A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Subjects With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
Semaglutide, and the Fixed-Dose Combination of Cilofexor and 
Firsocostat, Alone and in Combination, in Subjects With 
Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis 
(NASH) 
Study Acronym:
WAYFIND
Plain Language Short 
Title
Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in 
Combination, in Adults With Cirrhosis Due to Nonalcoholic 
Steatohepatitis (NASH)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EU CT Number:
ClinicalTrials.gov 
Identifier:
155550
2021-001445-12
NCT04971785
Indication:
Nonalcoholic steatohepatitis (NASH)
Protocol ID:
GS-US-454-6075
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol 
Version/Date:
Amendment 2: 
26 October 2023
Amendment History:
Original:
17 March 2021
Amendment 1:
25 June 2021
Amendment 2:
26 October 2023
High-level summaries of the history(ies) of amendment(s) are 
provided in Appendix 11.10.
[r) GILEAU 

Fixed-Dose Combination of Cilofexor and Firsocostat
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Country-specific 
Requirements:
Country-specific requirements, as applicable, are listed in 
Appendix 11.9.
This study will be conducted under United States Food and Drug Administration investigational 
new drug (IND) regulations (21 Code of Federal Regulations Part 312); however, sites located in 
the European Economic Area, the United Kingdom, and Switzerland are not included under the 
IND and are considered non-IND sites.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.

Fixed-Dose Combination of Cilofexor and Firsocostat 
Protocol GS-US-454-6075 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
Final 
Amendment2 
TABLE OF CONTENTS ................................................................................................................................................ 3 
LIST OF IN-TEXT TABLES ......................................................................................................................................... 7 
LIST OF IN-TEXT FIGURES ........................................................................................................................................ 7 
PROTOCOL SYNOPSIS ................................................................................................................................................ 8 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 21 
1. 
INTRODUCTION ................................................................................................................................................ 25 
1.1. 
Backgrowid .............................................................................................................................................. 25 
1.2. 
Semaglutide ............................................................................................................................................. 26 
1.2.1. 
General Infonnation .............................................................................................................. 26 
1.2.2. 
Nonclinical Pha1macology and Toxicology .......................................................................... 27 
1.2.3. 
Clinical Studies of Semaglutide ............................................................................................ 27 
1.3. 
Cilofexor .................................................................................................................................................. 32 
1.3.1. 
General Infonnation .............................................................................................................. 32 
1.3.2. 
Nonclinical Pha1macology and Toxicology .......................................................................... 32 
1.3 .3. 
Clinical Studies of CILO ....................................................................................................... 34 
1.4. 
Firsocostat. ............................................................................................................................................... 35 
1.4.1. 
General Infonnation .............................................................................................................. 35 
1.4.2. 
Nonclinical Pha1macology and Toxicology .......................................................................... 35 
1.4.3. 
Clinical Studies of FIR .......................................................................................................... 36 
1.5. 
CILO/FIR Combination ........................................................................................................................... 37 
1.5.1. 
Nonclinical Pha1macology and Toxicology .......................................................................... 37 
1.5.2. 
Clinical Studies Including CILO and FIR in Combination ................................................... 37 
1.5.3. 
Clinical Studies Including CILO, FIR, and SEMA .............................................................. .42 
1.6. 
Rationale for This Study ......................................................................................................................... .45 
1.7. 
Rationale for Dose Selection of Semaglutide ......................................................................................... .47 
1.8. 
Rationale for Dose Selection of CILO and FIR in Fixed-Dose Combination ± SEMA ........................ .48 
1.9. 
Benefit-Risk Assessment for the Study .................................................................................................. .49 
1.10. 
Coinpliance .............................................................................................................................................. 52 
2. 
OBJECTIVES ....................................................................................................................................................... 53 
3. 
STUDY DESIGN ................................................................................................................................................. 55 
3.1. 
Endpoints ................................................................................................................................................. 55 
3.2. 
Study Design ........................................................................................................................................... 56 
3.3. 
Study Treatments ..................................................................................................................................... 57 
3.4. 
Duration of Treatment ............................................................................................................................. 57 
3.4.1. 
Poststudy Care ....................................................................................................................... 57 
3.5. 
Discontinuation Criteria .......................................................................................................................... 58 
3.6. 
End of Study ............................................................................................................................................ 59 
3.7. 
Source Data ............................................................................................................................................. 59 
3.8. 
BiomarkerTesting ................................................................................................................................... 59 
3.8.1. 
Biomarker Sam les to Address the Stud ob·ectives ........................................................... 59 
4. 
PARTICIPANTPOPULATION .......................................................................................................................... 62 
4.1. 
Number of Participants and Participant Selection ................................................................................... 62 
4.1.1. 
Participant Replacement ........................................................................................................ 62 
4.2. 
Inclusion Criteria ..................................................................................................................................... 62 
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4.3.
Exclusion Criteria....................................................................................................................................63
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................67
5.1.
Randomization, Blinding, and Treatment Codes Access ........................................................................67
5.1.1.
Randomization.......................................................................................................................67
5.1.2.
Blinding .................................................................................................................................67
5.1.3.
Procedures for Breaking Treatment Codes............................................................................68
5.2.
Description and Handling of Semaglutide ..............................................................................................68
5.2.1.
Formulation ...........................................................................................................................68
5.2.2.
PDS290 Pen Injector for Semaglutide for Use in Clinical Studies .......................................69
5.2.3.
Storage and Handling ............................................................................................................70
5.2.4.
Shelf-life and In-use Time for Semaglutide in PDS290........................................................70
5.3.
Description and Handling of CILO/FIR..................................................................................................70
5.3.1.
Formulation ...........................................................................................................................70
5.3.2.
Packaging and Labeling ........................................................................................................71
5.3.3.
Storage and Handling ............................................................................................................71
5.4.
Labeling of Study Drug...........................................................................................................................71
5.5.
Dosage and Administration of CILO/FIR and SEMA ............................................................................71
5.5.1.
Dosage and Administration of CILO/FIR .............................................................................72
5.5.2.
Dosage and Administration of Semaglutide..........................................................................72
5.5.3.
Management of Semaglutide Dose Escalation......................................................................73
5.6.
Prior and Concomitant Medications........................................................................................................74
5.6.1.
Participants Treated With Insulin at Screening.....................................................................76
5.6.2.
Participants With Screening HbA1c ≤ 8.0% Treated With Insulin ........................................76
5.6.3.
Participants Treated With Sulfonylureas at Screening..........................................................76
5.7.
Accountability for Investigational Medicinal Product and Devices........................................................76
5.7.1.
Investigational Medicinal Product and Device Return or Disposal ......................................77
6.
STUDY PROCEDURES......................................................................................................................................78
6.1.
Participant Enrollment and Treatment Assignment ................................................................................78
6.2.
Pretreatment Assessments .......................................................................................................................78
6.2.1.
Screening Visit ......................................................................................................................78
6.2.2.
Day 1 Visit.............................................................................................................................81
6.3.
Randomization.........................................................................................................................................82
6.4.
Treatment Assessments ...........................................................................................................................82
6.5.
Unscheduled Visits..................................................................................................................................82
6.5.1.
Premature Discontinuation of Study Drug ............................................................................83
6.5.2.
Early Termination Visit.........................................................................................................84
6.6.
Follow-up Visit........................................................................................................................................85
6.7.
Study Visit Windows...............................................................................................................................87
6.8.
Description of Study Assessments ..........................................................................................................87
6.8.1.
Clinical Laboratory Assessments ..........................................................................................87
6.8.2.
Physical Examination ............................................................................................................89
6.8.3.
Fundoscopic Examination .....................................................................................................89
6.8.4.
Vital Signs .............................................................................................................................90
6.8.5.
Clinical Liver Assessments ...................................................................................................91
6.8.6.
Estimated Glomerular Filtration Rate Using MDRD Equation ............................................92
6.8.7.
Genomic Testing ...................................................................................................................92
6.8.8.
Pregnancy Testing .................................................................................................................93
6.8.9.
PRO Measures.......................................................................................................................93
6.8.10.
Liver Stiffness Measured by Transient Elastography (FibroScan) .......................................94
6.8.11.
Liver Biopsy ..........................................................................................................................95
6.8.12.
Lifestyle Counseling..............................................................................................................95
6.8.13.
Abdominal Ultrasound ..........................................................................................................95

