
11.9% 
Week 52 
CENTAUR 
(2018) 
Cenicriviroc 
F1 + F2 + F3 
10.4% 
Week 52 
ARREST (2018) 
Aramchol 
F1 + F2 + F3 
17.5% 
Week 48 
STELLAR3 
(2019) 
Selonsertib 
F3 
13.2% 
Week 48  
STELLAR4 
(2019) 
Selonsertib 
F4 
12.8% 
NASH resolution 
with no 
worsening in 
Fibrosis 
 
Month 18 
REGENERATE 
(2019) 
Obeticholic acid 
F1 + F2 + F3 
8% 
F2 + F3 
7.9% 
Week 52 
GOLDEN (2016) 
Elafibranor 
F0+F1+F2+F3 
9% 
Table 12-3 
Response rate setting used for sample size and power calculation 
Treatment 
Primary Endpoint 
True Response Rate 
Combination 
LJN452 
LIK066 
Placebo 
At least one stage improvement 
in fibrosis without worsening of 
NASH 
35% 
30% 
30% 
20% 
NASH resolution without 
worsening of fibrosis 
25% 
20% 
20% 
10% 
 
Table 12-3 shows the assumed response rates of treatments and placebo under the two primary 
endpoints. Since both endpoints involve fibrosis and NASH, it is reasonable to expect these 
endpoints associated with each other. The participant level correlation of the two endpoints is 
set at +0.5 to be conservative in evaluating sample size and power. 
Sample size is first determined by reaching 80% power for passing the combination therapy vs. 
placebo test on at least one of the primary endpoints under equal allocations of the four arms. 
Table 12-4 displays the powers under various sample sizes. From the table, it is clear to see that 
a sample size of 380 can obtain 80% power for the tests of interest. 


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Table 12-4 
Powers of different sample sizes under equal allocation  
Sample Size 
Power 
Total 
LJN452 
LIK066 
Combo 
Placebo 
Cmb vs. 
Plc on 
Endpoint 
A 
Cmb vs. 
Plc on 
Endpoint 
B 
Cmb vs. 
Plc on at 
least one 
of 
Endpoint 
A and B 
200 
50 
50 
50 
50 
0.31 
0.42 
0.52 
220 
55 
55 
55 
55 
0.33 
0.45 
0.56 
240 
60 
60 
60 
60 
0.37 
0.49 
0.60 
260 
65 
65 
65 
65 
0.39 
0.53 
0.63 
280 
70 
70 
70 
70 
0.41 
0.57 
0.67 
300 
75 
75 
75 
75 
0.45 
0.60 
0.70 
320 
80 
80 
80 
80 
0.47 
0.62 
0.72 
340 
85 
85 
85 
85 
0.50 
0.65 
0.75 
360 
90 
90 
90 
90 
0.51 
0.68 
0.77 
380 
95 
95 
95 
95 
0.55 
0.72 
0.80 
400 
100 
100 
100 
100 
0.57 
0.73 
0.82 
  
After total sample size is fixed, allocation of the four arms is assessed based on three factors:  
1. Increasing the power of passing at least one of the combination vs. placebo tests from the 
two primary endpoints;  
2. Slightly decreasing the power of passing any monotherapy vs placebo test (given that at 
least one of the combination vs. placebo tests have succeeded);  
3. Constraining the size of placebo arm no larger than that of any treatment arm. 
Table 12-5 
Powers of passing at least one of the combination vs. placebo tests 
under various allocations of 380 participants 
Sample Size 
Power 
LJN452 
LIK066 
Combo 
Placebo 
Cmb vs. Plc on at least one of Endpoint A and B 
34 
34 
278 
34 
0.72 
49 
49 
233 
49 
0.80 
65 
65 
185 
65 
0.84 
80 
80 
140 
80 
0.85 
95 
95 
95 
95 
0.80 
110 
110 
50 
110 
0.62 
According to Table 12-5, allocation of 80 (LJN452), 80 (LIK066), 140 (Combo), and 80 
(placebo) provides good power for passing at least one of the combination therapy vs. placebo 
tests from the two primary endpoints. 
Power calculations were performed with simulations (n=100000) implemented in R 3.5.3, 
where the primary analysis in each simulated study was performed using z-tests of difference 
in proportions without continuity correction for simplicity.  


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The missing Week 48 biopsy rate of the study is anticipated to be around 20%.  The missing 
response data due to intercurrent events will be addressed with intercurrent event strategies 
specified in ICH E9, whereas those not related to intercurrent events will be substituted with 
certain multiple imputation methods. Sample size adjustment is not needed because the 
treatment response rates are already assumed with conservative values.  
12.8.2 
Secondary endpoint(s) 
The tests of the key secondary endpoint are not used for sample size calculation. These tests are 
similar to the five tests of each primary endpoint and will be performed after the tests of primary 
endpoints succeed.  
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council for Harmonization (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g. 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).  
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes.  
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of participants included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Banks PA, Bollen TL, Dervenis C, et al (2013) Classification of acute pancreatitis—2012: 
revision of the Atlanta classification and definitions by international consensus. Gut. 2013; 
62:102–11. 
Bays H (2013) Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the 
Kidney to Improve Glycemic Control in Diabetes Mellitus. Diabetes Ther, 195-220. 
Bretz, F., Maurer, W., Brannath, W. and Posch, M. (2009). “A graphical approach to 
sequentially rejective multiple test procedures.” Statistics in Medicine 28: 586–604. 
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, 1387-95. 
Burke L. B, Kennedy D.L, Miskala P.H. et al (2008) The use of Patient-Reported Outcome 
Measures in the Evaluation of Medical Products for Regulatory Approval. Clinical 
Pharmcology and Therapeutics, 281-83.  
Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-
activated receptors LXR and FXR. Nat. Rev. Molecular Cell Biology, 13(4) 213-24. 
Cariou B (2008) The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis. 
Diabetes and Metabolism, 685-91. 
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, 2005-23. 
CellaD, Hahn E. A., Dineen K. (2002) Meaningful change in cancer-specific quality of life 
scores: Differences between improvement and worsening. Quality of Life Research, 207-21. 
Chao EC, Henry RR (2010) SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev 
Drug Discovery, 551-59. 
Ekstedt M, Hagström H, Nasr P, et al (2015) Fibrosis stage is the strongest predictor for disease-
specific mortality in NAFLD after up to 33 years of follow-up. Hepatology, 1547-54. 
Goodwin B, Watson M. A, Hwajin K et al (2003) Differential Regulation of Rat and Human 
CYP7A1 by the Nuclear Oxysterol Receptor Liver X Receptor. Molecular Endocrinology 386-
94.  
He YL, Haynes W, Meyers CD, et al (2019) The effects of licogliflozin, a dual SGLT1/2 
inhibitor, on body weight in obese patients with or without diabetes. Diabetes Obesity and 
Metabolism, 21: 1311-21. 
Hossain N, Afendy A, Stepanova M, et al (2009) Independent predictors of fibrosis in patients 
with nonalcoholic fatty liver disease. Clinical. Gastroenterology and Hepatology. 1224-29.  
J Hepatol (2009) European Association for the Study of the Liver. EASL Clinical Practice 
Guidelines: management of cholestatic liver diseases 237-67. 


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Komoroski B, Vachharajani N, Feng Y, et al (2009a) Dapagliflozin, a Novel, Selective SGLT2 
Inhibitor, Improved Glycemic Control Over 2 Weeks in Patients With Type 2 Diabetes Mellitus. 
Clinical Pharmacology and Therapeutics 513-19.  
Komorosky B, Vachharajani, Bouton D, et al (2009b) Dapagliflozin, a Novel SGLT2 Inhibitor, 
Induces Dose-Dependent Glucosuria in Healthy Subjects. Clinical Pharmacology and 
Therapeutics. 250-56.  
Lassailly G, Caiazzo R, Buob D, et al (2015) Bariatric Surgery Reduces Features of 
Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 379-88.  
Lindor KD, Gershwin ME, Poupon R, et al (2009) Primary biliary cirrhosis. Hepatology 291-
308. 
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 956-65. 
Patrick DL, Burke LB, Powers JH, et al (2007) Patient-Reported Outcomes to Support Medical 
Product Labeling Claims: FDA Perspective Value Health; 10 Suppl 2:S125-37 
Pattni SS, Brydon WG, Dew T, et al (2012) Fibroblast Growth Factor 19 and 7α-Hydroxy-4-
Cholesten-3-one in the Diagnosis of Patients With Possible Bile Acid Diarrhea. Clinical 
Translational Gastroenteroly.e18. 
Porez G, Prawitt J, Gross B, et al (2012) Bile acid receptors as targets for the treatment of 
dyslipidemia and cardiovascular disease. Journal of Lipid Research, 1723-37. 
Ratziu V, Bellentani S, Cortez-Pinto H, et al (2010) A position statement on NAFLD/NASH 
based on the EASL 2009 special conference. Journal of Hepatology, 372-84. 
Rohloff, JC, Amy D Gelinas, Thale C Jarvis, et al (2014) Nucleic Acid Ligands With Protein-
like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents. 
Molecular Therapy—Nucleic Acids 3, e20. 
Rubin DB (1976). Inference and Missing Data. Biometrika, 63:581–92.  
Rubin DB (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons. 
Sadry S, Drucker D (2013) Emerging combinatorial hormone therapies for the treatment of 
obesity and T2DM. Endocrinology, 425-33.  
Sanyal AJ, Mofrad PS, Contos MJ, et al (2004) A pilot study of vitamin E versus vitamin E and 
pioglitazone for the treatment of nonalcoholic steatohepatitis. Clinical Gastroenterology. 
Hepatology, 1107-15. 
Scheen A. J., Paquot N. (2014). Metabolic effects of SGLT-2 inhibitors beyond increased 
glucosuria: A review of the clinical evidence. Diabetes & Metabolism, S4-11.  
Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and 
hepatocellular carcinoma: a weighty connection. Hepatology, 1820-32. 
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. 
American Journal of Physiology Endocrinology and Metabolism, E462-68. 


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Targher G, Arcaro G (2007) Non-alcoholic fatty liver disease and increased risk of 
cardiovascular disease. Atherosclerosis, 235-40. 
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, 3541-46. 
Turk E, Zabel B, Mundlos S, et al (1991) Glucose/galactose malabsorption caused by a defect 
in the Na+/glucose cotransporter. Nature, 354-56. 
Turk C, Dworkin R. H, Burke L. B, et al (2006) Developing patient-reported outcome measures 
for pain clinical trials: IMMPACT recommendations. International Association for the Study 
of Pain, 208-15.  
Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural 
history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. 
Pharmacol. Ther, 274-85. 
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al (2015) Weight Loss Through 
Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. 
Gaestroenterology,367-78. 
World Health Organization (2011) Waist Circumference and Waist-Hip Ratio, Report of a 
WHO Expert Consultation , Geneva, 8-11 December 2008 
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, 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,547-55. 
WildingJ. P. H., Norwook P, Bastien A et al (2009) A Study of Dapagliflozin in Patients With 
Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers. Diabetes Care, 1656-
62.  
Williams J. A., Ruth Hyland, Barry C. Jones,  et al (2004) . Drug-Drug Interactions for UDP-
Glucuronosyltransferase substrates: a pharacokinetic explanation for typically observed low 
expsure (AUC/AUC) ratios. Drug Metabolism and Disposition, V 32 N 11, 1201-08.  
Youinossi Z,(2019) Positive Results from REGENERATE: A Phase 3 International, 
Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for NASH. 
Abstract Gs-06, EASL  
Zambrowicz B, Freiman J, Brown PM, et al (2012) LX4211, a dual SGLT1/SGLT2 inhibitor, 
improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled 
trial. Clin. Pharmacol. Ther, 158-69. 
 