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6.8.14.
Electrocardiogram .................................................................................................................95
6.8.15.
Counseling Regarding Adherence to Study Procedures........................................................96
6.9.
Sample Storage........................................................................................................................................96
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................97
7.1.
Definitions of Adverse Events and Serious Adverse Events...................................................................97
7.1.1.
Adverse Events......................................................................................................................97
7.1.2.
Serious Adverse Events.........................................................................................................97
7.1.3.
Serious Adverse Drug Reaction ............................................................................................98
7.1.4.
Adverse Events of Special Interest........................................................................................98
7.1.5.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports .........................99
7.2.
Assessment of Adverse Events and Serious Adverse Events................................................................100
7.2.1.
Assessment of Causality for Study Drugs and Procedures .................................................100
7.2.2.
Assessment of Severity........................................................................................................100
7.3.
Investigator Reporting Requirements and Instructions .........................................................................100
7.3.1.
Requirements for Collection Prior to Study Drug Initiation ...............................................100
7.3.2.
Adverse Events....................................................................................................................100
7.3.3.
Serious Adverse Events.......................................................................................................101
7.3.4.
Study Drug Special Situations Reports ...............................................................................101
7.3.5.
Concomitant Therapy Reports.............................................................................................101
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.....................................102
7.4.1.
Serious Adverse Event Reporting Process ..........................................................................102
7.4.2.
Special Situations Reporting Process ..................................................................................102
7.5.
Gilead Reporting Requirements ............................................................................................................104
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events.........................................................................................................................105
7.7.
Toxicity Management............................................................................................................................105
7.7.1.
Monitoring for DILI ............................................................................................................105
7.7.2.
Close Observation ...............................................................................................................106
7.7.3.
Study Drug Withholding .....................................................................................................107
7.7.4.
Lipid Management...............................................................................................................108
7.7.5.
Pruritus Management...........................................................................................................109
7.7.6.
Child-Pugh Score.................................................................................................................109
7.7.7.
MELD Score........................................................................................................................109
8.
STATISTICAL CONSIDERATIONS...............................................................................................................110
8.1.
Analysis Objectives and Endpoints.......................................................................................................110
8.1.1.
Analysis Objectives.............................................................................................................110
8.1.2.
Endpoints.............................................................................................................................111
8.2.
Planned Analyses...................................................................................................................................113
8.2.1.
Final Analysis......................................................................................................................113
8.2.2.
Multiplicity Adjustments.....................................................................................................113
8.3.
Analysis Conventions............................................................................................................................115
8.3.1.
Analysis Sets .......................................................................................................................115
8.3.2.
Data Handling Conventions ................................................................................................115
8.4.
Demographic and Baseline Characteristics Analysis............................................................................116
8.5.
Efficacy Analysis...................................................................................................................................116
8.5.1.
Primary Analysis .................................................................................................................116
8.5.2.
Secondary Analyses.............................................................................................................117
8.5.3.
Sensitivity Analysis.............................................................................................................120
8.6.
Safety Analysis......................................................................................................................................121
8.6.1.
Extent of Exposure ..............................................................................................................121
8.6.2.
Adverse Events....................................................................................................................121
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8.6.3.
Laboratory Evaluations .......................................................................................................122
8.6.4.
Other Safety Evaluations.....................................................................................................122
8.7.
Pharmacokinetic Analysis .....................................................................................................................122
8.8.
Biomarker Analysis...............................................................................................................................123
8.9.
Sample Size ...........................................................................................................................................123
8.10.
Data Monitoring Committee..................................................................................................................124
9.
INVESTIGATOR RESPONSIBILITIES...........................................................................................................125
9.1.
Investigator Responsibilities .................................................................................................................125
9.1.1.
Good Clinical Practice.........................................................................................................125
9.1.2.
Financial Disclosure ............................................................................................................125
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval..............................................................................................................................125
9.1.4.
Informed Consent ................................................................................................................125
9.1.5.
Confidentiality.....................................................................................................................126
9.1.6.
Study Files and Retention of Records .................................................................................126
9.1.7.
Case Report Forms ..............................................................................................................128
9.1.8.
Investigator Inspections.......................................................................................................128
9.1.9.
Protocol Compliance ...........................................................................................................128
9.2.
Sponsor Responsibilities .......................................................................................................................128
9.2.1.
Protocol Modifications ........................................................................................................128
9.2.2.
Study Report and Publications ............................................................................................129
9.3.
Joint Investigator/Sponsor Responsibilities ..........................................................................................129
9.3.1.
Payment Reporting ..............................................................................................................129
9.3.2.
Access to Information for Monitoring.................................................................................129
9.3.3.
Access to Information for Auditing or Inspections .............................................................129
9.3.4.
Study Termination...............................................................................................................129
10.
REFERENCES...................................................................................................................................................130
11.
APPENDICES....................................................................................................................................................134
11.1.
Investigator Signature Page...................................................................................................................135
11.2.
Pandemic Risk Assessment and Mitigation Plan ..................................................................................136
11.3.
Marketing Authorization Status of Study Interventions........................................................................139
11.4.
West Haven Criteria ..............................................................................................................................140
11.5.
Study Procedures Table.........................................................................................................................141
11.6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive 
Requirements.........................................................................................................................................144
11.7.
Lifestyle Recommendations Included in the 2019 American College of Cardiology/American 
Heart Association Guideline on the Primary Prevention of Cardiovascular Disease ...........................147
11.8.
Cardiovascular Risk Assessment for Participants With Nonalcoholic Fatty Liver Disease .................148
11.9.
Country-Specific Requirements ............................................................................................................149
11.9.1.
Additional Country-Specific Requirements for France.......................................................149
11.10. Amendment History ..............................................................................................................................150
11.10.1.
Amendment 2 (26 October 2023)........................................................................................150

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LIST OF IN-TEXT TABLES
Table 2.
Composition of Semaglutide Solution for Injection................................................................69
Table 3.
Semaglutide Dose-Escalation Schedule ..................................................................................73
Table 4.
Examples of Prohibited Medications and Agents Requiring Special Administration 
Considerations From 30 Days Prior to Day 1 Through End of Treatmenta ............................75
Table 5.
Study Visit Windows...............................................................................................................87
Table 6.
Child-Pugh Classification of the Severity of Cirrhosis ...........................................................92
Table 7.
Estimand Strategy for Primary Histologic Endpoint.............................................................117
Table 8. 
Estimand Strategy for Secondary Endpoint 1: Fibrosis Improvement Without 
Worsening of NASH at Week 72 in the SEMA+CILO/FIR Versus SEMA Groups ............118
Table 9. 
Estimand Strategy for Secondary Endpoint 2: NASH Resolution at Week 72 in the 
SEMA+CILO/FIR Versus Placebo Groups...........................................................................119
Table 10.
Estimand Strategy for Secondary Endpoint 3: NASH Resolution at Week 72 in the 
SEMA+CILO/FIR Versus CILO/FIR Groups.......................................................................120
LIST OF IN-TEXT FIGURES
Figure 1.
Study GS-US-384-3914 (Cohorts 12 and 13): Median Change From Baseline in 
Triglycerides by Visit and Treatment (VAS Versus FENO)...................................................38
Figure 2.
Study GS-US-384-3914 (Cohorts 12 and 13): Median Change From Baseline in 
Triglycerides by Visit, Treatment (VAS Versus FENO), and Pretreatment Baseline 
Triglyceride Level ...................................................................................................................39
Figure 3.
GS-US-454-6075 Study Schema.............................................................................................57
Figure 4.
On-Treatment Monitoring Requiring Close Observation......................................................106
Figure 5.
On-Treatment Monitoring Requiring Study Drug Withholding............................................107
Figure 6.
Multiple Testing Strategy ......................................................................................................113
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
Semaglutide, and the Fixed-Dose Combination of Cilofexor and 
Firsocostat, Alone and in Combination, in Subjects With 
Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis 
(NASH)
Study Acronym:
WAYFIND
Plain Language Short 
Title
Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in 
Combination, in Adults With Cirrhosis Due to Nonalcoholic 
Steatohepatitis (NASH)
Regulatory Agency Identifier Numbers:
IND Number:
EU CT Number:
ClinicalTrials.gov 
Identifier:
155550
2021-001445-12
NCT04971785
Study Sites Planned:
Approximately 250 sites globally
Objectives:
The primary objective of this study is as follows:
•
To evaluate whether the combination of semaglutide (SEMA) 
with the fixed-dose combination (FDC) of cilofexor (CILO; 
GS-9674) and firsocostat (FIR; GS-0976), hereafter referred 
to as CILO/FIR, causes fibrosis improvement (according to 
the NASH Clinical Research Network [CRN] classification) 
without worsening of NASH (defined as a ≥ 1-point increase 
in hepatocellular ballooning or lobular inflammation) in 
participants with compensated cirrhosis due to NASH, as 
compared with placebo

Fixed-Dose Combination of Cilofexor and Firsocostat 
Protocol GS-US-454-6075 
Final 
Amendment2 
Gilead Sciences, Inc. 
CONFIDENTIAL 
The secondaiy objectives of this study are as follows: 
• 
To confnm the contribution of CILO/FIR to fibrosis 
improvement without worsening of NASH in paiiicipants 
treated with the combination of SEMA and CILO/FIR by 
compai·ing with paiiicipants ti·eated with SEMA alone 
• 
To evaluate whether the combination of SEMA with the FDC 
of CILO/FIR causes NASH resolution ( defined as lobulai· 
inflammation of O or 1 and hepatocellulai· ballooning of 0) in 
paiiicipants with compensated cinhosis due to NASH, as 
compai·ed with placebo 
• 
To confnm the contribution of SEMA to NASH resolution in 
paiiicipants ti·eated with the combination of SEMA and 
CILO/FIR by compai·ing with paiiicipants ti·eated with 
CILO/FIR alone 
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Study Design:
This is a Phase 2, randomized, double-blind, double-dummy, 
placebo-controlled study evaluating the efficacy and safety of 
SEMA, CILO/FIR, and their combination in participants with 
compensated cirrhosis due to NASH.
Participants meeting the study’s entry criteria will be randomly 
assigned in a 3:3:3:2 ratio to 1 of 3 active treatment groups 
(SEMA + CILO/FIR, SEMA alone, CILO/FIR alone) or 
placebo-to-match (PTM), as shown in the figure below. 
Randomization will be stratified by the presence or absence of 
type 2 diabetes as determined by medical history or based on 
screening laboratory values if previously undiagnosed 
(ie, hemoglobin A1c [HbA1c] ≥ 6.5% or fasting plasma glucose 
≥ 126 mg/dL, confirmed on repeat testing), and by ELF score 
(≥ 11.30 or < 11.30 during screening).
CILO = cilofexor (GS-9674); firsocostat = FIR (GS-0976); PTM = placebo-to-
match; SEMA = semaglutide
CCI
-
§ 
f-+ 
r -
f-+ 
4 
-
,w .... 
GroupA 
SEMA+Cll.OIFIR(n=l20) 
Group B 
SE\1A + Oral PTM (n" 120) 
Group( 
lajeculble PTM + en.om (n "" 120) 
GroupD 
Inj«tablePThf +Oral PThf (n"'&O) 
72Weeks 
Wttk72 
Pnmay_(llu,,.,,,·) 
.... 
.... 
.... 
i 
> 
-+ 
.... 
j 
.... 
1,w .... l 

Fixed-Dose Combination of Cilofexor and Firsocostat
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Number of 
Participants Planned:
Approximately 440 participants
Study Population:
Men and nonpregnant, nonlactating women between 18 and 80 
years of age, inclusive, with compensated cirrhosis due to 
NASH, as determined by liver biopsy.
Duration of 
Treatment/
Intervention:
Participants will be treated for 72 weeks. Total study duration 
will be 85 weeks, including an 8-week screening period, a 72-
week treatment period, and a 5-week follow-up period.
Diagnosis and Main 
Eligibility Criteria:
Participants must meet all of the inclusion criteria and none of 
the exclusion criteria to be eligible for the study.
Inclusion Criteria:
1) Men and women between 18 and 80 years of age, inclusive, 
based on the date of the screening visit
2) Willing and able to give informed consent prior to any 
study-specific procedures being performed
3) Cirrhosis (F4) due to NASH as defined by 1 of the following:
a) A historical liver biopsy within 180 days of screening 
that, in the opinion of the central pathologists, is evaluable 
and consistent with cirrhosis (F4) and NASH (defined as the 
presence of steatosis Grade ≥ 1, hepatocellular ballooning 
Grade ≥ 1, and lobular inflammation Grade ≥ 1, according to 
NAS)
OR
b) In participants without a qualifying historical liver 
biopsy, if FibroScan ≥ 9.9 kPa at screening, a screening liver 
biopsy may be performed. The screening liver biopsy must, 
in the opinion of the central pathologists, be evaluable and 
meet histologic criteria as specified in inclusion criterion 3a)
OR
c) In participants with a historical liver biopsy completed 
more than 180 days prior to screening that is consistent with 
cirrhosis (F4) and NASH, as determined by a local reader, a 
screening liver biopsy may be performed. The screening liver 
biopsy must, in the opinion of the central pathologists, be 
evaluable and meet histologic criteria as specified in 
inclusion criterion 3a)

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4) The following laboratory parameters at screening, as 
determined by the central laboratory:
a) Estimated glomerular filtration rate (eGFR) 
≥ 30 mL/min/1.73m2, as calculated by the Modification of 
Diet in Renal Disease (MDRD) equation to estimate 
creatinine clearance (CLcr)
b) HbA1c ≤ 10% (or reflex serum fructosamine ≤ 
400 μmol/L if HbA1c result is not quantifiable)
c) Hemoglobin > 10.6 g/dL
d) International normalized ratio ≤ 1.4, unless due to 
therapeutic anticoagulation
e) Total bilirubin ≤ 1.3 × upper limit of normal (ULN) 
(unless due to an alternative etiology such as Gilbert’s 
syndrome or hemolytic anemia)
f)
Serum albumin ≥ 3.5 g/dL 
g) Serum alkaline phosphatase (ALP) ≤ 2 × ULN
h) Platelet count ≥ 125,000/μL
i)
Serum triglyceride level ≤ 250 mg/dL. If initial screening 
value is > 250 mg/dL, triglycerides may be retested 
during the screening period. Fasting serum triglycerides 
must be confirmed to be ≤ 250 mg/dL prior to Day 1. 
Management of hypertriglyceridemia may be initiated or 
modified at investigator discretion during the screening 
period
j)
ALT < 5 × ULN
5) Body mass index ≥ 23 kg/m2 at screening
Exclusion Criteria:
1) Any history of decompensated liver disease in the opinion of 
the investigator, including clinically relevant ascites, hepatic 
encephalopathy (HE), or variceal bleeding
2) Child-Pugh (CP) score > 6 at screening, unless due to an 
alternative etiology such as Gilbert’s syndrome or therapeutic 
anticoagulation
3) Model for End-Stage Liver Disease (MELD) score > 12 at 
screening, unless due to an alternative etiology such as 
therapeutic anticoagulation

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4) Chronic hepatitis B virus infection (hepatitis B surface 
antigen positive)
5) Chronic hepatitis C virus (HCV) infection (HCV antibody 
and HCV RNA positive). Participants cured of HCV 
infection less than 2 years prior to the screening visit are not 
eligible
6) Other causes of liver disease based on medical history and/or 
central pathologists review of liver histology, including but 
not limited to: alcoholic liver disease, autoimmune disorders 
(eg, primary biliary cholangitis, primary sclerosing 
cholangitis, autoimmune hepatitis), drug-induced 
hepatotoxicity, Wilson disease, clinically significant iron 
overload, or alpha-1-antitrypsin deficiency
7) History of liver transplantation
8) Current or prior history of hepatocellular carcinoma (HCC)
9) HIV infection
10) Weight loss > 10% within 180 days of screening, or > 5% 
between the date of the biopsy used for eligibility and the 
date of screening
11) Any weight reduction surgery or procedure in the 2 years 
prior to screening or malabsorptive weight loss surgery 
(eg, Roux-en-Y or distal gastric bypass) at any time prior to 
screening
12) History of intestinal resection that could result in 
malabsorption of study drug
13) Planned coronary, carotid, or peripheral artery intervention or 
unstable cardiovascular disease in the opinion of the 
investigator, including any of the following:
a) Unstable angina, myocardial infarction, coronary artery 
bypass graft surgery, or coronary angioplasty within 
180 days prior to screening
b) Transient ischemic attack or cerebrovascular accident 
within 180 days prior to screening
c) Symptomatic valvular heart disease or hypertrophic 
cardiomyopathy
d) Symptomatic congestive heart failure
e) Uncontrolled or recurrent ventricular tachycardia or 
arrhythmia requiring an automatic implantable 
cardioverter defibrillator. Stable, controlled atrial 
fibrillation is allowed

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f)
An emergency room visit or hospitalization for confirmed 
cardiovascular disease within 180 days prior to screening
14) History of uncontrolled chronic pulmonary disease in the 
opinion of the investigator (eg, chronic obstructive 
pulmonary disease, interstitial lung disease) within 180 days 
prior to screening
15) Men who habitually drink greater than 21 units/week of 
alcohol or women who habitually drink greater than 
14 units/week of alcohol (1 unit is equivalent to 12 
oz/360 mL of beer, a 4 oz/120 mL glass of wine, or 1 oz/30 
mL of hard liquor)
16) Positive urine drug screen for amphetamines, cocaine, or 
opiates (eg, heroin, morphine) at screening, unless due to a 
prescription medication (eg, oxycodone, methylphenidate) 
and the prescription and diagnosis are reviewed and approved 
by the investigator. Participants on stable methadone or 
buprenorphine maintenance treatment for at least 180 days 
prior to screening may be included in the study
17) Use of any prohibited concomitant medication prior to 
enrollment as described in Table 4:
a) Participants on vitamin E regimen ≥ 800 IU/day, or 
pioglitazone, must be on a stable dose in the opinion of 
the investigator for at least 180 days prior to the historical 
or screening liver biopsy
b) Participants taking antidiabetic medications must be on a 
stable dose, in the opinion of the investigator, for at least 
90 days prior to the historical or screening liver biopsy
18) Participation in another investigational study of a drug or 
device within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to the date of 
screening and through the end of the study. Participation in a 
study of an investigational device may be approved by the 
medical monitor or designee
19) History of malignancy within 5 years of screening with the 
following exceptions:
a) Adequately treated carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other 
localized nonmelanoma skin cancer
20) For participants with type 2 diabetes diagnosed prior to the 
date of the screening visit OR based on screening visit HbA1c 
≥ 6.5%, participants must have no evidence of uncontrolled 
and potentially unstable retinopathy or maculopathy as 

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determined by a fundoscopic examination performed starting 
90 days prior to screening visit date through Day 1. If there 
has been worsening of the participant’s visual function since 
a historical fundoscopic examination in the opinion of the 
investigator, then the fundoscopic examination must be 
repeated prior to Day 1 for eligibility. Pharmacological pupil 
dilation is a requirement unless using a digital fundus 
photography camera specified for nondilated examination
21) Acute pancreatitis within 180 days prior to screening
22) History or presence of chronic pancreatitis
23) History of symptomatic gallbladder or biliary tract disease in 
the opinion of the investigator within 6 months prior to 
screening, unless a cholecystectomy has been performed
24) Presence or history of type 1 diabetes 
25) Personal or first-degree relative(s) history of multiple 
endocrine neoplasia type 2 or medullar thyroid carcinoma
26) Treatment with a glucagon-like peptide-1 receptor agonist 
(GLP-1 RA) in the period from 90 days prior to the screening 
visit and from 90 days prior to the date of the historical 
qualifying liver biopsy (if applicable)
27) Female who is pregnant, breastfeeding, intends to become 
pregnant, or is of childbearing potential and not using an 
adequate contraceptive method 
28) Men who engage in heterosexual intercourse not using an 
adequate method of contraception 
29) Presence of any laboratory abnormality or condition that, in 
the opinion of the investigator, could interfere with or 
compromise a participant’s treatment, assessment, or 
compliance with the protocol and/or study procedures. This 
includes a history of substance abuse and/or psychiatric 
condition requiring hospitalization and/or emergency room 
visit within 2 years of screening
30) Known hypersensitivity to the study drug(s), metabolites, or 
formulation excipient(s)
31) For participants who have not completed a series of an 
authorized COVID-19 vaccination regimen prior to 
screening, a positive result for COVID-19 on SARS-CoV-2 
reverse transcriptase-polymerase chain reaction (RT-PCR) 
test

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Study Procedures/
Frequency:
After signing the informed consent form (ICF), participants will 
complete a screening visit which will include the following 
assessments: complete medical history, complete physical 
examination (PE), vital signs, measurement of hip and waist 
circumference, assessment of ascites and HE, lifestyle 
counseling, calculation of the CP and MELD scores, laboratory 
assessments and biomarker sample collection, SARS-CoV-2 RT-
PCR test (if necessary), serum pregnancy test (for women of 
child-bearing potential), urine drug screen, liver biopsy (if 
necessary), liver stiffness measured using FibroScan, abdominal 
ultrasound for evaluation of presence of HCC, gallstones, or 
other hepatobiliary disease (if applicable), standard 12-lead 
electrocardiogram (ECG), fundoscopic examination (if 
applicable), stool sample collection kit for Day 1 visit, and 
review of adverse events (AEs) and concomitant medications. 
Eligible participants will be randomly assigned on Day 1 in a 
3:3:3:2 ratio to 1 of 3 active treatment groups or placebo: 
Group A: SEMA+CILO/FIR 
Group B: SEMA+PTM CILO/FIR
Group C: PTM SEMA+CILO/FIR 
Group D: PTM SEMA+PTM CILO/FIR
Prior to initial dosing, the following Day 1 assessments will be 
performed: symptom-driven PE, vital signs, measurement of hip 
and waist circumference, assessment of ascites and HE, lifestyle 
counseling, calculation of the CP and MELD scores, laboratory 
assessments and biomarker sample collection, urine pregnancy 
test (for women of child-bearing potential), PROs, and review of 
AEs and concomitant medications. 
After the screening period and randomization at Day 1, study 
visits will occur at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72 or an 
early termination (ET) visit for those who discontinue from the 
study early, and a follow-up visit 5 weeks after the Week 72 or 
ET visit. At minimum, review of AEs and concomitant 
medications and safety laboratory tests will be performed at 
every visit. 