 


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16 
Appendices 
16.1 
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 16.2 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 participant by the Investigator. 
For vital signs, please see Table 16-1 for notable abnormalities. 
Table 16-1 
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 
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16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-2 describes detailed thresholds and actions needed when elevations of liver parameters 
is observed or symptoms / adverse events indicative of liver toxicity appear. These symptoms 
could include jaundice, clinical evidence of liver decompensation, histology findings suggestive 
of drug induced liver injury or development of benign or malignant liver neoplasms. 
For transaminases (ALT, AST), GGT, ALP, DBL and TBL, the baseline value will be 
calculated as the mean of the assessments before first administration of the study drug, which 
are those taken at the Screening and Baseline visits. 
For normal reference ranges for AST, ALT, GGT, TBL and ALP, please refer to the values provided 
by the Central Laboratory. 
Table 16-2 
Management of Participants with Confirmed ALP, ALT, AST, or 
Bilirubin Elevations With or Without Liver Related Clinical Symptoms 
Baseline 
Treatment-Emergent 
(Confirmeda) 
Liver-
Related 
Clinical 
Symptomsb 
Action taken 
Monitoringc 
Study Drug 
ALT and/or AST 
Baseline ALT 
and/or AST < 2 × 
ULN 
ALT and/or AST  
> 3 × ULN but 
≤ 5 × baseline 
None 
Laboratory 
monitoring and 
causality 
evaluation 
Continue 
dosing 
Present 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd,
 
 
Interrupt 
dosinge 
ALT and/or AST 
 > 3 × ULN but 
≤ 5 × baseline 
AND  
total bilirubin > 2 × ULN  
(in Gilbert’s syndrome, 
see footnotef) 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd,
 
 
Interrupt 
dosinge 
ALT and/or AST  
> 3 × ULN and > 5 × 
baseline 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd,
 
 
Permanently 
discontinue 


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Baseline 
Treatment-Emergent 
(Confirmeda) 
Liver-
Related 
Clinical 
Symptomsb 
Action taken 
Monitoringc 
Study Drug 
Baseline ALT 
and/or AST ≥ 2 × 
ULN 
ALT and/or AST  
> 2 × baseline but 
≤ 3 × baseline 
None 
Laboratory 
monitoring and 
causality 
evaluation 
Continue 
dosing 
Present 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd, 
 
 
Interrupt 
dosinge 
ALT and/or AST  
> 2 × baseline but 
≤ 3 × baseline AND 
total bilirubin > 2 × ULNf 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd,
 
 
Interrupt 
dosinge 
ALT and/or AST 
> 3 × baseline 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd, 
 
 
Permanently 
discontinue 
Baseline normal or 
elevated ALT 
and/or AST values 
ALT and/or AST  
> 3 × ULN 
and > 2 × baseline AND 
either  
total 
bilirubin > 2 × baseline 
OR  
INR increase by >0.3 to 
a value >1.5 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
well as causality 
evaluationd, 
 
 
Interrupt 
dosinge 
ALP 
Baseline ALP ≤ 
ULN 
ALP > 1.5 × ULN 
(not due to known bone 
pathology) 
None 
Laboratory 
monitoring and 
causality 
evaluationc 
Continue 
dosing 
Present 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoring, as 
Interrupt 
dosinge 
 


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


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Baseline 
Treatment-Emergent 
(Confirmeda) 
Liver-
Related 
Clinical 
Symptomsb 
Action taken 
Monitoringc 
Study Drug 
Baseline normal or 
elevated direct 
bilirubin 
Direct 
bilirubin > 1.5 mg/dL 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoringc, as 
well as causality 
evaluationd, 
 
 
Interrupt 
dosinge 
 
ALT, AST, ALP and Total Bilirubin 
Baseline normal  
Normal or elevated 
values 
Present 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoringc, as 
well as causality 
evaluationd,
 
 
Continue or 
Interrupt dosing  
as appropriateg 
 
Potential DILI  cases 
defined as ALT or AST > 
3 × ULN and TBL > 2 × 
ULN  
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoringc, as 
well as causality 
evaluationd, 
 
 (Refer 
Section 10.2.1 
for required 
investigations) 
Interrupt 
dosinge 
 
Baseline elevated 
Potential DILI cases 
defined as [AST or 
ALT > 2 x baseline] OR 
[AST or ALT >7 × ULN] 
whichever occurs first 
combined with [total 
bilirubin > 2 x baseline 
AND > 2.0 x ULN] 
With or 
without 
liver-related 
clinical 
symptoms 
Comprehensive 
clinical 
evaluation and 
laboratory 
monitoringc, as 
well as causality 
evaluationd, 
 
 (Refer 
Section 10.2.1 
for required 
investigations) 
Interrupt 
dosinge 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eCRF = electronic case report form; INR = international normalized ratio; 
; 
ULN = upper limit of normal 
 
a The required confirmatory measurement should be obtained within 48 to 72 hours after the 
laboratory results become available. If prompt evaluation is not possible, study drug should be 
interrupted immediately (date of last study drug dose must be recorded in the eCRF). 
b Combination of clinical symptoms of abdominal pain, worsening or new fatigue, anorexia, 
nausea, rash, vomiting, diarrhea, fever, pruritus, and/or eosinophilia (> 5%). 
c Frequent hepatic laboratory testing and clinical assessments, including a thorough causality 
evaluation, should be performed every other week at minimum, in consultation with the sponsor, 


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Baseline 
Treatment-Emergent 
(Confirmeda) 
Liver-
Related 
Clinical 
Symptomsb 
Action taken 
Monitoringc 
Study Drug 
until resolution of clinical symptoms and/or stabilization of liver biochemistries to baseline levels or 
baseline grade of abnormality. Also, see Section 10.2 for suggested investigations particularly for 
Potential Hy’s law.  
d The sponsor should be notified of laboratory abnormalities and any clinical symptoms, and 
participants should be closely monitored until resolution of clinical symptoms/stabilization of liver 
biochemistries to baseline levels or baseline grade of abnormality. 
e Study drug must be interrupted (date of last study drug dose must be recorded in the eCRF). 
The sponsor should be notified of laboratory abnormalities and any clinical symptoms, and 
participants should be closely monitored until resolution of clinical symptoms/stabilization of liver 
biochemistries to baseline levels or baseline grade of abnormality. In participants with elevations 
in liver biochemistry but who do not meet permanent drug discontinuation criteria, study drug may 
be resumed if it is determined that complete resolution to normal or clinically comparable to 
baseline levels or baseline grade of abnormality (baseline value will be calculated as the mean of 
the assessments before first administration of the study drug, which are those taken at the 
screening and baseline visit) has occurred and it is not considered that the deterioration in liver 
function was related to study drug. This must be documented based on biochemical parameters 
and clinical symptoms, per the discretion of the investigator and in consultation with the sponsor. 
If significant liver abnormalities recur at any time after restarting study drug, then study drug must 
be permanently discontinued. 
f  In participants with Gilbert’s syndrome, in place of the total  bilirubin criterion, use direct  
bilirubin > 2 × baseline. 
 g Development of liver-related clinical symptoms in absence of biochemical abnormalities is an 
indication for prompt biochemical and physical evaluation to decide whether continued dosing is 
appropriate. If prompt evaluation is not possible, study drug should be interrupted and participant 
followed for laboratory monitoring and causality evaluation. 
 
 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Serum Event 
Serum creatinine increase 25 – 49% compared 
to baseline 
Confirm 25% increase after 24-48h 
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine 
increase > 50% compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Consider participants hospitalization /specialized 
treatment 
GFR is <60 ml x min1 x 1.73 m2  
Follow up within 24-48h if possible 
Consider study treatment interruption 
 
GFR is <30 ml x min1 x 1.73 m2 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Urine Event 
Albumin- or Protein-creatinine ratio increase ≥ 2-
fold (2 x baseline) 
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 3 
mg/mmol; 
Protein-creatinine ratio (PCR ) ≥ 1g/g or ≥ 
100mg/mmol  
 
Confirm value after 24-48h 
Perform urine microscopy 
Consider study treatment interruption / or 
discontinuation 
New onset dipstick proteinuria (≥ 3+) 
Confirm assessment within 24-48 hours 
Consider causes and possible interventions 
Assess serum albumin & serum total protein 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset dipstick hematuria (≥ 3+), (after 
excluding menstruation, urinary infection, 
extreme exercise, or trauma) 
Confirm assessment within 24-48 hours 
 Urine sediment microscopy 
Perform serum creatinine, ACR 
For all renal events: 
Document contributing factors in the eCRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed 
Monitor participant regularly (frequency at investigator’s discretion) until either: 
Event resolution:  
• sCr within 10% of baseline   
• protein-creatinine ratio within 50% of baseline,   
• albumin-creatinine ratio within 50% of baseline. 
Event stabilization:  
• sCr level with ± 10% variability over last 6 months   
• protein-creatinine ratio stabilization at a new level with ± 50% variability over last 6 months  
• albumin-creatinine ratio stabilization at a new level with ± 50% variability over last 6 months. 
 
 


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16.5 
Appendix 5: The American Heart Association (AHA) 
Recommended Diet 
Optimization of diet can result in a marked triglyceride-lowering effect that ranges between 20% 
and 50%. Good practices include weight loss, reducing simple carbohydrates at the expense of 
increasing dietary fiber, eliminating industrial-produced trans fatty acids, restricting fructose 
and saturated fatty acids, implementing a Mediterranean-style diet, and consuming marine-
derived omega-3 PUFA. 
American Heart Association (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/LIK066 
Clinical Trial Protocol CLJN452D12201C / NCT04065841
A randomized, double-blind, parallel-group, multicenter 
study to assess efficacy, safety, and tolerability of oral 
tropifexor (LJN452) & licogliflozin (LIK066) combination 
therapy, compared to each monotherapy, for treatment of 
adult patients with nonalcoholic steatohepatitis (NASH) and 
liver fibrosis (ELIVATE) 
Statistical Analysis Plan (SAP)
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
09-Dec-2019
Number of pages: 
47 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
09-
Dec-
2019 
Prior 
to 
FPFV 
Creation of 
final version 
N/A - First version 
NA 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information.......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 18 
2.4.2 
Prior and concomitant therapies ............................................................ 18 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.5.4 
Supportive analyses ............................................................................... 22 
2.6 
Analysis of the key secondary objective ................................................................ 23 
2.6.1 
Key secondary endpoints ...................................................................... 23 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 24 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 24 
2.7.1 
Secondary efficacy endpoints ................................................................. 24 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 25 
2.8 
Safety analyses ....................................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 26 
2.8.2 
Deaths .................................................................................................... 27 
2.8.3 
Laboratory data ..................................................................................... 27 
2.8.4 
Other safety data .................................................................................... 28 
 
 28 


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 28 
 
 29 
 
 29 
 
 30 
 
 30 
 
 30 
2.14 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ...................................................................................................... 32 
3.1 
Power considerations for primary analysis ............................................................ 32 
3.2 
Power considerations for key secondary analysis ................................................. 33 
4 
Change to protocol specified analyses ............................................................................... 34 
5 
Appendix ........................................................................................................................... 36 
5.1 
Imputation rules ..................................................................................................... 36 
5.1.1 
First and last dose dates of study treatment .......................................... 36 
5.1.2 
AE start and stop dates .......................................................................... 36 
5.1.3 
Start and stop dates of prior/concomitant medications or non-drug 
therapies / procedures ............................................................................ 37 
5.1.4 
Other imputations .................................................................................. 37 
5.2 
AEs coding/grading ............................................................................................... 37 
5.3 
Derivations ............................................................................................................. 37 
5.3.1 
Laboratory parameters ........................................................................... 37 
 
 39 
 
 39 
 
 39 
 
 39 
 
 39 
5.3.7 
T2DM status .......................................................................................... 39 
5.3.8 
Total NAS score .................................................................................... 40 
 
 40 
5.3.10 
Vital signs.............................................................................................. 40 
5.3.11 
Definitions for biopsy based endpoints ................................................. 40 
5.4 
Statistical models ................................................................................................... 41 
5.4.1 
Logistic regression model for primary and key secondary analysis ....... 41 
5.4.2 
Multiple imputation for missing primary and key secondary 
analysis .................................................................................................. 43 


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5.4.3 
Repeated measurement ANCOVA (MMRM) for secondary 
 
 analyses .............................................................................. 45 
5.4.4 
CMH method for sensitivity analysis .................................................... 45 
5.5 
Rule of exclusion criteria of analysis sets .............................................................. 46 
5.6 
Other statistical aspects .......................................................................................... 46 
5.6.1 
Risk difference and Wald asymptotic 100*(1-α)% CI .......................... 46 
6 
References ......................................................................................................................... 47 
 
 
 


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List of abbreviations 
ACR 
Albumin-creatinine ratio 
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 
BMI 
Body mass index 
 
 
 
 
CI 
Confidence interval 
 
 
 
 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
Coefficient of variation 
DMC 
Data monitoring committee 
 
 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
 
 
EOS 
End of study 
EOT 
End of treatment 
FAS 
Full analysis Set 
FGF 
Fibroblast growth factor 
 
 
GGT 
Gamma glutamate transaminase 
HA 
Hyaluronic acid 
 
 
HDL-C 
High density lipoprotein cholesterol 
 
 
IL 
Interleukin  
INR 
International normalized ratio 
ITT 
Intent-to-treat 
LDL-C 
Low density lipoprotein cholesterol 
LLOQ 
Lower limit of quantification 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
MMP 
Matrix metalloproteinase 


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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 
PCR 
Protein-creatinine ratio 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
PT 
Preferred term / Prothrombin time 
RAN 
Randomized set 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAF 
Safety set 
SAP 
Statistical analysis plan 
SCR 
Screened analysis set 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
TBL 
Total bilirubin 
TD/EOT 
Treatment discontinuation / End of treatment 
TFLs 
Tables, figures, listings 
TIMP 
Tissue inhibitors of metalloproteinases 
 
 
TT 
Thrombin Time 
ULN 
Upper limit of normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
VLDL-C 
Very low density lipoprotein cholesterol 
WHO 
World Health Organization 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details on the implementation 
of analyses outlined in section 12 of the study protocol and to be reported in the core Clinical 
Study Report (CSR). 
Analyses based on this SAP will be executed after all patients complete the study.  
Data analyses for Data Monitoring Committee (DMC) meetings will be specified in a separate 
DMC SAP.  
 