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While on the study, participants will undergo the following 
procedures and laboratory assessments:
•
Vital signs and body weight at each visit
•
Symptom-driven PE at each visit
•
Assessment of ascites and HE at each visit
•
Hip and waist circumference at Weeks 24, 48, and 72
•
Lifestyle counseling at each visit
•
FibroScan at Weeks 24, 48, and 72
•
ELF test at Weeks 12, 24, 48, and 72
•
Chemistry panel, hematology panel, lipid panel, coagulation 
and eGFR by MDRD at each visit
•
HbA1c and glycemic panel at Weeks 12, 24, 48, and 72
•
Urine pregnancy test (for women of childbearing potential) 
every 4 weeks
•
Blood and urine for biomarkers at Weeks 24, 48, and 72
•
Stool for biomarkers at Weeks 48 and 72
•
PROs at Weeks 24, 48, and 72
•
Single PK blood sample at Week 4 (15 minutes to 3 hours 
postdose), Week 24 (anytime postdose), Week 48 (predose), 
Week 60 (15 minutes to 3 hours postdose), Week 72 
(predose), and the ET visit (anytime). For PK sampling at 
Weeks 4, 48, 60, and 72, participants should be reminded not 
to take their oral study drug until advised to do so at their 
clinic visit
•
12-lead ECG at Week 72
•
Liver biopsy at Week 72
•
Abdominal ultrasound at Weeks 24, 48, and 72
•
Fundus examination (participants with type 2 diabetes only) 
at Weeks 48 and 72, or ET visit (at discretion of investigator)
Participants who prematurely discontinue study drug are 
encouraged to return for an unscheduled visit at the discretion of 
the investigator or request of the medical monitor or designee for 
a safety evaluation. Participants should be encouraged to 
complete their remaining study visits in accordance with the 
Study Procedures Table if appropriate.

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Participants prematurely discontinuing from the study should 
complete an ET visit. At the ET visit, participants will undergo 
symptom-driven PE, vital signs, measurement of hip and waist 
circumference, assessments of ascites and HE, lifestyle 
counseling, calculation of the CP and MELD scores, laboratory 
tests, PK blood sample collection (anytime), pregnancy test (for 
women of childbearing potential), 
, and 
review of concomitant medications and AEs. The following 
assessments should be performed unless completed within 12 
weeks of the ET visit: abdominal ultrasound and FibroScan. The 
following assessments will be performed at the discretion of the 
investigator: PROs, ECG, fundus examination, biomarker sample 
collection (including blood and urine), and liver biopsy. 
All participants will have a follow-up visit 5 weeks after the 
Week 72 or ET visit. At the follow-up visit, participants will 
undergo a symptom-driven PE, vital signs, measurement of hip 
and waist circumference, assessment of ascites and HE, lifestyle 
counseling, calculation of the CP and MELD scores, laboratory 
tests, blood and urine collection for biomarkers, pregnancy test 
(for women of childbearing potential), and review of concomitant 
medications and AEs.
Test Product, Dose, and 
Mode of Administration:
SEMA 3.0 mg/mL solution for injection administered 
subcutaneously (SC) at a once-weekly dose from 0.24 mg to 
2.4 mg (dose escalation over 16 weeks) using the 3.0 mL 
PDS290 prefilled pen injector
CILO/FIR 30 mg/20 mg FDC tablet containing 30 mg (free-form 
equivalent) CILO and 20 mg FIR administered orally once daily 
with or without food
Reference Therapy, 
Dose, and Mode of 
Administration:
Placebo-to-match SEMA 3.0 mg/mL solution for injection 
administered SC at a once-weekly dose from 0.24 mg to 2.4 mg 
(dose escalation over 16 weeks) using the 3.0 mL PDS290 
prefilled pen injector
Placebo-to-match CILO/FIR 30 mg/20 mg FDC tablet 
administered orally once daily with or without food
CCI

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Criteria for Evaluation:
Safety:
The safety of study drug in participants with cirrhosis due to 
NASH will be assessed during the study through the assessment 
of vital signs, clinical laboratory tests, AEs, and concomitant 
medication usage.
An external data monitoring committee (DMC) that consists of 2 
hepatologists and a statistician will review the progress of the 
study. The DMC will convene after at least 55 participants have 
completed the Week 4 visit and approximately every 6 months 
thereafter to monitor the study for safety events.
Efficacy:
Primary endpoint:
•
≥ 1-stage improvement in fibrosis (according to the NASH 
CRN classification) without worsening of NASH (defined as 
a ≥ 1-point increase in hepatocellular ballooning or lobular 
inflammation) at Week 72 in the SEMA+CILO/FIR versus 
placebo groups
Pharmacokinetics:
The PK of CILO, FIR, and relevant metabolite(s) will be 
evaluated, as applicable, and plasma concentrations will be 
provided in a listing.
Statistical Methods:
Efficacy Analysis:
A stratified Mantel-Haenszel test will be used to compare the 
difference in proportions of participants who achieve a ≥ 1-stage 
improvement in fibrosis without worsening of NASH at Week 72 
between the SEMA+CILO/FIR and placebo groups, adjusting for 
stratification factors.
Safety Analysis:
Safety analyses include summaries of extent of exposure, AEs, 
laboratory evaluations, and vital sign assessments. 
Pharmacokinetic 
Analysis:
Plasma concentrations of CILO, FIR, and their respective 
metabolites will be listed, if available. Data from this study may 
be combined with data from other studies in a population PK 
meta-analysis. 

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Sample Size:
The power calculation is based on the estimated proportions of 
participants in the SEMA+CILO/FIR group to achieve the 
primary endpoint at Week 72 as compared with the placebo 
group. Assuming the proportion of participants in the 
SEMA+CILO/FIR and placebo groups to achieve fibrosis 
improvement ≥ 1-stage without worsening of NASH at Week 72 
is 35% and 12%, respectively, with a sample size of 120 
participants in the SEMA+CILO/FIR group and 80 participants 
in the placebo group, the study has 97% power to detect a 
difference at a 2-sided significance level of 0.05.
If the primary endpoint is achieved, the contribution of 
CILO/FIR to fibrosis improvement ≥ 1-stage without worsening 
of NASH will be evaluated by comparing the SEMA+CILO/FIR 
and SEMA groups for this endpoint. Assuming the proportion of 
participants to achieve ≥ 1-stage fibrosis improvement without 
worsening of NASH at Week 72 is 35% and 20% in the 
SEMA+CILO/FIR and SEMA groups, respectively, with a 
sample size of 120 participants in each group, the study has 74% 
power to detect a difference at a 2-sided significance 
level of 0.05. 
If the contribution of CILO/FIR to fibrosis improvement 
≥ 1-stage without worsening of NASH is demonstrated, the 
overall effect of NASH resolution will be evaluated by 
comparing the SEMA+CILO/FIR versus placebo groups. 
Assuming the proportion of participants in the SEMA+CILO/FIR 
and placebo groups to achieve NASH resolution at Week 72 is 
45% and 10%, respectively, the study has > 99% power to detect 
a difference at a 2-sided significance level of 0.05. 
If the superiority of SEMA+CILO/FIR versus placebo for the 
overall effect of NASH resolution is achieved, the contribution of 
SEMA to NASH resolution will be evaluated by comparing the 
SEMA+CILO/FIR and CILO/FIR groups for this endpoint. 
Assuming the proportion of participants to achieve NASH 
resolution at Week 72 is 45% and 15% in the SEMA+CILO/FIR 
and CILO/FIR groups, respectively, with a sample size of 
120 participants in each group, the study has 99% power to 
detect a difference at a 2-sided significance level of 0.05.
The power calculations are based on Pearson’s chi-square test 
using a normal approximation.
This study will be conducted in accordance with the guidelines of Good Clinical Practice, 
including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ACC
acetyl-coenzyme A carboxylase
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCx-xx
partial area under the concentration versus time curve from time “x” to time “xx”
AUCinf
area under the concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/z)
BMI
body mass index
CAP
controlled attenuation parameter
Cavg
average observed concentration of drug
CI
confidence interval
CILO
cilofexor (GS-9674)
CK
creatine kinase
CK18 M30
cytokeratin 18 M30 fraction
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
COVID-19
coronavirus disease 2019
CP
Child-Pugh
CPK
creatine phosphokinase
CRF
case report form
CRN
Clinical Research Network
CRO
contract research organization
CRP
C-reactive protein
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CVOT
cardiovascular outcomes study
CYP
cytochrome P450 enzyme
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture

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eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis
ET
early termination
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDC
fixed-dose combination
FENO
fenofibrate
FGF19
fibroblast growth factor 19
FIR
firsocostat (GS-0976)
FSH
follicle-stimulating hormone
FWER
family-wise type I error rate
FXR
farnesoid X receptor
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
Gilead
Gilead Sciences/Gilead Sciences, Inc.
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HE
hepatic encephalopathy
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HOMA-IR
homeostasis model assessment of insulin resistance
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IND
investigational new drug
INR
international normalized ratio
IQR
interquartile range
IQR/M
interquartile range/median value

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IRB
institutional review board
IRT
Interactive Response Technology
JP
Japanese Pharmacopeia
LDL
low-density lipoprotein
LSM
least-squares mean
MACE
major adverse cardiac event(s)
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
MRE
magnetic resonance elastography
MRI-PDFF
magnetic resonance imaging-proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NAS
nonalcoholic fatty liver disease activity score
NASH
nonalcoholic steatohepatitis
NOAEL
no observed adverse effect level
oz
ounce
PBC
primary biliary cholangitis
PD
pharmacodynamic(s)
PE
physical examination
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
Ph. Eur.
European Pharmacopeia
PI
principal investigator
PK
pharmacokinetic(s)
PRO
patient-reported outcome
PS
Patient Safety 
PSC
primary sclerosing cholangitis
PT
preferred term
PTM
placebo-to-match
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
RT-PCR
reverse transcriptase-polymerase chain reaction
SADR
serious adverse drug reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous(ly)
SDV
SEL
source data verification
selonsertib (GS-4997)
SEMA
semaglutide

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SF-36
36-Item Short Form Survey
SOC
system organ class
SOP
standard operating procedure
SSR
special situation report
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
Tmax
time (observed time point) of Cmax
ULN
upper limit of normal
US, USA
United States, United States of America
USP
United States Pharmacopeia
VAS
icosapent ethyl (Vascepa®)
VLDL
very low-density lipoprotein

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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity, metabolic syndrome, and type 2 diabetes that are leading to an increased 
incidence of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease is 
characterized by the excess accumulation of lipid droplets within the liver, also known as hepatic 
steatosis. Prevalence rates of NAFLD range from 6% to 37% worldwide {Ong 2007, Vernon 
2011} with a recent reported pooled global prevalence of 25% {Younossi 2016}.
The aggressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is present in 
approximately 30% of NAFLD patients and is associated with increased liver-related mortality 
{Younossi 2016}. Pathologically, NASH is characterized by inflammation and hepatocellular 
ballooning, with or without fibrosis{Ong 2007, Williams 2011}. In the United States (US), it has 
been estimated that 3% to 6% of the population {Vernon 2011}, or the equivalent of 
approximately 15 million adults, have NASH. Modeling of NASH prevalence across 
4 European Union (EU) countries (France, Germany, Italy, Spain) projects the prevalence of 
NASH to increase from 2.6% to 4.4% in 2016 to 5.0% to 6.3% in 2030, which translates to 2.7 to 
4.7 million cases across these countries in 2030 {Estes 2018}. Furthermore, as NASH is a 
manifestation of metabolic syndrome, risk factors for cardiovascular disease are frequent 
comorbidities in this patient population {Dietrich 2014, Faramawi 2008, Voulgari 2010}, and 
thus cardiovascular outcomes are also relevant. Given the absence of any approved therapies for 
patients with advanced fibrosis due to NASH, and the increasing prevalence of NASH 
comorbidities, NASH is expected to represent an increasingly large unmet medical need. 
Nonalcoholic steatohepatitis is thought to occur as the result of metabolic syndrome: the impact 
of obesity, insulin resistance, and dyslipidemia in the liver. Nonalcoholic steatohepatitis is the 
result of a chronic state of hepatocyte cell death and activation of sterile innate immune 
pathways leading to a vicious cycle of inflammation, liver injury, and ultimately, fibrosis. 
Increased circulating bile acids and excessive accumulation of lipids within hepatocytes are 
hallmarks of NASH and are each thought to contribute to hepatocyte cell death. Circulating bile 
acid levels are increased in NASH and contribute to disease progression by promoting tissue 
damage leading to hepatic inflammation and fibrosis {Donnelly 2005, Neuschwander-Tetri 
2010}. Excessive hepatic lipids may result from dysregulated metabolic processes such as 
increased lipolysis in adipose tissue and flux of non-esterified fatty acids to the liver, increased 
hepatic de novo lipogenesis (DNL), reduced mitochondrial function, and/or insufficient 
β-oxidation of fatty acids in the liver {Donnelly 2005, Lambert 2014, Neuschwander-Tetri 
2010}. Lipotoxic intermediates derived from fatty acids are thought to contribute to the etiology 
of NASH {Neuschwander-Tetri 2010}.

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Over time, in the setting of persistent risk factors, fibrosis due to NASH may progress to an 
advanced stage, specifically bridging fibrosis or cirrhosis, with the latter occurring in 10% to 
20% of patients. Advanced fibrosis due to NASH is characterized by extensive collagen 
deposition and remodeling of the extracellular matrix, driven predominantly by activation of 
hepatic stellate cells {Mederacke 2013}. Clinically, advanced fibrosis is associated with 
increased morbidity and mortality {Ekstedt 2015, Yeh 2014}. Cirrhosis increases the risk of 
hepatocellular carcinoma (HCC) and other complications of end-stage liver disease, including 
jaundice, fluid retention (edema and ascites), portal hypertension and variceal bleeding, impaired 
coagulation, and hepatic encephalopathy (HE). Decompensated liver disease, as defined by the 
development of 1 of the above complications, has a high mortality rate and the only known 
effective treatment is liver transplantation. Given the increasing prevalence of obesity and 
obesity-related diseases in the US, as of 2016, NASH is the leading indication for liver 
transplantation among women and the second leading indication among men {Noureddin 2018}. 
Among patients undergoing liver transplant for HCC, NASH is the leading etiology {Afzali 
2012, Wong 2014}.
1.2.
Semaglutide
Please refer to the investigator’s brochure (IB) for further information on semaglutide (SEMA) 
not included below. 
1.2.1.
General Information
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed by Novo 
Nordisk A/S for weight management and is under investigation for treatment of NASH at a dose 
of 2.4 mg once weekly. Semaglutide at doses of 0.5 mg and 1.0 mg once weekly has been 
approved as an adjunct to diet and exercise for the management of type 2 diabetes and to reduce 
the risk of major adverse cardiac events (MACE) in adults with type 2 diabetes and established 
cardiovascular disease under the trade name, Ozempic®. 
Semaglutide is based on the same technology as used for liraglutide (Victoza®, Saxenda®), with 
fatty acid acylation and albumin binding as the protraction principle, and with maintained high 
homology to human GLP-1. Semaglutide has been modified resulting in a longer half-life 
suitable for once-weekly dosing and is stabilized against degradation by the DPP-4 enzyme. The 
extended half-life of the SEMA molecule is primarily obtained by increased albumin binding, 
which is facilitated by a large fatty acid-derived chemical moiety. 

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1.2.2.
Nonclinical Pharmacology and Toxicology
Nonclinical efficacy data have shown that SEMA lowers blood glucose, food intake, and body 
weight in animal models of diabetes and obesity. Furthermore, SEMA attenuated the 
development of atherosclerosis and had an anti-inflammatory action in the cardiovascular 
system. In a mouse model of NAFLD, SEMA reduced liver triglyceride levels, expression of 
collagen genes, and inflammation markers. Semaglutide exerts its actions through the GLP-1 
receptor using similar pathways and with similar cellular actions as native GLP-1. The 
mechanism of action is consistent with that of other long-acting GLP-1 RAs, for example 
liraglutide. 
The general toxicology program comprised studies in mice, rats and monkeys of up to 13, 26, 
and 52 weeks, respectively. In all 3 species, dose levels were limited by the pharmacological 
effects on food intake and body weight. The majority of the treatment-related changes were 
considered to be due to the pharmacological effects of SEMA. Non-lethal thyroid C-cell tumors 
observed in rodents are a class effect for the GLP-1 RAs. In 2-year carcinogenicity studies in rats 
and mice, SEMA caused thyroid C-cell tumors at clinically relevant exposures. The C-cell 
changes in rodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism 
to which rodents are particularly sensitive. Recent data have shown that the GLP-1 receptor is 
not expressed in normal human thyroid C-cells. Accordingly, the human relevance of rodent 
C-cell tumors is considered low but cannot be completely excluded. 
Semaglutide adversely affected embryofetal development in the rat by a GLP-1 
receptor-mediated impaired function of the inverted yolk sac placenta during a period of 
gestation when the rat embryo is entirely dependent on the yolk sac placenta for its nutrient 
supply. Due to species differences in yolk sac anatomy and function, and due to the lack of 
GLP-1 receptor expression in cynomolgus monkey yolk sac, this mechanism is considered 
unlikely to be of relevance to humans. Involvement of additional mechanisms cannot be 
excluded. In rabbits and monkeys, increased number of pregnancy losses and slightly increased 
incidences of fetal abnormalities, which did not resemble the findings in rats, were observed. 
These findings might be incidental or related to the markedly reduced maternal body weight; 
however, relevance to humans cannot be completely excluded for these findings.
1.2.3.
Clinical Studies of Semaglutide
1.2.3.1.
Diabetes
As part of the type 2 diabetes development program, SEMA administered subcutaneously (SC) 
once weekly was evaluated in 8 Phase 3 studies (including a 2-year cardiovascular outcomes 
study [CVOT]). Across all Phase 3 efficacy studies, both SEMA SC 0.5 mg and 1.0 mg were 
superior in lowering glycosylated hemoglobin A1c (HbA1c) and body weight as compared with 
placebo (both as monotherapy and in combination with insulin) or compared with the respective 
marketed comparators. Cardiovascular safety of SEMA SC was established in the CVOT with an 
estimated hazard ratio for SEMA SC versus placebo of 0.74 (95% CI: 0.58-0.95) corresponding 
to a reduced risk of MACE by 26% versus placebo.