 
 
1.1 
Study design 
This is a randomized, double-blind, parallel-group, multiple-arm study to assess the efficacy, 
safety and tolerability of tropifexor and licogliflozin combination therapy compared to each 
monotherapy in patients with non-alcoholic steatohepatitis (NASH) and advanced fibrosis. 
The study consists of 1) a screening period, 2) a treatment period starting from randomization 
on Day 1 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of 
study treatment. The screening period starts from the time of the signing informed consent and 
continues for up to 8 weeks when all inclusion/exclusion criteria have been evaluated and all 
baseline assessments have been performed. The study duration from first dose of study 
medication is 52 weeks. The total duration of participation may be up to 60 weeks. 
Approximately 210 patients with NASH and F2-F3 fibrosis will be randomized in a 1:1:1 ratio 
to one of the following treatments: 
• Arm A: tropifexor + licogliflozin combination therapy, 
• Arm B: tropifexor monotherapy, 
• Arm C: licogliflozin monotherapy 


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Figure 1-1 
Study Design 
The primary endpoint data for efficacy is collected at Week 48. 
In case of any protocol amendment, this SAP may be amended accordingly. 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate the efficacy of 
tropifexor + licogliflozin as assessed 
by histologic improvement after 48 
weeks of combination treatment 
compared to each monotherapy 
treatment in patients with NASH and 
stage 2 or 3 fibrosis. 
Proportion of patients with resolution of NASH and 
no worsening of fibrosis OR improvement in fibrosis 
by at least one stage without worsening of NASH 
(no worsening of hepatocellular ballooning or 
lobular inflammation) at Week 48 compared with 
baseline. The criteria for resolution of NASH 
(absence of ballooning with no or minimal 
inflammation by histology) and other changes 
in histologic endpoints are further detailed in 
Section 5.3.11. 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Improvement in fibrosis by at least 
one stage with no worsening of NASH 
after 48 weeks of treatment 
• 
Key secondary endpoint: Proportion of 
patients who have at least one stage 
improvement in fibrosis without worsening of 
NASH (no worsening of hepatocellular 
ballooning or lobular inflammation) at Week 48 
compared with baseline 


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Objective(s) 
Endpoint(s) 
• 
Resolution of NASH with no 
worsening of fibrosis after 48 weeks 
of treatment  
• 
Key secondary endpoint: Proportion of 
patients with resolution of NASH and no 
worsening of fibrosis at Week 48 compared with 
baseline 
• 
Improvement in fibrosis by at least 
one stage 
• 
Proportion of patients who have at least one 
stage improvement in fibrosis at Week 48 
compared with baseline 
• 
Improvement in fibrosis by at least 
two stages with no worsening of 
NASH after 48 weeks of treatment 
• 
Proportion of patients who have at least two 
stage improvement in fibrosis without worsening 
of NASH (no worsening of hepatocellular 
ballooning or lobular inflammation) at Week 48 
compared with baseline 
• 
Reduction in body weight from 
baseline after 48 weeks of treatment  
• 
Proportion of patients with 5% or more 
reduction in body weight at Week 48 compared 
to baseline  
• 
Change in liver fat content after 48 
weeks of treatment 
• 
Change in liver fat content based on MRI - 
PDFF over time up to Week 48 compared with 
baseline 
• 
To determine the relationship of 
investigational treatment and markers 
of hepatic inflammation in NASH (ALT 
and AST) 
• 
Change in ALT and AST over time up to Week 
48 compared with baseline 
• 
To determine the relationship of 
investigational treatment and GGT, a 
marker of cholestasis and oxidative 
stress 
• 
Change in GGT over time up to Week 48 
compared with baseline 
• 
To evaluate the safety and tolerability 
of tropifexor (LJN452) in combination 
with licogliflozin (LIK066), compared 
to monotherapy of each compound 
from baseline  
• 
Occurrence of adverse events, serious adverse 
events, adverse events resulting in 
discontinuation of study treatment, adverse 
events of special interest and changes in vital 
signs and laboratory tests 


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2 
Statistical methods 
2.1 
Data analysis general information 
This SAP guides the statistical analysis for the core CSR after all patients complete (including 
early withdrawal) the study. There is no planned interim analysis for statistical inference. DMC 
analyses are described in a separate SAP. 
Novartis statisticians and programmers will perform this statistical analysis, primarily using 
SAS 9.4 or newer. Additional analysis software (e.g. R), in their newest versions available in 
the validated data analysis environment, may also be used. 
Descriptive summaries will be presented by study treatment without a total column, unless 
requested in a specific section. Categorical variables will be summarized with count and 
percentages.  If not otherwise specified, continuous variables will be summarized with n, 
arithmetic mean, standard deviation, minimum, maximum, median, first quartile and third 
quartile. 
Confidence intervals (CI) in this SAP refers to 2-sided confidence intervals unless clarified 
differently. P-values will be reported only if a formal hypothesis test is performed. 
Analyses performed at pre-specified analysis visits, including the primary efficacy endpoint at 
week 48, will be based on the analysis visit instead of original CRF visits. The derivation of 
analysis visits is detailed in Section 2.1.1. As an example, if the scheduled visit 5 (W4) of a 
patient is delayed and occurs on study day 48 instead of on Day 28, the data from that visit will 
be mapped to analysis visit 6 (W8). 
Analysis by visit (or “over time”) will present baseline and only post-baseline visits at which 
an assessment for the endpoint is scheduled according to protocol (Protocol Table 8-1). 
Summaries at post-baseline visit will include only patients with non-missing baseline and at 
least one non-missing post baseline results for the endpoint. 
Data listings will be presented by study treatment and include, in addition to the columns 
explicitly requested in specific section, following columns: patient ID, age/gender/race, 
first/last dose date of study treatment and date (study day) of assessment/event/sampling. All 
listings will present data as collected without any imputation needed for other data analysis 
purpose.  
2.1.1 
General definitions 
Study treatment in this SAP refers to the investigational regimens, i.e. the combination of 
tropifexor (LJN452) 140 µg and licogliflozin (LIK066) 30 mg, or each of them as 
monotherapies combined with matching placebo for the other. For simplicity hereafter, 
“LJN452” and “LIK066” in this SAP refer to the two specific dose strength of LJN452 140 µg 
and LIK066 30 mg unless otherwise specified. 


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Date of first study treatment (“first dose date” or “FDDT” ) is the date of first administration 
of study treatment during the study as recorded in eCRF (Dosage Administration Record 
summary page).  
Date of last study treatment (“last dose date” or “LDDT”) is the date of last administration 
of study treatment during the study as recorded in eCRF (Dosage Administration Record 
summary page). 
Study day is number of days counted from the first dose date (Day 1).  
For dates on or after FDDT, study day = date of interest – FDDT + 1.  
For dates prior to FDDT, study day = date of interest – FDDT. 
If first dose date is missing, the randomization date will instead be used for the 
calculation. 
Baseline for analysis, in general, is the last assessment with valid data before the date and time 
of first administration of study treatment. If the date of assessment is the same as first dose date 
but time is not available for comparison, the assessment is assumed to be prior to the 
administration of study treatment. For ALT, AST, ALP, GGT and total bilirubin, however, the 
baseline is the average of values from two screening visits and the baseline visit collected before 
first administration of study treatment. If there is unscheduled visit with lab assessment after a 
planned screening visit, the value from this unscheduled visit will also be used in the calculation 
of baseline. 
End of study (EoS) or last contact date of a patient is the date of his/her last office visit or 
other route of follow-up in the study.  
Treatment period is the period from the Baseline visit (included) to the TD/EOT (W48) visit 
(included) as defined in protocol Table 8-1. 
Follow-up period is the period from TD/EOT (W48) visit (not included) to EoS (included). 
Analysis visit is the visit label derived based on study day of assessment and the analysis visit 
windows defined in Table 2-1. For laboratory and bioanalytical parameters specified for both 
Group 1 and Group 2 in Table 2-1, two sets of analysis visits will be derived and will be referred 
to as “AV1” and “AV2” respectively. The AV1 is derived according to Group 1 for by visit 
analysis on full analysis set (FAS).  For AV2, assessments >14 days after the last dose date will 
be slotted into the analysis visit window for follow up visit for by-visit analysis of laboratory 
data on safety analysis set (SAF).      
Analysis visit windows are non-overlapping periods each associated with a visit planned in 
protocol and all together cover the entire study period of a patient. If multiple measurements of 
same parameter for a patient fall in the same window, the value of this analysis visit is selected 
according to Table 2-2. If no assessment falls into a window, the value of that analysis visit will 
be set to missing unless imputation rule(s) are defined for the parameter. Repeat and 
unscheduled visits will be mapped to analysis visits in the same way as scheduled visits.   
Table 2-1 
Analysis visit windows 
Analysis Visit Windows 


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Analysis 
Visit 
Target 
Study 
Day 
Group 1 
Group 4 
Group 5 
Baseline 
1 
≤ 1* 
≤ 1* 
≤ 1* 
Week 2 
15 
2-22 
 
 
Week 4 
29 
23-43 
 
 
Week 8 
57 
44-71 
 
 
Week 12 
85 
72-99 
2-127 
2-169 
Week 16 
113 
100-127  
 
 
Week 20 
141 
128-155 
 
 
Week 24 
169 
156-197 
128-253 
 
Week 32 
225 
198 – 253
 
 
Week 40 
281 
254 – 309
 
 
Week 48 
337 
310 –  
351 
254 - 351 
170 - EoS 
Wk 
52/FU 
365# 
352 – 
EoS 
352 - EoS 
NA 
* The first dose date of the study is defined as Day 1. If first dose date is missing, the date of randomization will be 
used as day 1.  
# The target study day for the FU visit of Group 2 will be LDDT+28  
Group 1: vital signs and anthropometric measurements, liver function tests (ALT, AST, TBL, Albumin, ALP and 
GGT), lipids panel, coagulation panel, 
 BUN, creatinine, eGFR 
 
 
Group 4: Waist/Hip circumference, 
 
Group 5: MRI, liver biopsy  
Table 2-2 
Choose value among multiple assessments in the same analysis visit 
window 
Timing of 
measurement 
Type of data 
Value selection rules 
Baseline 
All data 
excluding ALT, 
AST, ALP, GGT, 
TBL, 
 
. 
Choose the latest non-missing measurement before the 
first administration of study treatment (FDDT).  
If a patient did not receive any dose of study treatment, the 
latest measurement on or before the randomization date is 
used.  
If the date of a measurement is the same as FDDT but time 
is not available for comparison, the measurement is 
assumed to be prior to the first administration of study 
treatment.  
ALT, AST, ALP, 
GGT, TBL,
 
The average of valid values from all visits before first 
administration of study treatment will be calculated as 
baseline.  
Post-baseline  
Continuous 
parameters  
Choose the measurement closest to the target study day.  
If more than one measurements on the same date, choose 
the last (based on time, or visit label if time not available) 
measurement on that day. 