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The pharmacokinetic (PK) and pharmacodynamic (PD) properties of SEMA SC once weekly 
were investigated as part of the type 2 diabetes development program including a total of 
16 clinical pharmacology studies. Semaglutide has PK properties compatible with once-weekly 
administration with a median time to maximum concentration (Tmax) of 1 to 3 days and an 
elimination half-life (t1/2) of approximately 1 week. The exposure of SEMA in participants with 
various degrees of impaired renal function and with various degrees of impaired hepatic function 
was similar to the exposure in participants with normal renal function and normal hepatic 
function, respectively. No clinically relevant drug-drug interactions (DDIs) were observed 
between SEMA and any of the orally administered compounds tested (including metformin, 
warfarin, digoxin, atorvastatin and oral contraceptive combination drugs) and thus, no dose 
adjustments of the orally administered study drug are required. Semaglutide circulates in plasma, 
highly bound to plasma protein. Prior to excretion, SEMA is metabolized and excreted in urine 
and feces, with only 3% of the administered dose excreted as intact SEMA.
The established safety profile of SEMA SC 0.5 mg and 1.0 mg once weekly in type 2 diabetes is 
consistent with the GLP-1 RA drug class in general. Semaglutide SC is associated with a higher 
frequency of gastrointestinal (GI) adverse events (AEs) compared with placebo and active 
comparators. Gastrointestinal AEs generally occur early during dose escalation, are mild or 
moderate in severity and resolve without sequelae. Known or potential risks identified with 
SEMA SC in type 2 diabetes include cholelithiasis, pancreatic abnormalities (including 
pancreatitis), neoplasms and diabetic retinopathy complications. Cholelithiasis occurred more 
frequently with SEMA SC than with comparators, though the absolute risk was low; few of the 
events were serious and they did not appear to be preceded by a large and rapid weight loss. No 
concerns were identified for pancreatic safety and no causal association between SEMA SC and 
any type of neoplasm has been observed in the type 2 diabetes development program.
Data from the CVOT in type 2 diabetes showed that SEMA SC treatment was associated with an 
increased risk of diabetic retinopathy complications in participants with preexisting diabetic 
retinopathy, albeit at low risk. This finding is believed to be attributable to the rapid initial 
improvement in blood glucose levels with SEMA, consistent with the early worsening 
phenomenon described with insulins. Given these findings, patients with a history of diabetic 
retinopathy should be monitored for worsening and treated according to clinical guidelines, and 
patients with unstable diabetic retinopathy are excluded from this study. Of note, a Phase 3 study 
(FOCUS; NN9535-4352) is ongoing to evaluate the long-term effects of SEMA SC, compared 
with placebo, on diabetic eye disease in participants with type 2 diabetes.
1.2.3.2.
Weight Management
Novo Nordisk A/S conducted a Phase 2 dose-finding clinical study of SEMA SC treatment in 
857 participants with obesity (NN9536-4153). Eligible participants were randomized to a target 
daily dose of SEMA 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg, liraglutide 3.0 mg, or 
corresponding placebo-to-match (PTM) in each of the active treatment arms. Overall, a 
dose-dependent decrease in body weight was observed at Week 52, with the greatest weight loss 
(−13.84% estimated mean change in body weight from baseline) observed at the highest SEMA 
dose tested (0.4 mg once daily). No unexpected safety findings were identified, and the 

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tolerability and safety profiles were consistent overall with previous findings in the SEMA SC 
development program for type 2 diabetes and the GLP-1 RA class in general. The most 
frequently reported AEs were GI disorders (mainly nausea). Results from this Phase 2 study 
showed that the SEMA 0.4 mg once-daily dose was the most effective in terms of weight loss 
while displaying an acceptable tolerability profile. The rationale for the equivalence of SEMA 
0.4 mg SC daily dose with 2.4 mg SC weekly dose is presented in Section 1.7.
For the evaluation of SEMA in weight management, Novo Nordisk A/S completed a Phase 3a 
clinical study program utilizing SEMA 2.4 mg SC treatment in participants with obesity (the 
Semaglutide Treatment Effect in People With Obesity [STEP] program). In the pivotal study 
(NN9536-4373), SEMA led to a statistically significant reduction in body weight compared with 
placebo at Week 68. Participants treated with SEMA achieved a weight loss of 14.9%, from a 
mean baseline body weight of 105.3 kg, compared with a 2.4% weight loss with placebo. In 
addition, 86.4% of those who received SEMA achieved weight loss of 5% or more after 
68 weeks, compared with 31.5% with placebo. In this study, SEMA appeared to be safe and well 
tolerated. The most common AEs among participants treated with SEMA were GI events, most 
of which were transient, and mild or moderate in severity. Based on the Phase 3a study data, 
SEMA was approved for a weight management indication in the US and EU.
1.2.3.3.
NASH
As of 15 February 2021, the clinical development program for SEMA SC monotherapy for the 
treatment of NASH comprises 1 completed Phase 1 study (in participants with NAFLD), 
1 completed Phase 2 study (in participants with F1-F3 fibrosis due to NASH), 1 completed 
Phase 2 study (in participants with NASH and compensated F4) and 1 ongoing Phase 3 study (in 
participants with NASH and F2-F3). Completed Phase 1 and 2 studies are described in full in the 
SEMA IB; brief summaries of the results from the completed Phase 2 NASH studies follow 
below.
In the Phase 2 NASH Study NN9931-4492, 71 participants with cirrhosis (F4 fibrosis) due to 
NASH were randomized to receive SEMA 2.4 mg (47 participants), or placebo (24 participants) 
as once-weekly SC injections {Loomba 2023}. After randomization, the participants entered a 
dose-escalation period, with dose increases every 4 weeks until the target dose was reached.
The mean age of the study population was 59.5 years, 69% were women, and 87% were White. 
At baseline the mean body mass index (BMI) was 34.9 kg/m2 and 75% had type 2 diabetes, with 
a mean HbA1c of 7.1%. Use of glucose-lowering medication was generally well balanced 
between the groups. Histological parameters and baseline liver parameters were also generally 
balanced between treatment groups, though the SEMA group contained a greater number of 
participants with Ishak score 6/6 at baseline. Participants had a mean nonalcoholic fatty liver 
disease activity score (NAS) of 4.8, more than 75% of participants overall had an Ishak score of 
6/6, the mean baseline Model for End-Stage Liver Disease (MELD) score was 7.6, and mean 
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At 48 weeks there was no significant difference in the proportion of patients in each group with 
improvement in liver fibrosis without worsening of NASH. There was no significant difference 
in the proportion of patients in each group with NASH resolution or for components of NASH 
between treatment groups. Change in liver stiffness by magnetic resonance elastography (MRE) 
from baseline was not significantly different between groups. Improvement in liver steatosis by 
magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline was 
significantly greater in the SEMA group (49% with ≥ 30% reduction) than in the placebo group 
(13% with ≥ 30% reduction), accompanied by greater reduction in liver fat volume and thus total 
liver volume in the SEMA group. Reductions in the liver enzymes alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) from baseline 
were significantly greater in the SEMA group compared with placebo over 48 weeks of 
treatment. Reductions in Pro-C3 and high-sensitivity C-reactive protein (CRP) levels were also 
significantly greater in the SEMA group versus placebo. Greater reduction in enhanced liver 
fibrosis (ELF) was observed in the SEMA group over 48 weeks compared with placebo, though 
the difference between groups was not significant. Body mass index and waist circumference 
were significantly lower with SEMA versus placebo at Week 48, and, among patients with type 
2 diabetes, a significantly greater reduction in HbA1c and fasting plasma glucose from baseline 
was observed in the SEMA group compared with the placebo group. Reductions in levels of 
triglycerides and very low-density lipoprotein (VLDL) cholesterol from baseline were 
significantly greater with SEMA than with placebo, but this was not the case for low-density 
lipoprotein (LDL) or total cholesterol. Blood pressure was reduced from baseline in patients who 
received SEMA at 24 weeks but increased again and was not significantly different to placebo at 
48 weeks.
A total of 48 weeks of treatment with SEMA SC 2.4 mg once weekly was safe and well tolerated 
in this compensated cirrhotic NASH population. Overall, the safety profile of SEMA seen in this 
study was consistent with previous studies in patients with type 2 diabetes, obesity, and NASH, 
with mild to moderate, transient GI effects accounting for most on-treatment AEs. No effects 
were observed on hepatic or renal function with SEMA treatment, and although the study was 
not powered to assess decompensating events, no decompensating events were observed during 
the study period. Similar proportions of patients experienced AEs (42 [89%] patients in the 
SEMA group and 19 [79%] in the placebo group, of which 6 [13%] and 2 [8%], respectively, 
were serious). No serious events were considered related to study drug and there were no deaths 
during the study. Most AEs were mild or moderate in severity, but there were 8 severe events in 
the SEMA group versus 1 in the placebo group; additionally, more AEs in the SEMA group than 
in the placebo group were judged as possibly or probably related to study drug. No patients 
withdrew from the study due to AEs. A total of 5 patients had 8 AEs leading to dose reduction 
(6 AEs in 4 patients in the SEMA group, and 2 AEs in 1 patient in the placebo group). Three 
patients had AEs leading to premature treatment discontinuation (2 with GI disorders [nausea] 
considered probably related to treatment and 1 with an eye disorder [vitreous detachment] 
considered unlikely related to treatment), all in the SEMA group. In total, 64 (90%) patients 
completed treatment, and 3 patients (2 in the SEMA group and 1 in the placebo group) withdrew 
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This study was limited by a relatively small sample size and relatively short treatment duration 
but did not raise any new safety concerns and demonstrated overall improvement in 
cardiometabolic parameters and noninvasive markers of liver fat and liver injury with SEMA 
treatment.
In the Phase 2 NASH Study NN9931-4296, 320 participants with F1-F3 fibrosis due to NASH 
were randomized to receive SEMA 0.1 mg (80 participants), SEMA 0.2 mg (78 participants), 
SEMA 0.4 mg (82 participants), or placebo (80 participants) as once-daily SC injections. After 
randomization, the participants entered a dose-escalation period, with dose increases every 
4 weeks until the target dose was reached. 
The mean age of the study population was 55 years, 60.6% were women, and 77.5% were White. 
At baseline, the mean BMI was 35.8 kg/m2 and the mean body weight was 98.4 kg, which was 
similar across treatment groups. Approximately 62% of the participants had type 2 diabetes at 
baseline, with a mean duration of 7.5 years and a mean HbA1c value of 7.3%. Approximately 
half of the participants (49.4%) had fibrosis stage 3 and approximately a quarter each had 
fibrosis stages 1 or 2. Overall, the majority of participants had a total NAS of 4 (41.6%), 
5 (35.6%), or 6 (18.4%), with a mean NAS of 4.9, similar across treatment groups. In the overall 
population, baseline noninvasive tests of liver fibrosis included a mean ELFTM score of 9.8, and a 
mean liver stiffness by vibration-controlled transient elastography (FibroScan®) of 12.2 kPa. 
Mean liver enzyme values (ALT: 63 U/L, AST: 49 U/L, GGT: 85 U/L) at baseline were slightly 
elevated compared with reference ranges.
The proportion of participants with F2 or F3 fibrosis who achieved NASH resolution with no 
worsening in liver fibrosis at Week 72 was statistically significantly higher in the SEMA groups 
than in the placebo group, and highest in the SEMA 0.4 mg group (58.9% vs 17.2% in the 
placebo group). The proportion of participants with F2 or F3 fibrosis who achieved a ≥ 1-stage 
improvement in liver fibrosis without worsening of steatohepatitis at Week 72 was higher in the 
SEMA 0.1 mg and 0.4 mg groups, and similar in the SEMA 0.2 mg group, compared with the 
placebo group, but the differences were not statistically significant. The liver enzymes ALT, 
AST, and GGT showed a dose-dependent decrease from baseline to Week 72 in all treatment 
groups, with the greatest reductions observed with the SEMA 0.4 mg daily dose. The reductions 
in body weight showed a dose-response relationship, with the greatest reduction in the SEMA 
0.4 mg group (−12.51% vs −0.61% in the placebo group). At Week 72, the reductions in HbA1c 
were statistically significantly greater in each of the SEMA groups than in the placebo group, 
with the greatest treatment differences in the SEMA 0.2 mg and 0.4 mg groups. Semaglutide 
generally increased levels of high-density lipoprotein (HDL) cholesterol and reduced levels of 
free fatty acids, triglycerides and VLDL cholesterol from baseline to Week 72. The changes in 
HDL cholesterol, free fatty acids, triglycerides, and VLDL cholesterol at Week 72 statistically 
significantly favored SEMA 0.4 mg daily dose over placebo. 
A total of 72 weeks of treatment with SEMA SC 0.1 mg, 0.2 mg, or 0.4 mg once daily was safe 
and well tolerated in this noncirrhotic NASH population. The observed safety and tolerability 
profile was consistent with that of SEMA SC in type 2 diabetes and weight management and 
with the GLP-1 RA drug class in general. No dose relationship among the SEMA SC group was 