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Timing of 
measurement 
Type of data 
Value selection rules 
If two measurements are equally away before and after the 
target study day, use the mean.  
 
Categorical 
efficacy  
parameters 
Choose the measurement closest to the target study day.  
If more than one measurements on the same date, choose 
the last (based on time, or visit label if time not available) 
measurement. 
If two measurements are equally away before and after the 
target study day, use the first measurement.  
Notable 
laboratory 
abnormalities; 
shift from 
baseline;   
The most extreme measurement in the window will be 
used.  Note that this means a patient can have a notably 
high and notably low measurement within a window.  
Geographical regions are defined according to countries of study sites at which patients are 
randomized: 
Table 2-3 
Geographical regions 
Region 
Countries 
Europe 
Belgium, Bulgaria, Denmark, Estonia, France, Germany, Italy, Russia and CIS, 
Spain, United Kingdom 
North America 
Canada, USA, 
Latin America 
Argentina, Brazil, Canada, Chile, Colombia, Mexico 
Asia 
China, India, Japan, Singapore, South Korea, Taiwan, 
Other 
Australia, Egypt, Saudi Arabia, South Africa, Turkey 
2.2 
Analysis sets 
The following analysis sets are defined for analysis purpose: 
Screened analysis set (SCR) comprises of all patients who signed the informed consent. This 
analysis set includes also screen failures. 
Randomized set (RAN) comprises of all patients who received a randomization number, 
regardless of whether patient received study medication. Mis-randomized (not qualified for 
randomization but randomized inadvertently) patients will be included in this analysis set. 
Full Analysis Set (FAS) comprises of all patients to whom study treatment has been assigned 
by randomization. Patients who were mis-randomized (not qualified for randomization but 
randomized inadvertently) and did not receive investigational medication are excluded from the 
FAS. Efficacy analysis will be conducted on FAS. Following the intent-to-treat (ITT) principle, 
patients are analyzed according to the study treatment assigned during the randomization 
regardless of actual treatment received and according to the true stratum the patient belongs to 
in case a patient is assigned to wrong stratum during randomization. 


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Safety Analysis Set (SAF) includes all patients who received at least one dose of study 
treatment. Patients with the following unusual situations, if it occurs, will be excluded from 
SAF. 
- Had no safety assessment after first dose of study treatment (e.g. lost to follow-up). Of 
note, the statement that a subject had no adverse events constitutes a safety assessment. 
- Took only matching placebo tablet or capsules during the study. Of note, such situation 
will be identified only after study unblinding. 
SAF will be used for analysis of Safety 
 in this SAP. 
 
 
In the SAF, patients will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned study treatment if the patient took at least one 
dose of that treatment or the first treatment received if the randomized/assigned study treatment 
was never received. 
2.2.1 
Subgroup of interest 
Exploratory analysis on the primary endpoint (Section 2.13.1) will be performed on following 
subset of FAS.  
- 
FAS with baseline fibrosis stage of F2 
- 
FAS with baseline fibrosis stage of F3 
- 
FAS with T2DM at baseline 
- 
FAS without T2DM at baseline 
- 
FAS asian (Based on race collected on the Demographics CRF page) 
- 
FAS non-asian (Based on race collected on the Demographic CRF page)   
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographics and baseline characteristics listed below will be summarized by study treatment 
on FAS.  
- 
Age (years): per demographics CRF 
- 
Age Group: two categories derived for age <65 years or age  ≥65 years 
- 
Gender: per demographics CRF 
- 
Region: derived based on country of study site (Section 2.1) 
- 
Ethnicity: per demographics CRF 
- 
Race: per demographics CRF 
- 
Height (cm) at screening visit 
- 
Body Weight (kg) 
- 
Waist circumference (cm) 
- 
Hip circumference (cm) 
- 
BMI 


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- 
Liver function (ALT, AST, ALP, GGT, TBL): see Section 2.1.1 for special baseline 
definition 
 
 
 
- 
Steatosis stage (0, 1, 2 or 3) based on liver biopsy: categorical data summary 
- 
Lobular inflammation stage (0, 1, 2 or 3) based on liver biopsy: categorical data 
summary 
- 
Hepatocyte ballooning stage (0, 1 or 2) based on liver biopsy: categorical data 
summary 
- 
NAS score (Section 5.3.8) based on liver biopsy: continuous data summary 
- 
Fibrosis stage based on liver biopsy: categorical data summary for score 2 and 3  
- 
Hepatic fat fraction based on MRI-PDFF 
- 
Fasting lipids (HDL-C, LDL-C, VLDL-C, triglycerides, free glycerol, free fatty acid, 
total cholesterol, ApoA1)  
- 
hsCRP 
 
 
 
 
- 
T2DM status (Section 5.3.7) 
 
 
 
 
 
 
 
Relevant medical histories up to baseline, including NASH specific co-morbidities, will be 
summarized by system organ class, preferred term and by study treatment on FAS.  
2.3.1 
Patient disposition 
The number of subjects in each analysis set will be presented overall for SCR and by study 
treatment (as randomized) for other analysis sets. Patients with the treatment received (Section 
2.2 for SAF) different from the treatment group as randomized will be listed in the footnote. 
The number (%) of subjects in RAN who completed the study, who withdraw from study early 
and the reason for early withdrawal will be presented by study treatment. 
The number (%) of patients with protocol deviations and criteria leading to their exclusion from 
FAS and SAF will be presented for RAN. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The analyses of treatments will use SAF.  


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2.4.1 
Study treatment / compliance 
The duration of exposure (days) to study treatment will be calculated as the LDDT – FDDT +1 
and summarized by study treatment. In addition, the number (%) of patients with LDDT in the 
following time intervals after FDDT will be summarized by study treatment: 
- 
< 4 weeks 
- 
≥4 and < 8 weeks 
- 
≥ 8 and < 12 weeks 
- 
≥ 12 and < 16 weeks 
- 
≥ 16 and  < 20 weeks 
- 
≥ 20 and < 24 weeks 
- 
≥ 24 and < 32 weeks 
- 
≥ 32 and < 40 weeks 
- 
≥ 40 and < 48 weeks 
- 
≥ 48 weeks 
The proportion of patients with dose reduction (including interruption) due to adverse event, as 
recorded in the change in dosing log CRF page, will be presented by study treatment.  
Dose intensity is derived as the ratio between the cumulative dose of each active ingredient 
(tropifexor and licogliflozin) received during the study and duration of exposure (days). Patients 
in combination arm will have dose intensities derived separately for tropifexor and licogliflozin. 
The relative dose intensity (compliance) is derived as the ratio between the actual dose intensity 
and the planned dose intensity which equals to the actual duration of exposure * the daily dose 
of tropifexor or licogliflozin as planned according to protocol.  
Number (%) of patients incompliant with planned regimen, defined as relative dose 
intensity >1.25 or <0.75, will be summarized for tropifexor in the LJN452 monotherapy arm, 
for licogliflozin in the LIK066 monotherapy arm, and for both tropifexor and licogliflozin 
separately in the combination arm.  
2.4.2 
Prior and concomitant therapies 
Medications or other significant non-drug therapies during the study will be coded using the 
WHO dictionary. 
Prior therapies are defined as any medications or significant non-drug therapies taken prior to 
the first administration of study treatment, regardless of whether stopped or continued after 
randomization.  
Concomitant medications or non-drug therapies are defined as those received during the study 
treatment and follow-up periods (i.e., until end of study visit) regardless of whether started 
before randomization. Therefore, a medication can be BOTH prior and concomitant. 
Number (%) of patients using prior and concomitant medications will be summarized separately 
by the 3rd and 5th level ATC terms and by study treatment on FAS.  


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2.5 
Analysis of the primary objective 
The primary objective of the study is to demonstrate the efficacy of tropifexor + licogliflozin 
as assessed by histologic improvement after 48 weeks of combination treatment compared to 
each monotherapy treatment in patients with NASH and stage 2 or 3 fibrosis. 
The following estimands framework is adopted to evaluate the objective. 
1. Population: Full Analysis Set (FAS), for the adult population with NASH and stage 2 
or 3 liver fibrosis as further defined with study inclusion and exclusion criteria. 
2. Variables of interest: histological response defined as resolution of NASH (absence of 
ballooning with no or minimal inflammation by histology) and no worsening of fibrosis 
OR improvement in fibrosis by at least one stage without worsening of NASH 
(worsening of hepatocellular ballooning or lobular inflammation) at week 48 compared 
with baseline. The criteria for changes in histologic endpoints are further detailed in 
Section 5.3.11.  
3. Summary measure: odds ratio for the proportion of patients achieving histological 
response at week 48 between the combination and each monotherapy treatment. 
4. Intercurrent events include  
- 
Early discontinuation of study treatment or withdrawal from study before week 48 
visit. 
- 
Non-histologic clinical event suggesting treatment failures (e.g progression to 
cirrhosis, liver transplant and death due to disease). 
- 
Study treatment incompliance defined as relative dose intensity >1.25 or <0.75. 
- 
More than four weeks of accumulative exposure to any prohibited medications 
(Protocol Section 6.2.2), alcohol usage more than what is permitted in the 
protocol, initiation of other T2DM or lipid lowering medication (e.g. GLP-1 
modulator), initiation of other treatment being evaluated or approved for NASH, 
or new concomitant interventions for weight control (e.g bariatric surgery) before 
the assessment for primary endpoint. The identification of relevant medications 
will be based on ATC3 and/or ATC5 codes, which will be included in analysis 
data set specifications. The list of concomitant interventions with significant effect 
for general weight loss will be determined based on blinded review of the study 
data. 
All practical measures will be exercised in the study to collect as much data as possible at week 
48 despite intercurrent events (e.g. early discontinuation of study treatment). In the case of early 
withdrawal from the study on or after week 24, patient's histological response will be assessed 
if possible at the early termination visit. 
A combination of the while-on-treatment and hypothetical strategies as defined in ICH E9 (R1) 
on handling intercurrent events will be adopted for the primary analysis.  
If a patient discontinued study treatment early or withdrew early from the study without other 
inter-current event, but has histological response status collected after at least 24 weeks of study 
treatment, the primary endpoint will be imputed with their last histological response status 


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assessed after at least 24 weeks of treatment. Patients with missing primary endpoint or primary 
endpoint after inter-current event(s) will have their primary endpoint data imputed with a 
multiple imputation (MI) method as outlined in Section 2.5.3 to estimate the treatment effect 
that would have been observed if all patients had continued on treatment for 48 weeks without 
intercurrent event.  
2.5.1 
Primary endpoint 
The primary endpoint is the proportion of patients experiencing histological response, which is 
defined as resolution of NASH (absence of ballooning with no or minimal inflammation by 
histology) and no worsening of fibrosis OR improvement in fibrosis by at least one stage 
without worsening of NASH (worsening of hepatocellular ballooning or lobular inflammation) 
at week 48 compared with baseline. . The criteria for resolution of NASH (absence of 
ballooning with no or minimal inflammation by histology) and other changes in histologic 
endpoints are further detailed in Section 5.3.11. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
To demonstrate improved efficacy of tropifexor+licogliflozin in combination, the response rate 
in the combination arm will be compared with each monotherapy arm. A one-sided test 
(∝=0.05) of statistical superiority is planned for each comparison. A stepwise gatekeeping 
hierarchical test procedure, in which the second test is only performed if the first null hypothesis 
is rejected, will be adopted to maximize the power for the first test while still maintaining a 
strong control of family wise type 1 error rate (FWER-1) at 0.05. 
The hierarchical testing will be performed in the following sequence. 
1. Combination vs. licogliflozin (LIK066) 
2. Combination vs. tropifexor (LJN452) 
The order of the hierarchical tests is determined under a preliminary assumption that tropifexor, 
by targeting the Farnesoid X receptor that directly modulates liver inflammation and fibrosis 
associated with NASH, could potentially be more effective than licogliflozin hence results in 
smaller add-on effect of the combination when used as the reference in the comparison. If 
external data newly available during the study warrants different assumptions, the order of tests 
could be switched before the study unblinding without inflation of the FWER-1. 
For these two tests on the same endpoint and sharing a common comparator (combination arm), 
the hierarchical testing approach also allows an intrinsic adjustment of the correlation between 
them for the power of the second test.  
The proportions of histological responders in the three treatment arms are assumed following 
binomial distributions (n, P) and the sample distribution of the difference p1-p2i will be 
asymptotically normal with mean P1-P2i and variance P1*(1-P1)/n1 + P2i*(1-P2i)/n2i., where 
i ∈ {1, 2} ~ the level of the hierarchical test  
P = (P1, P21, P22) ~ True probabilities of histological responses after 48 weeks of treatment with 
the combination, licogliflozin and tropifexor respectively  