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observed for AEs leading to treatment discontinuation; a higher proportion of participants 
discontinued treatment due to AEs in the SEMA SC 0.2 mg group (12.8%) than in the other 
treatment groups (ranging between 3.8% and 5.0%). Serious AEs (SAEs) were reported by a 
higher proportion of participants in all SEMA SC groups (range: 14.8% to 19.2%) than in the 
placebo group (10.0%) but with no dose-relationship among the SEMA SC groups. The most 
frequently reported AEs were GI disorders which were reported by a higher proportion of 
participants in all SEMA SC groups (range: 63.8% to 76.9%) than with placebo (45.0%). 
Nausea, the most frequent GI AE, increased dose-dependently with SEMA SC. There were no 
apparent dose-dependent findings for any other safety parameters. Hepatic events were reported 
by a lower proportion of participants with SEMA SC (range: 7.7% to 11.3%) than with placebo 
(13.8%), whereas gallbladder-related disorders were reported by a higher proportion of 
participants exposed to SEMA SC (range: 5.1% to 7.4%) than with placebo (2.5%). Neoplasms 
(benign, malignant, unspecified including cysts and polyps) were reported by 12.5% to 17.3% of 
the participants in the SEMA SC groups and by 7.5% in the placebo group. Except for events of 
large intestine polyp and renal cysts, which were mostly incidental findings, there was no notable 
pattern with respect to organ system of origin or distribution between treatment groups. Increases 
in amylase and lipase were observed with SEMA SC and are well known from other GLP-1 
RAs. No events of acute pancreatitis were reported.
Of note, acute pancreatitis is considered a risk associated with the use of the GLP-1 RA class, 
therefore, patients with a history of chronic pancreatitis or recent acute pancreatitis are excluded 
from this study. No causal association between SEMA and any type of neoplasm has been seen 
in the clinical development program.
1.3.
Cilofexor
Please refer to the current IB for cilofexor (CILO; GS-9674) for further information not included 
below.
1.3.1.
General Information 
Cilofexor is a potent and selective agonist of the farnesoid X receptor (FXR) whose activity in 
intestinal epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is 
an endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Given the role of metabolic 
dysregulation and bile acid homeostasis in NASH pathogenesis, activation of FXR with CILO is 
expected to improve NASH. Cilofexor as a single agent has also been evaluated in participants 
with primary biliary cholangitis (PBC), and in Phase 2 and Phase 3 studies in participants with 
primary sclerosing cholangitis (PSC).
1.3.2.
Nonclinical Pharmacology and Toxicology
The nonclinical toxicity profile of CILO and its major metabolites (GS-716070 and 
GS-1056756) were assessed in mice, rats, and cynomolgus monkeys administered CILO orally 
for up to 26, 13, and 39 weeks, respectively (Studies TX-402-2009; TX-402-2010; 
TX-402-2025). Findings attributed to CILO administration were primarily related to the liver 
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triglycerides; increases in liver weight; and hepatocellular hypertrophy). These findings were 
minimal to mild, nonadverse, and reversible after discontinuation of treatment. The no observed 
adverse effect levels (NOAELs) in the repeat-dose toxicity studies were associated with exposure 
margins ≥ 12 times higher than the human exposure at the 30 mg dose. Cilofexor and its major 
metabolites are nongenotoxic and CILO was noncarcinogenic in a 2-year mouse carcinogenicity 
study. In the 2-year rat carcinogenicity study, there was an increased incidence in hepatocellular 
adenomas and carcinomas in males at all CILO doses (ie, ≥ 250 mg/kg/day) and in females at 
1000 mg/kg/day (highest dose tested). Also, there was an increased incidence of 
hepatocholangiocellular adenoma at ≥ 500 mg/kg/day, and hepatocholangiocellular carcinoma at 
1000 mg/kg/day in male rats. The clinical relevance of these findings is unknown given the lack 
of similar findings in mice and the predominance of findings in male rats. The mechanism for the 
liver tumors associated with CILO is unknown; however, CILO does not have activity through 
known carcinogenic mechanisms with relevance to humans (DNA reactivity, estrogenic activity, 
cytotoxicity, infection, iron overload).
There was no effect on embryofetal development in mice and rabbits at doses of up to 
300 mg/kg/day in mice (Studies TX-402-2016; TX-402-2017) and 200 mg/kg/day in rabbits 
(Study TX-402-2018). These doses were associated with exposures that are 49- and 47-fold 
higher than the human exposure (AUC0-24h) at the 30 mg once-daily dose based on a preliminary 
population PK model of NASH. The decreased fetal weights observed at 1000 mg/kg/day in the 
pregnant rabbit dose range–finding study were attributed to maternal toxicity and not a direct 
fetal effect (Study TX-402-2015).
In addition, GS-1056756, a prominent metabolite of CILO, had no effect on embryofetal 
development in mice at 300 mg/kg/day (Study TX-402-2033), corresponding to 2-fold higher 
than the human exposure (AUC0-24h) at the 30 mg once-daily dose based on a preliminary 
population PK model of NASH. 
Decreased fertility and copulation/conception indices and longer mean pre-coital interval was 
noted at 300 mg/kg/day (highest dose evaluated) as compared with controls (Study TX-402-
2022). There were no effects on male or female fertility at 60 mg/kg/day. This dose was 
associated with exposures in male and female mice that were 12- and 19-fold higher, 
respectively, than the human exposure (AUC0-24h) at the 30 mg once-daily dose. Also, there were 
no effects on early embryonic development at up to 300 mg/kg/day. This dose was associated 
with exposures in male and female mice that were 37- and 93-fold higher, respectively, than the 
human exposure (AUC0-24h) at the 30 mg once-daily dose.
Drug-drug interaction study data do not suggest a potential for interaction with hormones used 
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1.3.3.
Clinical Studies of CILO
As of 22 September 2022, across all indications, 9 Phase 1 studies and 6 Phase 2 studies were 
completed. One Phase 3 clinical study was terminated after the results of a planned futility 
analysis did not satisfy the predefined efficacy criteria in participants with PSC 
(Study GS-US-428-4194). Completed Phase 1 and 2 studies are described in full in the IB; a 
brief summary of clinical pharmacology results from relevant prior studies follows. Results from 
completed clinical studies (GS-US-384-3914, GS-US-454-4378, and GS-US-454-5533) 
including CILO in combination with firsocostat (FIR; GS-0976) and/or SEMA are presented in 
Section 1.5.2.
Following single and multiple oral doses (10 to 300 mg) in healthy participants (Study 
GS-US-402-1851), CILO was rapidly absorbed with minimal to no accumulation observed at 
steady state, consistent with the median half-life of 10 to 15 hours. GS-716070 (CILO metabolite 
with > 40-fold less potency than CILO against FXR) exhibited a steady-state 
metabolite-to-parent AUC ratio of 0.57, with plasma PK mirroring trends observed for CILO 
with respect to linearity and accumulation. A second metabolite of CILO, GS-1056756, 
exhibited an AUC accumulation ratio of 11.4 on Day 14, consistent with its long half-life 
(approximately 175 h) and a metabolite-to-parent AUC ratio of approximately 0.86 (Study 
GS-US-402-1851). Cilofexor and GS-716070 exposures in participants with NASH were higher 
(approximately 2- to 3-fold) than those observed in healthy participants, whereas GS-1056756 
concentrations were similar in participants with NASH compared with healthy participants. 
Administration of a single oral 100 mg dose of CILO (Study GS-US-454-5280) indicated that the 
effect of food on CILO PK is meal-type dependent; CILO AUCinf was 35% lower or 9% lower 
when administered with a light- or high-fat meal, respectively. These data support dosing of 
CILO without regard to food.
Across the range of CILO doses evaluated (10 to 300 mg once daily), doses > 30 mg provide 
comparable intestinal FXR agonism as assessed by increases in plasma FGF19 exposure. 
Exposure-response relationships show that changes in C4 exposure are negatively correlated 
with changes in exposures of FGF19 and CILO.
Cilofexor was administered at doses up to 300 mg in Phase 1 studies. In Study GS-US-402-1851, 
CILO was well tolerated in healthy adult participants at doses up to 300 mg once daily for up to 
14 days. The incidence of AEs did not increase with ascending doses of CILO, and no 
dose-dependent toxicities were noted.
In the Phase 1 Study GS-US-402-3885, CILO 30 mg and 10 mg single-dose administration was 
well tolerated in participants with normal or impaired hepatic function. Based on the available 
overall exposure-safety profile of CILO, dose adjustments are not considered necessary in 
participants with mild hepatic impairment. Limited clinical safety data are available at the free 
exposures observed in participants with moderate or severe hepatic impairment. As such, 
participants with moderate or severe hepatic impairment are excluded from the current study.
In 4 completed Phase 2 studies in NASH (Studies GS-US-402-1852, GS-US-454-4378, 
GS-US-454-5533, GS-US-384-3914), 1 completed Phase 2 study in PBC 