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n = (n1, n21, n22) ~ Number of patients in the combination, licogliflozin and tropifexor groups 
respectively in the study  
p = (p1, p21, p22) ~ Proportion of histological responders observed in the study after 48 weeks 
of treatment with the combination, licogliflozin and tropifexor respectively  
With the sample data collected in the study, the naive differences P1-P2i can be estimated using 
p1-p2i with unpooled standard error SE = sqrt( p1*(1-p1)/n1 + p2i*(1-p2i)/n2i).  
The hierarchical testing procedure based on odds ratio can be formulated as one-sided statistical 
tests (∝=0.05) for  
H0i : 
𝑃𝑃1(1−𝑃𝑃2𝑖𝑖)
𝑃𝑃2(1−𝑃𝑃1𝑖𝑖)<= 1 vs. H1i : 
𝑃𝑃1(1−𝑃𝑃2𝑖𝑖)
𝑃𝑃2(1−𝑃𝑃1𝑖𝑖)>1 
executed sequentially for i=(1, 2), where H02 is tested only if H01 is rejected.  
A logistic regression model with the logit of probability for histological response as the 
dependent variable, treatment groups as the main effect, baseline fibrosis stage (2 vs. 3) and 
T2DM (No/Yes) status as co-factors, and baseline BMI as a covariate will be utilized to test the 
hypothesis at each step of the hierarchical testing procedure.  
The choice of co-factors/covariates, the considerations for their collinearity, potential 
interactions with treatment effect and model specifications are further discussed in Section 
5.4.1.  
The logistic regression analyses can be implemented in SAS LOGISTIC procedure with the 
scale=williams and firth options in the model statement, executed together with the 
multiple imputation (MI) methods outlined in Section 2.5.3. 
Odds ratios and 95% CI of the probabilities of histologic response between study treatments 
can be back calculated as the exponentiation of the corresponding coefficients estimated from 
the logistic regression.  
One logistic regression model can be fitted on all FAS data from the three treatment arms to 
estimate the pairwise odds ratios and associated p-values.  
Given placebo effects (Table 3-1) reported in the published literature and with Firth correction, 
a model convergence issue is not expected.  In the case a convergence issue occurs and cannot 
be resolved with other appropriate technical approaches, a reduced model may be used for the 
primary analysis. The reduced model will be determined by removing baseline BMI, fibrosis 
stage and T2DM status sequentially from the full model until the convergence issue is resolved. 
If a reduced model has to be used, impacts on the interpretation of primary analysis results will 
be discussed in the core CSR in combination with results from sensitivity analysis. 
Existence of extremely influential baseline BMI values will be examined with Cook’s distance 
plot based on complete cases before MI.  
The numbers and percentages of histological responders will be summarized by study treatment. 
The difference between the combination therapy and each monotherapy will be presented along 
with 95% CI calculated based on the normal approximation for distribution of the difference 


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between two binomial random variables (Wald asymptotic CI). Odds ratios (95% CI) and p-
values from the logistic regression model will be reported. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Especially due to the clinical burden of liver biopsy, missing data is possible and could be 
related to observable data or even the unobserved primary endpoint.  
While not possible to confirm missing completely at random (MCAR), the histological response 
status from the early termination visit after at least 24 weeks of study treatment will be used for 
the primary analysis in case of missing primary endpoint at week 48. Patients otherwise with 
primary endpoint missing or any primary endpoint after intercurrent events will have the values 
imputed using multiple imputation (MI) methods (Rubin 1976, 1987) under a missing at random 
(MAR) assumption.  
An arbitrary missing pattern will be assumed and a fully conditional specification (FCS) method 
with logistic regression will be applied. Baseline fibrosis stage (2 vs. 3), baseline T2DM 
(No/Yes), baseline BMI (as categorical predictor) and decrease of ALT at week 24 (<= -17 U/L 
vs. >-17 U/L) will be included as predictors for the imputer’s model. The logistic model outlined 
for primary analysis will be used to analyze the multiply imputed datasets, and pooled results 
will be obtained based on Rubin’s combination rules.  
More details for the MI method are discussed in Section 5.4.2. 
The MI methods may be implemented using the SAS MI procedure with FCS LOGISTIC 
statement and the MIANALYZE procedure. The order of variable imputation will be specified 
with ORDER=VAR option in FCS statement. The VAR statement will list variables for baseline 
fibrosis stage (2 vs. 3), baseline T2DM status (No/Yes), baseline BMI (as continuous predictor) 
and decrease of ALT at week 24 (<= -17 U/L vs. >-17 U/L) in sequence. The number of 
imputations will be set to 50.  
The number (%) of patients with missing primary endpoint at week 48 will be summarized by 
study treatment.  
2.5.4 
Supportive analyses 
Supportive analyses will be performed to cross check with the results from primary analysis.  
1. The primary analysis will be repeated with an intent-to-treat (ITT) approach, 
recognizing that inter-current events could happen in real clinical practice potentially 
as a result of the treatment policy. Patients’ histological response status collected at 
week 48 or early termination visit will be used in this sensitivity analysis regardless of 
inter-current event(s). Patients otherwise with missing primary endpoint will be 
counted as non-responders. This approach is considered more conservative for 
estimating the benefit of combination therapy. 
2. Tests in the two hierarchical steps of primary analysis will be repeated separately 
using Cochran-Mantel-Haenszel (CMH) method stratified by baseline fibrosis stage (2 
vs. 3), T2DM (No/Yes) and BMI (>= 35 vs. < 35). Primary endpoint observed at week 
48 or last visit after at least 24 weeks of exposure to study treatment will be used 
regardless of intercurrent event(s). Patients otherwise will be counted as non-


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responders. More details on the CMH methods are discussed in Section 5.4.4. The 
CMH analysis may be implemented using SAS FREQ procedure with the CMH option 
in TABLES statement. 
2.6 
Analysis of the key secondary objective 
Descriptive summaries of key secondary endpoints (Table 2-4) will be presented by study 
treatment on FAS.  Hypothesis tests for treatment differences in key secondary endpoints will 
be performed if and only if both null hypothesis in the primary analysis are rejected.  
2.6.1 
Key secondary endpoints 
Table 2-4 
Key secondary endpoints and methods of analysis 
Endpoints 
Analysis method 
Key secondary endpoint: Proportion of patients 
achieving at least one point improvement of 
fibrosis stage without worsening of NASH (no 
worsening of hepatocellular ballooning or 
lobular inflammation) at Week 48 compared 
with baseline 
Same logistic regression model as used in the 
primary analysis for each step of hierarchical 
test 
Key secondary endpoint: Proportion of patients 
achieving resolution of NASH without 
worsening of fibrosis stage at Week 48 
compared with baseline 
Same logistic regression model as used in the 
primary analysis for each step of hierarchical 
test 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Extending the hierarchical testing procedure for primary analysis and defining a general one-
sided (∝=0.05) statistical hypothesis test Hi for  
Hi0: 
𝑃𝑃𝑃𝑃1(1−𝑃𝑃𝑃𝑃2)
𝑃𝑃𝑃𝑃2(1−𝑃𝑃𝑃𝑃1)<=1 vs. Hi1: 
𝑃𝑃𝑃𝑃1(1−𝑃𝑃𝑃𝑃2)
𝑃𝑃𝑃𝑃2(1−𝑃𝑃𝑃𝑃1) > 1 
at each step of hypothesis test, where i=1, ..., 6 with Pi1 and Pi2 correspond to the true 
probabilities of response for combination vs. monotherapy in the ith test,  the extended 
hierarchical testing procedure can be formalized following general principles in the graphical 
approach (Bretz et al 2009) to maintain a strong control of an overall type I FWER at 0.05. 
where 
H1: Combo vs. LIK066 comparison in primary endpoint (Section 2.5.2) 
H2: Combo vs. LJN452 comparison in primary endpoint (Section 2.5.2) 
H3: Combo vs. LIK066 comparison in proportion of patients achieving at least one point 
improvement of fibrosis stage without worsening of NASH (no worsening of 
hepatocellular ballooning or lobular inflammation) at Week 48 compared with baseline 
H4: Combo vs. LJN452 comparison in proportion of patients achieving at least one point 
improvement of fibrosis stage without worsening of NASH (no worsening of 
hepatocellular ballooning or lobular inflammation) at Week 48 compared with baseline 
H5: Combo vs. LIK066 comparison in proportion of patients achieving resolution of NASH 
without worsening of fibrosis stage at Week 48 compared with baseline 


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H6: Combo vs. LJN452 comparison in proportion of patients achieving resolution of NASH 
without worsening of fibrosis stage at Week 48 compared with baseline 
A specific hypothesis test Hi will be performed if and only if the null hypotheses in all previous 
testing steps are rejected.  
The number (%) of responders will be summarized by study treatment. The difference between 
the combination therapy and each monotherapy will be presented along with Wald asymptotic 
95% CI. The same logistic regression model and MI method for primary analysis will be 
adopted for hypothesis tests on key secondary endpoints and odds ratios (95% CI) will be 
presented. If no hypothesis test is performed for a step based on the pre-specified hierarchical 
testing procedure, the p-values will not be reported. 
2.6.3 
Handling of missing values/censoring/discontinuations 
The same MI methods outlined in Section 2.5.3 for primary analysis will be used for missing 
data imputation during key secondary analysis. 
2.7 
Analysis of secondary efficacy objective(s) 
Secondary efficacy endpoints in Table 2-5 will be summarized by visit and by study treatment 
on FAS.  
2.7.1 
Secondary efficacy endpoints 
Table 2-5 
Secondary efficacy variables and methods of analysis 
Endpoint 
Analysis 
Proportion of patients who have at least one 
stage improvement in fibrosis at week 48 
compared with baseline 
Same analysis methods as for the primary 
endpoint following the ITT principle (Section 
2.5.4) without hypothesis test.  
Proportion of patients who have at least two 
stage improvement in fibrosis and no 
worsening of NASH (no worsening of 
hepatocellular ballooning or lobular 
inflammation) at week 48 compared with 
baseline 
Same analysis methods as for the primary 
endpoint following the ITT principle (Section 
2.5.4) without hypothesis test.  
Change in liver fat content based on MRI - 
PDFF (in 60% of patients) over time up to 
Week 48 compared with baseline 
Repeated measurement analysis of covariance 
(ANCOVA) model (Section 5.4.3) will be used 
to estimate treatment group differences in 
mean change from baseline and 95% CI. This 
analysis is on FAS patients with at least one 
MRI-PDFF assessment. 
Proportion of patients with 5% or more 
reduction in body weight at Week 48 compared 
to baseline  
CMH test stratified with baseline T2DM status 
will be performed to estimate odds ratio (95% 
CI) between combination arm and each 
monotherapy 
2.7.2 
Statistical hypothesis, model, and method of analysis 
There is no hypothesis test planned for these additional secondary endpoints.  


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Binary histologic endpoints will be analyzed using the same logistic regression model for 
primary endpoint following an ITT approach (Section 2.5.4). The number (%) of responders 
will be summarized by study treatment. The difference between the combination therapy and 
each monotherapy will be presented along with Wald asymptotic 95% CI. The Odds Ratios 
(with 95% CI) between combination and each monotherapy estimated from the logistic 
regression model will also be provided. 
Repeated measurements ANCOVA models for the change in liver fat fraction will include time 
(visit) and treatment group as categorical explanatory variables, with interaction between 
treatment and visit also included in the model. More details of the model are discussed in 
Section 5.4.3. The analysis may be implemented with SAS MIXED procedure, assuming an 
unstructured variance-covariance matrix for repeated measurements and using Kenward-
Rogers type degrees of freedom. Estimates of the differences (95% CI) between treatment groups 
may be obtained using the LSMEANS and ESTIMATE statements in the SAS procedure at 
individual time points. Descriptive statistics, adjusted mean and adjusted mean differences (95% 
CI) between combination and monotherapies will be presented by visit. 
For proportion of patients with at least 5% reduction of body weight at week 48, the number 
(%) of patients will be summarized by study treatment. Difference in percentages will be 
presented with Wald asymptotic 95% CI.  A CMH analysis stratified by baseline T2DM status 
will be performed to estimate the common odds ratio (95% CI) between combination and each 
monotherapy. CMH analysis may be implemented with the SAS FREQ procedure following 
similar implementation in the sensitivity analysis on primary endpoint (Section 5.4.4) but with 
only baseline T2DM status as stratification factor. 
2.7.3 
Handling of missing values/censoring/discontinuations 
The repeated measures ANCOVA (MMRM) model implicitly imputes missing data under 
MAR assumption. For variables with only one post-baseline assessment, a missing post-
baseline value will be imputed by the baseline value. Patients without any post-baseline 
assessment will not be included in the analysis.  
Histologic endpoint at the week 48 or early termination visit after at least 24 weeks of exposure 
to study treatment will be used for secondary efficacy analysis regardless of intercurrent 
event(s). Patients will otherwise be counted as non-responders. 
Missing body weight at week 48 will be imputed by the last non-missing assessment, 
including baseline value, before week 48 (LOCF). 
2.8 
Safety analyses 
All safety analyses will be on SAF and presented by study treatment actually received (Section 
2.2). 
If not clarified otherwise, safety summaries will include only data from the on-treatment period 
except that baseline data may also be summarized where appropriate (e.g. change from baseline 
summaries). The on-treatment period lasts from the date of first administration of study 
treatment to 30 days after the date of the last dose date. 


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2.8.1 
Adverse events (AEs) 
All reported AEs will be coded based on the latest MedDRA version practically possible before 
database lock and clarified in footnotes of reports.  
The number (%) of patients with treatment emergent adverse events (TEAE, defined as events 
that started after the first dose of study treatment or events that were present prior to start of 
study treatment but increased in severity during on-treatment period) will be summarized by 
study treatment and in the following ways: 
- 
by primary system organ class (SOC) and preferred term (PT). 
- 
by primary SOC, PT and maximum severity. 
- 
by Standardized MedDRA Query (SMQ) and PT. 
- 
by SOC and PT for study treatment related adverse events,  
- 
by SOC and PT for serious adverse events (SAE),  
- 
by SOC and PT for TEAE leading to study treatment discontinuation.  
A patient with multiple adverse events of same SOC or PT will only be counted once towards 
the specific SOC or PT and according to the greatest severity reported. 
Clinical Trial Safety Disclosure 
Regulatory-required safety disclosure tables will be produced with the final CSR. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than 5% and on <on-treatment/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 and for the overall study period. 
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 
Number (%) of patients with treatment emergent pruritus, diarrhea, hypoglycemia and 
pancreatitis) will be summarized separately for each event(in total and by the PTs contributing 
to it) by study treatment. Kaplan-Meier curves for the time (days) from baseline to patient’s 
first incidence of pruritus, diarrhea and hypoglycemia by study treatment will also be provided 


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separately for each of the three AEs. 
 
 
Number (%) of patients who experienced following safety events will be presented by study 
treatment separately. 
- 
liver safety events identified according to protocol section 16.2  
- 
renal safety events identified according to protocol section 16.3 
2.8.2 
Deaths 
Patients who died any time during the study will be listed with the date (study day) and reason of 
death as well as the preferred term, verbatim term, start date (study day) and action taken of 
SAEs leading to such deaths.  
2.8.3 
Laboratory data 
Summary statistics of values and changes from baseline will be provided by visit (AV2) and by 
study treatment for laboratory tests listed in Table 2-6. Change from baseline will be 
summarized for patients with both baseline and post baseline values.  
Table 2-6 
Laboratory safety endpoints 
laboratory test group 
Parameters 
Hematology 
Hemoglobin (Hb), Hematocrit (Hct), Red blood cells (RBC), Mean 
corpuscular volume (MCV), Platelets, White blood cells (WBC), 
absolute WBC differential counts ((Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils separately) 
General Clinical 
Chemistry 
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorus, uric acid, haptoglobin 
Liver  
ALT, AST, ALP, GGT, creatine kinase (CK), lactate dehydrogenase 
(LDH), total bilirubin, albumin, total protein 
Renal 
BUN, creatinine, estimated glomerular filtration rate (eGFR) 
Urinalysis 
Albumin-creatinine ratio (ACR), Protein-creatinine ratio (PCR) 
Coagulation 
INR, APTT, Prothrombin Time (PT) and Thrombin Time (TT) 
Lipids and vascular risk  
Total cholesterol, HDL-C, LDL-C, VLDL-C, triglycerides, free glycerol 
and free fatty acids, ApoAI, high sensitivity C-reactive protein (hsCRP)  
Shift tables for normal / abnormal (low and high based on the low/normal/high classifications 
from central lab) from baseline to the most extreme post-baseline value will be provided. 
Number (%) of patients with post-treatment changes in laboratory criteria related to 
hepatotoxicity or nephrotoxicity criteria (Section 5.3.1) will also be summarized by criteria and 
by study treatment. In addition, patients meeting a criterion for hepatotoxicity, nephrotoxicity 
or other notable abnormalities defined in Section 5.3.1 will be listed, including the criteria met 
as well as the laboratory test name, date (study day) of lab sampling, results and units for that 
test and related lab tests throughout the study.  


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For summaries of shift, hepatotoxicity/nephrotoxicity events or other notable laboratory 
abnormalities outlined above, all post-treatment data will be used regardless of last dose date. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
The PR, QRS, QT, QTcF, and RR intervals will be summarized by visit and by study treatment. 
Number (%) of patients shifting from baseline in the overall normal or abnormal ECG 
abnormality will be presented by visit and by study treatment. 
The Fridericia QT correction formula (QTcF) will be used for clinical decisions and for 
analyses. Notable QTcF values and changes from baseline will be summarized as categorical 
variable by visit and by study treatment, where a notable value is defined as a QTcF interval of 
greater than 450 ms and the categories used for the change (increase) in QTcF are: ≤ 30 ms, > 
30 to ≤ 60 ms and > 60 ms.  
2.8.4.2 
Vital signs 
The value and change from baseline in vital sign parameters (i.e. pulse rate, systolic blood 
pressure and diastolic pressure) and anthropometric measurements (i.e. body weight, waist 
circumference and hip circumference) and derivations (BMI, waist:hip ratio) will be 
summarized by visit and by study treatment.  
Patients with clinically notable vital signs as defined in Section 5.3.10 will be listed with the 
abnormality criteria met as well as the specific test name, date (study day) of measurement, 
results and units for that and related measurements throughout the study. 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 


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Descriptive summaries of values and changes from baseline in pre-dose FGF19 and C4 will be 
presented by visit and by study treatment. The geometric mean and coefficient of variation will 
also be presented in the summaries for concentration values. The time (hours) elapsed since 
previous dose of study treatment will also be summarized by visit and by study treatment 
together in the same output. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.14 Interim analysis 
Not Applicable.  


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3 
Sample size calculation 
The sample size of the study is determined based on power consideration for proving superiority 
of the tropifexor-licogliflozin combination therapy compared to at least one of the 
monotherapies. 
3.1 
Power considerations for primary analysis 
No data is currently available for histological responses after licogliflozin or tropifexor 
monotherapy, neither is there any definitive theory established for complementary or antagonist 
interactions between the two molecules. Historical studies published so far also suggest 
unignorable placebo effect ranging from 8% to 18% for different populations and endpoints, 
which introduces additional uncertainties about the add-on effect size of the tropifexor-
licogliflozin combination therapy compared to either monotherapy even under a bliss 
independence assumption.  
Table 3-1 
Placebo effects on histological responses 
Histological 
Response 
definition 
Time point 
Histological study 
NASH population 
with Fibrosis 
stages 
Placebo 
response rate 
Fibrosis 
improvement of 1 
stage and no 
worsening in 
NASH 
Month 18 
REGENERATE 
(2019) 
Obeticholic acid 
F1 + F2 + F3 
10.6% 
F2 + F3 
11.9% 
Week 52 
CENTAUR (2018) 
Cenicriviroc 
F1 + F2 + F3 
10.4% 
Week 52 
ARREST (2018) 
Aramchol 
F1 + F2 + F3 
17.5% 
Week 48 
STELLAR3 
(2019) 
Selonsertib 
F3 
13.2% 
Week 48  
STELLAR4 
(2019) 
Selonsertib 
F4 
12.8% 
NASH resolution 
with no worsening 
in Fibrosis 
Month 18 
REGENERATE 
(2019) 
Obeticholic acid 
F1 + F2 + F3 
8% 
F2 + F3 
7.9% 
Week 52 
GOLDEN (2016) 
Elafibranor 
F0+F1+F2+F3 
9% 
The response rates for the monotherapies are deemed less likely to exceed 30%. For the stepwise 
gatekeeping testing procedure adopted for primary analysis, total sample size of 210 (70:70:70) 
is chosen so that there is approximately 80% power for the first hypothesis test (combination vs 
licogliflozin) if the true add-on effect is 20% for combination therapy. 
 


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Table 3-2 
Power under different assumptions of mono and combination therapy 
effect sizes 
True response rate assumptions 
Add-on effect 
size in 1st 
test 
power of 1-sided hierarchical 
tests α=0.05 
Licogliflozin 
Tropifexor 
Combination 
1st test 
Both tests 
30% 
30% 
38% 
8% 
25% 
12% 
23% 
23% 
33% 
10% 
38% 
22% 
30% 
30% 
44% 
14% 
53% 
34% 
30% 
30% 
47% 
17% 
67% 
52% 
23% 
30% 
41% 
18% 
75% 
34% 
20% 
20% 
40% 
20% 
84% 
75% 
25% 
25% 
45% 
20% 
80% 
69% 
30% 
30% 
50% 
20% 
79% 
67% 
30% 
30% 
51% 
21% 
82% 
72% 
23% 
30% 
46% 
23% 
89% 
60% 
Power calculations were performed with simulations (n=100000) implemented in R 3.3.3, 
where the primary analysis in each simulated study was performed using z-tests of difference 
in proportions without continuity correction for simplicity.  
The dropout rate of the study is anticipated to be around 10%. Because early termination and 
missing response data will be incorporated into the primary analysis with multiple imputations, 
no adjustment for early dropouts from study were implemented for the sample size calculations.  
3.2 
Power considerations for key secondary analysis  
While key secondary efficacy endpoints will be further tested in a hierarchical order if both 
null hypothesis in the primary analysis are rejected, no power evaluation was performed for 
secondary analysis given the anticipated diminishing power after two primary hypothesis tests. 


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4 
Change to protocol specified analyses 
Analysis details, as well as editorial and semantic changes where appropriate, are implemented 
for different sections without altering the planned methods of analysis. The following 
significant changes from protocol are implemented in this SAP. 
4.1 
For the estimand definition in Section 2.5, one intercurrent event “Early 
discontinuation of study treatment or withdrawal from study before week 48 visit” 
is added to cover the two separately listed events "early stop of study treatment 
before week 24" and "premature study discontinuation before week 24" in original 
protocol. This updated intercurrent event also include the situation of early stop of 
study treatment or withdrawal from study after week 24 but before week 48. Such 
situation was implicitly considered as an intercurrent event, addressed with 
imputation but not explicitly listed as an intercurrent event in study protocol. This 
update does not change the primary analysis planned in the study protocol.   
4.2 
For the intercurrent events associated with prohibited medications, any alcohol 
usage more than what is permitted in the protocol, initiation of other T2DM or lipid 
lowering medication (e.g. GLP-1 modulator) or initiation of other treatment being 
evaluated or approved for NASH are also included as intercurrent event. This 
change is in consideration of newly identified interventions that may confound 
study treatment effect but not listed in the current version of study protocol. 
4.3 
Key secondary analyses are added into the hierarchical testing procedure after the 
primary analysis (Section 2.6). This change enables potentially more statistical 
evidence accumulation without affecting the primary analysis. 
4.4 
Formulation of the null and alternative hypotheses in Section 2.5 and 2.6 are 
updated based on odds ratio instead of difference as the test statistics. This update 
does not change the analysis method originally planned in protocol but to keep 
consistent with the actual test statistics that will be used for the hypothesis tests. 
4.5 
P-values will not be provided if formal hypothesis test is not performed. This 
change is implemented to avoid potential confusions or misinterpretation of the 
results.  
4.6 
For secondary 
 analysis using repeated measurement ANCOVA 
model, inclusion of interaction between time (visit) and treatment are explicitly 
clarified. This change is to ensure consistent implementation of the analysis to 
account for the possibility that treatment effects change over time. 
4.7 
Additional sensitivity analysis for the primary endpoint based on CMH test is added 
(Section 2.5.4), given its robustness against risk of potential misassumption for the 
logistic regression for primary analysis. This change is implemented also in 
response to FDA comments. 
4.8 
Multiple imputations will be performed based on FCS with logistic regression 
instead of discriminant function (Section 2.5.3). This change is implemented for the 
convenience of including dichotomous predictors in the imputer’s model.  


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4.9 
Multiple imputations will be implemented by excluding treatment from the 
imputer’s model instead of performing MI separately within each treatment group 
(Section 2.5.3). This change helps to reduce the computational burden during 
implementation and enables more complete cases for the MI.  
4.10 Deaths will be listed instead of presented in aggregated summary (Section 2.8.2). 
This change is implemented because limited incidence of deaths is expected during 
the study. In addition, a listing provides the convenience of including additional 
patient specific data for the evaluation of each case of death. 
4.11 Demographics and baseline characteristics summary will be only for FAS (Section 
2.3). This change is implemented in the spirit of lean SAP because limited, if any, 
difference between SAF and FAS is expected. 
4.12 Listing of safety data pre- or post treatment will not be produced. This change is 
implemented in the spirit of lean SAP and such listings are considered not essential 
for the objectives of the study. To support data review and writing of narratives, 
informal listings can be used.  


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
First and last dose dates of study treatment 
Partially missing start or stop date of study treatment is not expected given the eCRF design.   
Missing first dose date for patients with known exposure to study treatment will be resolved 
through data queries.  
For patients with non-missing first dose date, a missing last dose date (e.g. due to lost to follow 
up) will be imputed with patient’s first dose date or the last known exposure to study treatment 
according to change in dosing CRF page, whichever is later.  
5.1.2 
AE start and stop dates 
AE Start Date Imputation: 
AE start date with missing year or with missing month but non-missing day will be resolved 
through data queries.  
Defining AE reference date as 
- 
If AE end date (after imputation if needed) <= first dose date, AE reference date = min 
(informed consent date, earliest visit date of SVs) 
- 
Else AE reference date = first dose date 
and following date components  
Day 
Month 
Year 
Partial AE Start Date 
 
MON 
YYYY 
AE reference Date 
REFD 
REFM 
REFY 
incomplete AE start date will be inputted according to logic matrix 
(Imputation) 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY MISSING 
NC 
NC 
NC 
NC 
YYYY < TRTY 
(D) 
(C) 
(C) 
(C) 
YYYY = TRTY 
(B) 
(C) 
(B) 
(A) 
YYYY > TRTY 
(E) 
(A) 
(A) 
(A) 
where 
NC 
No convention - require data query 
(A) 
01-MON-YYYY 
(B) 
AE reference date 
(C) 
 Last day of month MON-YYYY 
(D) 
 Last day of year YYYY 
(E) 
01-JAN-YYYY 
 


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The algorithms will be reflected in the Variable Source Derivation column as #IMPUTAEV 
(event) where event is the incomplete start date of the adverse event. 
AE End Date Imputation: 
If all AE end date components are missing after data queries, the AE is considered ongoing for 
analysis purpose. 
If AE end month is missing, the AE end date is imputed as the last day of AE end year or  
patient’s study completion/discontinuation visit date, whichever is earlier. 
If AE day is missing, then AE end date is imputed as the last day of the month or patient’s study 
completion/discontinuation visit date, whichever is earlier. 
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 
Start and stop dates of prior/concomitant medications or non-drug 
therapies / procedures  
The imputation for incomplete start or stop date of medications or non-drug therapies / 
procedures patients received in addition to study treatment during the study will follow the same 
algorithms for imputations of incomplete AE start/stop date.   
5.1.4 
Other imputations 
Imputation of missing primary or secondary endpoints are included in corresponding sections 
2.5, 2.6 and 2.7 for the corresponding analyses. There will be no imputation for other analysis 
in this SAP. 
5.2 
AEs coding/grading 
AEs are coded using the latest version of MedDRA dictionary practically implementable before 
study database lock.  
5.3 
Derivations 
5.3.1 
Laboratory parameters 
Laboratory criteria of potential hepatotoxicity for liver safety monitoring in protocol section 
10.2.1 (not including additional non-lab criteria): 
- 
ALT or AST > 5 × ULN 


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- 
ALP > 2 × ULN 
- 
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 
Laboratory criteria of potential nephrotoxicity for renal safety monitoring in protocol section 
10.2.2: 
- 
Two or more consecutive serum creatinine increase >=25% compared with baseline 
- 
serum creatinine increase >=50% compared with baseline 
- 
eGFR < 60 mL/(min*1.73m2) 
- 
Two or more consecutive albumin- or protein-creatinine ratio increase ≥ 2-fold 
- 
Two or more consecutive albumin-creatinine ratio (ACR) ≥ 30 mg/g; 
- 
Two or more consecutive protein-creatinine ratio (PCR ) ≥ 150 mg/g  
- 
Dipstick glycosuria ≥ 1+ for patients with negative reading at baseline 
- 
Dipstick hematuria ≥ 1+ not due to trauma for patients with negative reading at 
baseline 
Criteria for other notable laboratory abnormality: 
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 
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 


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Calculated eGFR 
<60 
mL/min 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
5.3.7 
T2DM status 
The T2DM status at baseline is determined as follows: T2DM = Yes if: 
- 
Type 2 diabetes mellitus is reported in Medical History OR 
- 
Baseline fasting plasma glucose (FPG) >= 7.0 mmol/L (126 mg/dL)  
Otherwise T2DM = No. 


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5.3.8 
Total NAS score 
NAS score is calculated as the sum of scores of steatosis (0-3), lobular inflammation (0-3) and 
hepatocyte ballooning (0-2).  
 
 
 
 
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 
≥ 120 and increase from baseline ≥ 15 
< 40 
≤ 50 and decrease from baseline ≥ 15 
Blood pressure (mmHg) 
Systolic 
> 200 
≥ 180 and increase from baseline ≥ 20 
<75 
≤ 90 and decrease from baseline ≥ 20 
Diastolic 
> 115 
≥ 105 and increase from baseline ≥ 15 
< 40 
≤ 50 and decrease from baseline ≥ 15 
5.3.11 
Definitions for biopsy based endpoints 
Assessment of fibrosis staging and NAFLD Activity Scores (NAS) including specifically 
steatosis, lobular inflammation and hepatocyte ballooning will be performed by pathological 
Central Reader(s). 
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 
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 NASH 
Worsening of NASH in primary estimand is defined as meeting one of the two criteria below. 
- 
Any increase in lobular inflammation score 


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- 
Any increase in hepatocyte ballooning score 
 
5.3.11.3 Resolution of NASH 
Resolution of NASH in primary estimand is defined as meeting both criteria below. 
- 
Lobular inflammation score ≤ 1  
- 
Hepatocyte ballooning = 0  
 
5.4 
Statistical models 
5.4.1 
Logistic regression model for primary and key secondary analysis 
Hierarchical testing procedure and the hypothesis tests at each step for primary and key 
secondary analyses are defined in Section 2.5 and Section 2.6.   
For binary dependent variable and considering the link of NASH with many metabolic risk 
factors, a logistic regression model is used to allow more flexibility in adjusting for both 
categorical and continuous explanatory variables.         
The efficacy of LIK066 for NASH is postulated due to its ability to improve obesity and 
diabetes. Frequently regarded as two manifestations of metabolic syndrome, T2DM and 
NAFLD commonly exist together with, for example, insulin resistance as one of the key 
pathological factors. The randomization of this study is stratified by patient’s T2DM status at 
baseline. Links between obesity and histologic NASH were also well known (Lassailly et al 
2015, Vilar-Gomez et al 2015).  
Table 5-4 
Association of weight loss with NASH resolution or liver fibrosis 
improvement 
Study 
Intervention 
population 
Histologic endpoint 
effect 
Vilar-Gomez 
et al 2015 
Weight loss 
by life style 
change 
Obese w. 
NASH 
Resolution of NASH 
p <0.01a 
Fibrosis status 
p<0.00a 
Lassailly et al 
2015 
Bariatric 
surgery for 
weight loss 
Obese w. 
NASH 
NASH resolution 
85% 
Fibrosis improvement 
p<0.0001b 
Ballooning 
p<0.0001b 
Lobular inflammation 
p<0.0001b 
a:  p-value based on Cochran-Mantel-Haenszel  χ2 trend test between weight loss categories and the histologic endpoint stratified 
by age older than 55 years, sex, type 2 diabetes, BMI>=35 
b:  p-value based on Wilcoxon signed rank test for paired data before and 1 year after bariatric surgery 
Hence BMI and T2DM status are anticipated to be prognostic of histologic changes, with or 
without therapeutic intervention, and will be included in the logistic regression model as 
confounding factors.   


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LJN452 is anticipated to improve liver fibrosis, with or without NASH resolution, based on 
previous studies of other FXR modulators (Neuschwander Tetri et al 2015, Younossi 2019). 
The baseline stage of fibrosis is a plausible prognostic factor for histologic response, especially 
for the fibrosis improvement itself, and included also as a factor in the logistic regression model.  
Table 5-5 
FXR modulation for NASH resolution or fibrosis improvement 
Study 
Intervention 
(Target/MOA) 
Population 
Patients with histologic improvement in NASH 
over control 
Endpoint 
Diff. over 
control 
Statistical 
significance 
FLINT 
(Neuschwander 
et. Al. 2015) 
Obeticolic acid 
(FXR / NAFLD) 
Borderline or 
definite NASH 
Fibrosis 
improvement 
35% vs. 
19% 
p=0.004a 
Resolution of 
definite NASH 
22% vs. 
13% 
p=0.08a 
Hepatocellular 
ballooning 
improvement 
46% vs. 
31% 
p=0.03 a 
Lobular 
inflammation 
improvement 
53% vs. 
35% 
p=0.006 a 
Portal 
inflammation 
improvement  
12% vs. 
13% 
p=0.90 a 
REGENERATE 
(Youinossi 2019) 
OCA 25mg 
(FXR/ NASH) 
NASH w 
stage 2/3 
fibrosis 
Fibrosis 
improvement 
w/o NASH 
worsening 
21% vs. 
10.6% 
p=0.0002b 
NASH 
resolution w/o 
fibrosis 
worsening 
11.7% vs. 
8.0% 
p=0.1268b 
a:  p-value based on Cochran-Mantel-Haenszel  χ2 trend test stratified by clinic and diabetes status 
b:  no details on calculation of p-value in the press release 
The logistic regression model assumes patient’s week 48 histological response status y ∈(0, 1) 
~ binomial (1, pjklm), where pjklm is the probability of histologic response and related to the 
collection of factors/covariates X corresponding to patient’s study treatments j, baseline fibrosis 
stage k, baseline T2DM status l and baseline BMI m through logit link function (Nelder and 
Wedderburn 1972) 
For patients sampled in this study, it follows that log ቀ
𝑝𝑝𝑖𝑖
1−𝑝𝑝𝑖𝑖ቁ = 𝜷𝜷𝑻𝑻𝑿𝑿𝒊𝒊 for i=(1, 2, ..., n), where n 
is the sample size of the study and 𝜷𝜷 is the vector of coefficients to be estimated for the effects 
of independent variables.  
Under the aforementioned binomial distribution, the probability function can be derived as  
𝑓𝑓(𝑦𝑦𝑖𝑖) = 𝑝𝑝𝑖𝑖
𝑦𝑦𝑖𝑖(1 −𝑝𝑝𝑖𝑖)1−𝑦𝑦𝑖𝑖 
with log likelihood function  


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𝑙𝑙= ෍(𝑦𝑦𝑖𝑖log (𝑝𝑝𝑖𝑖) + (1 − 𝑦𝑦𝑖𝑖)log (1 −𝑝𝑝𝑖𝑖))
𝑛𝑛
𝑖𝑖=1
 
where 𝑝𝑝𝑖𝑖= 
exp (𝜷𝜷𝑻𝑻𝑿𝑿𝒊𝒊)
1+exp (𝜷𝜷𝑻𝑻𝑿𝑿𝒊𝒊)   
The basic maximum likelihood estimators (MLE)𝜷𝜷෡ ~ 𝑁𝑁(𝛽𝛽, 𝐼𝐼(𝛽𝛽)−1), where 𝐼𝐼(𝛽𝛽) is the Fisher’s 
information matrix, for such logistic regression model is known to suffer from small sample 
bias. Given the uncertainties on benefits of LJN452 and LIK066 over placebo effects (Table 3-
1), the penalized likelihood method proposed by Firth (1993) will be adopted to reduce potential 
small-sample bias and to consistently produce finite MLEs in case of complete or quasi-
complete separations during the calculations.  
Over-dispersion associated with the estimation of variances for binomial data will be corrected 
using the Williams method (1982).  
With randomization and blinding, the possibility of collinearity between study treatment and 
other independent variables can be reasonably ignored so inflation on standard errors of the 
coefficients for treatment effect is not expected in the analysis model despite potential 
collinearity among other cofactors.  
5.4.1.1 
Interactions among independent variables and subgroup analysis 
It is possible that the different mechanisms of actions with LJN542 and/or LIK066 may lead to 
differential effects on the components of the primary endpoints, which is potentially an 
advantage achieved with combination therapy. If such differential effects exist, however, it may 
also lead to interactions between covariates and main treatment effect, which is not included in 
the primary analysis model.  
The statistical inference of primary analysis is on the overall patient population targeted by this 
study, notwithstanding the possibility of such granular modulation of the treatment effect. 
Nevertheless, better understanding on what limits or enhances the add-on effect of the 
combination therapy, and for whom or under what circumstances it exists, could inform 
decisions on future development of the combination therapy.  
Considering the sample size of the study and unknown treatment effects, adding additional 
interaction effect in the logistic model could increase the risk of small sample (small number of 
events/non-events within class) bias and failures to converge. Hence subgroup analysis  as 
outlined in Section 2.13.1 will be performed. 
 
 
5.4.2 
Multiple imputation for missing primary and key secondary analysis 
MI method for missing data allows the flexibility of including additional auxiliary variables in 
the imputer model and accounts for the uncertainty on real value with multiple inputted values.  
For the binary dependent variable, a Fully Conditional Specification (FCS) logistic regression 
method is chosen for the imputer model considering the convenience of including dichotomous 
predictors. Baseline fibrosis stage (2 vs. 3), baseline T2DM (No/Yes), baseline BMI (as 


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categorical predictor) and decrease of ALT at week 24 (<= -17 U/L vs. >-17 U/L) will be 
included as predictors for the imputer’s model.  
The exclusion of treatment from the imputer model ensures a more conservative estimate of 
treatment effect in that it would bias only toward null (for superiority test) if a relationship 
between treatment and response does exist (Schafer 1997). The inclusion of decrease in ALT at 
week 24 (<= -17 U/L vs. >-17 U/L) into the imputer’s model is based on findings by Loomba 
et. al. (2019) and considering the balance between general validity of analysis model and some 
loss in precision in case a trivial factor is additionally added in imputer’s model (Rubin 1996).   
If a reduced logistic regression model has to be adopted (Section 2.5.2), the reduced list of 
predictors in primary analysis model will also be used for the imputer model, except for the 
treatment which will still be excluded.  
The imputer’s model is first fitted using observations (n0) with non-missing data 
logit (p) = βTX 
where  
p is the true probability of response 
X is the n0 by p matrix of covariates 
β is the vector of coefficients to be estimated as the first step of MI.  
Based on the estimated regression coefficients 𝛃𝛃෡ and associated covariance matrix, posterior 
predictive distribution for β is built and a new set of parameters β# is randomly sampled from 
it.  
For ith patient with missing data, expected probability qi =Pr (response) is calculated as 
qi =  
exp൫𝛃𝛃#
𝐓𝐓𝑿𝑿𝒊𝒊൯
1+exp൫𝛃𝛃#
𝐓𝐓𝑿𝑿𝒊𝒊൯ 
and this patient’s response status will be imputed as Yes if qi is larger than a random number 
sampled from uniform distribution between 0 and 1.  
These imputation steps can be implemented using SAS MI procedure. A total of >=50 iterations 
of imputations will be executed to create 50 imputed complete data sets.  
The logistic regression model for primary or key secondary analysis is then executed separately 
for these data sets with results (parameter estimates) stored in an output data set. 
The SAS MIANALYZE procedure reads in the parameter estimates, standard errors or 
covariance matrix in the output data set generated by the logistic regression analyses, and 
produces estimates and 95% confidence limits to back calculate the odds ratios (95% CI). P-
values will be presented if formal hypothesis test is to be performed according to hierarchical 
testing procedure outlined in Sections 2.5 and 2.6. 


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5.4.3 
Repeated measurement ANCOVA (MMRM) for secondary 
 
 analyses 
Suppose the continuous dependent variable vector yi   = (yi1, … , yimi)′ of a patient i = 1,...,n  
observed at different time points (visits) j=1, ..., m follows a m-dimensional multivariate normal 
distribution with some non-trivial off-diagonal elements in its mi × mi variance - covariance 
matrix.  
The MMRM is chosen because it can explicitly account for such correlation and non-constant 
variability in data with a schematic model  
Y = Xβ +Zγ +ε  
where  
X ~ covariates of fixed effects (including treatment effect of interest) with coefficients vector β  
Z ~ random effects with coefficients γ normally distributed with expected value 0 and covariance matrix (G) 
ε ~ is random error not accounted for in the model with expected value 0 and a covariance matrix (R) 
It follows that the variability of Y can be structured as V=ZGZ`+R for parameterization. 
The parameterization of the covariance matrix structures for repeated measurements could be 
pre-specified based on trial design and assumptions. For analysis in this study, an unstructured 
covariance matrix is assumed. In case of failure to converge that cannot be resolved with other 
approaches, compound symmetry structure may be used if it resolves the issue.    
Both covariance parameters and the fixed/random effects (including 95% confidence limits) 
can then be estimated based on likelihood methods, such as the restricted maximum 
likelihood (REML) method which accommodates the situation of some data missing at random 
(Rubin 1976; Little 1995) and will be adopted in this study. 
The analysis can be implemented in the SAS MIXED procedure with TYPE=UN and 
subject=<patient ID> in the REPEATED statement and DDFM=KR in model statement. The 
REML is the default method. 
Model assumptions will be checked based on diagnostic plots and influence diagnostics if 
necessary. The possible impact of questionable models will be discussed in CSR if needed.  
5.4.4 
CMH method for sensitivity analysis 
The CMH analysis will be performed separately for combination vs. LJN452 and for 
combination vs. LIK066. Each CMH analysis is stratified by three binary predictors, baseline 
fibrosis stage (<=2 vs. >2), T2DM (No/Yes) and BMI (>= 35 vs. < 35) added to TABLES 
statement before treatment and response status in the SAS FREQ procedure.  
The stratification factors subgroup data into a series of i=8 separate 2x2 contingency tables 
 
Primary 
endpoint 
Combination 
Therapy 
Mono-
therapy 
Total 
Responder 
ai 
bi 
t1.i 


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Non-responder 
ci 
di 
t2.i 
Total 
t.1i 
t.2i 
Ti 
A common odds ratio (OR) between combination and monotherapy in the probability of 
response can be estimated as proposed by Mantel and Haenszel (1959)  
                                                𝑂𝑂𝑂𝑂
෢ = 
∑
𝑎𝑎𝑖𝑖𝑑𝑑𝑖𝑖
𝑇𝑇𝑖𝑖
8
𝑖𝑖=1
∑
𝑐𝑐𝑖𝑖𝑏𝑏𝑖𝑖
𝑇𝑇𝑖𝑖
8
𝑖𝑖=1
 
and asymptotic 95% confidence limits for the common odds ratio can be calculated based on 
estimated variance for the odds ratio on log scale (Robins et. al. 1986). 
The exact test for the common odds ratio = 1 will be performed using the EXACT statement 
with the COMOR option in the SAS FREQ procedure to report a p-value.  
5.5 
Rule of exclusion criteria of analysis sets 
Table 5-6 
Scenarios causing subjects to be excluded 
Scenarios 
Exclusion from 
Patient was rescreened but did not sign a new ICF 
All analysis sets 
ICH-GCP non-compliance of study site with impact on data quality 
All analysis sets 
No drug taken after randomization 
SAF 
ICF not signed 
All analysis sets 
Mis-randomized and received no study treatment 
FAS 
5.6 
Other statistical aspects 
5.6.1 
Risk difference and Wald asymptotic 100*(1-α)% CI 
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. 
For two proportions p1= x1/n1 and p2=x2/n2, the risk difference d=p1-p0 has asymptotic 
standard error se(d) = sqrt{p1(1-p1)/n1 + p2(1-p2)/n2}. The Wald asymptotic 100(1-α)% 
confidence limits for the difference are d ± se(d)*zα/2 . Wald asymptotic 95% CI for difference 
can be calculated using SAS procedure PROC FREQ and option RISKDIFF in the TABLES 
statement, specifying the RISKDIFF option also in the EXACT statement in case exact CI is 
needed for rare events. 


Novartis 
For business use only 
Page 47 
SAP 
 
CLJN452D12201C 
 
 
 
6 
References 
Robins, J. M., Breslow, N., and Greenland, S. (1986). “Estimators of the Mantel-Haenszel 
Variance Consistent in Both Sparse Data and Large-Strata Limiting Models.” Biometrics 
42:311–323. 
Mantel, N., and Haenszel, W. (1959). “Statistical Aspects of Analysis of Data from 
Retrospective Studies of Disease.” Journal of the National Cancer Institute 22:719–748. 
Rubin, D. B. (1976). “Inference and Missing Data.” Biometrika 63:581–592.  
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
& Sons.  
Rubin, D. B. (1996). “Multiple Imputation after 18+ Years.” Journal of the American 
Statistical Association 91:473–489.  
Nelder, J. A. and Wedderburn, R. W. M. (1972), “Generalized Linear Models,” Journal of the 
Royal Statistical Society, Series A, 135, 370–384. 
Firth, D. (1993), “Bias Reduction of Maximum Likelihood Estimates,” Biometrika, 80, 27–38. 
Williams, D. A. (1982), “Extra-binomial Variation in Logistic Linear Models,” Applied 
Statistics, 31, 144–148. 
Schafer, J. L. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 
Little, R. J. A. (1995). “Modeling the Drop-Out Mechanism in Repeated-Measures Studies.” 
Journal of the American Statistical Association 90:1112–1121. 
Bretz, F., Maurer, W., Brannath, W. and Posch, M. (2009). “A graphical approach to 
sequentially rejective multiple test procedures.” Statistics in Medicine 28, 586–604. 
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al (2015) “Weight Loss Through 
Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis,” 
Gaestroenterology 367-78. 
Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. (2015) “Bariatric 
surgery reduces features of nonalcoholic steatohepatitis in morbidly obese 
patients,” Gastroenterol 149:379–88. 
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 956-65. 
Youinossi Z (2019) “Positive Results from REGENERATE: A Phase 3 International, 
Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for NASH,” 
Abstract Gs-06, EASL 
Loomba R, Sanyal AJ, Kowdley KV, et al. (2019) “Factors Associated With Histologic 
Response in Adult Patients With Nonalcoholic Steatohepatitis,” Gastroenterology 156:88-
95.e5.