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(Study GS-US-427-4024), and 1 completed Phase 2 study in PSC (Study GS-US-428-4025), 
CILO 30 mg and 100 mg as monotherapies appear to be well tolerated, and incidences of 
Grade 3 AEs, discontinuations due to AEs, and SAEs were similar to those observed in the 
participants in the placebo group. Rash and pruritus are common and very common, respectively, 
among NASH patients.
1.4.
Firsocostat
Please refer to the current FIR IB for further information not included below.
1.4.1.
General Information
Firsocostat is a small molecule allosteric inhibitor that acts at the protein-protein homodimer 
interface of acetyl-coenzyme A carboxylases (ACC) ACC1 and ACC2 to prevent dimerization. 
ACC1 and ACC2 are important regulators of fatty acid metabolism. ACC1 catalyzes the first 
step of DNL by converting acetyl-coenzyme A to malonyl coenzyme A while ACC2 regulates 
the entry of fatty acids into the mitochondria where beta oxidation can occur. Therefore, 
inhibition of ACC1 and ACC2 will reduce DNL and increase fatty acid beta oxidation, 
respectively.
1.4.2.
Nonclinical Pharmacology and Toxicology
Firsocostat has been characterized in several biochemical and cellular assays to enhance the 
understanding of the mechanism of action in vivo, in several mechanistic models to demonstrate 
target engagement, and in animal disease models to demonstrate activity on endpoints relevant to 
metabolic disease. Moreover, extensive safety pharmacology and receptor screening studies have 
been conducted.
The results of these PD studies indicate that FIR can reduce the DNL, hepatic steatosis, insulin 
resistance, and fibrosis produced in nonclinical models of metabolic disease and fibrosis without 
adversely affecting food consumption or markers of liver function.
As described in the FIR IB, GS-834356, a liver-targeted ACC inhibitor and analog of FIR, 
reduced steatosis in a murine model of NASH induced by a diet enriched in fat, cholesterol, and 
fructose (fast food diet, FFD). In this model, ACC inhibition by GS-834356 dose-dependently 
reduced hepatic steatosis, liver triglycerides and cholesterol, plasma ALT and AST, and markers 
of hepatic fibrosis and fibrogenesis, but also dose-dependently increased plasma triglycerides. 
GS-834356 also decreased hepatic triglycerides and increased plasma triglycerides in a rat 
high-fat, high-sucrose model of hepatic steatosis. These findings are consistent with a recent 
report that pharmacologic or genetic inhibition of ACC in the liver decreases hepatic triglyceride 
levels and increases plasma triglyceride levels {Goedeke 2018, Kim 2017}. GS-834356 also 
significantly inhibited fibrosis progression over 6 weeks of treatment in the rat choline-deficient 
high-fat diet model of advanced fibrosis {Bates 2020}.

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The nonclinical toxicologic profile of FIR and its major metabolite (GS-834773) has been well 
characterized in single- and repeat-dose toxicity studies up to 39 weeks in duration and in genetic 
toxicity, carcinogenicity, fertility and embryofetal developmental toxicity, phototoxicity, and 
local tolerance studies. The primary target organ toxicity was the presence of cataracts in dogs 
based on ophthalmic and histological examinations at doses of ≥ 60 mg/kg/day and lens 
degeneration in mice at 15 mg/kg/day. The NOAELs in the repeat-dose toxicity study were 
associated with exposure margins ≥ 3 times higher than the clinical exposure at the 20 mg dose. 
Additionally, FIR and its major metabolite were nongenotoxic and FIR was noncarcinogenic in 
2-year rat carcinogenicity study. There were no effects on embryofetal development at exposures 
24 and 121 times the clinical exposure in rats and rabbits, respectively. Firsocostat was 
nonphototoxic and was also considered noncorrosive and does not require classification as an 
eye irritant.
No formal studies have been conducted to evaluate the reproductive toxicity of FIR; therefore, 
the reproductive toxicity of FIR in humans is unknown. However, mutant mice lacking ACC1, 
one of the targets of FIR, are embryonically lethal. Therefore, FIR is contraindicated in 
pregnancy. Nonclinical data in human hepatocytes indicate that FIR is a mild inducer of 
cytochrome P450 enzyme (CYP) 3A4 isoenzymes. Clinical data demonstrates no decrease in 
exposure of a representative oral hormonal contraceptive indicating no loss of contraceptive 
efficacy is expected upon administration of FIR with hormonal contraceptives.
1.4.3.
Clinical Studies of FIR
As of 22 September 2022, 12 Phase 1 and 3 Phase 2 clinical studies including FIR have been 
completed. Completed Phase 1 and 2 studies are described in full in the IB; a brief summary of 
clinical pharmacology results from relevant prior studies follows below. Results from completed 
clinical studies (GS-US-454-4378, GS-US-454-5533, and GS-US-384-3914) including FIR in 
combination with CILO and/or SEMA are presented in Section 1.5.2 and 1.5.3. 
Following single and multiple oral doses (20 to 1000 mg) in healthy participants, FIR was 
rapidly absorbed with minimal to no accumulation of FIR observed at steady state, consistent 
with a median half-life of approximately 5 to 10 hours. Firsocostat exhibited approximately 
dose-proportional PK over the clinically relevant dose range (20 to 500 mg). GS-834773, a 
glucuronide conjugate metabolite of FIR, exhibited a steady-state metabolite-to-parent AUC 
ratio of 0.1, with plasma PK mirroring trends observed for FIR with respect to linearity and 
accumulation. Food alters the rate of absorption, as evidenced by changes in FIR and GS-834773 
Cmax but does not alter the extent of absorption (no change in AUC); FIR may be administered 
without regard to food.
In obese, but otherwise healthy, male participants in whom DNL was stimulated with fructose, 
FIR demonstrated dose-dependent inhibition of fractional DNL, with reductions (relative to 
placebo) of change from baseline in fractional DNL as a function of the area under effect curve 
of approximately 70%, 85%, and 104% following administration of 20, 50, and 200 mg FIR, 
respectively. A similar reduction in fractional DNL (68% inhibition relative to baseline) was 
observed in healthy participants not administered fructose who received FIR 20 mg once daily.

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Overall, FIR as a monotherapy has been well tolerated. The majority of AEs reported in healthy 
participants and participants with NASH were Grade 1 or Grade 2 in severity and resolved by 
study completion. The most frequently reported AEs were nausea, abdominal distention, 
abdominal pain, constipation, diarrhea, abdominal tenderness, dyspepsia, and vomiting. 
Triglyceride elevations were observed in a repeat-dose study (0976-102) in healthy participants 
and in participants with NASH who received FIR 20 mg (Studies GS-US-426-3989, 
GS-US-384-3914, and GS-US-454-4378). 
1.5.
CILO/FIR Combination
Please refer to the current CILO/FIR fixed-dose combination (FDC) IB for further information 
not provided below. 
1.5.1.
Nonclinical Pharmacology and Toxicology
Combinations of CILO and the FIR analog GS-834356 had synergistic effects to reduce liver 
triglycerides and markers of fibrogenesis in the mouse Amylin Liver NASH Diet-induced model 
of NASH. Further, a combination of CILO and GS-834356 also partially inhibited fibrosis 
progression over 10 weeks of dosing in the 18-week rat choline-deficient high-fat diet of 
advanced fibrosis where the monotherapies were no longer efficacious. There were no adverse 
findings when CILO and FIR were dosed in combination to mice by the oral route for 13 weeks 
at doses of 20 mg/kg/day of CILO and 3 mg/kg/day of FIR. Exposures to CILO and FIR at these 
doses were 5 and 4 times higher, respectively, than the exposure to CILO and FIR in humans at 
the 30 mg and 20 mg doses, respectively.
1.5.2.
Clinical Studies Including CILO and FIR in Combination
1.5.2.1.
Study GS-US-384-3914
Study GS-US-384-3914 is a completed Phase 2, proof-of-concept, open-label study that 
evaluated the safety, tolerability, and efficacy of selonsertib (SEL; GS-4997), FIR, and CILO as 
single agents and combinations in participants with NAFLD/NASH. The study consisted of 
13 cohorts, with select cohorts receiving CILO and FIR as monotherapy or in combination. Final 
results for Cohorts 1 through 11 are included in the IB and safety and efficacy results for 
Cohorts 12 and 13 are presented below. 
1.5.2.1.1.
Triglyceride Laboratory Evaluations in Participants Treated With CILO+FIR and 
Icosapent Ethyl (Vascepa®; VAS) or Fenofibrate (FENO) (Study 
GS-US-384-3914 Cohorts 12 and 13)
Participants with suspected NASH and fibrosis, as determined by biopsy or liver stiffness by 
transient elastography (≥ 9.9 kPa or MRE ≥ 2.88 kPa) with serum triglycerides ≥ 150 and 
< 500 mg/dL were randomized to treatment with VAS 2 g twice daily (Cohort 12; n = 33) or 
FENO 145 mg daily (Cohort 13; n = 33) for 2 weeks (starting on Day −14) followed by the 
addition of FIR 20 mg + CILO 30 mg daily on Day 1 for 6 weeks. Randomization was stratified 
by screening triglycerides (< 250 mg/dL vs ≥ 250 mg/dL). Safety results and triglyceride 
laboratory evaluations for Cohorts 12 and 13 as of 29 January 2021 are presented below.

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The median (first quartile [Q1], third quartile [Q3]) age of participants in Cohorts 12 and 13 was 
55 (46, 63) years and most participants had diabetes (69.4%) and were obese (82%). At baseline 
(Day −14), median (Q1, Q3) triglycerides were 177 mg/dL (154, 205) in Cohort 12 and 
190 mg/dL (144, 258) in Cohort 13, including 13% and 31% with triglycerides ≥ 250 mg/dL, 
respectively. After 2 weeks of VAS or FENO monotherapy, median changes in triglycerides 
were −12 mg/dL (−33, 7 [P = 0.0898 vs baseline]) and −32 mg/dL (−76, 6 [P = 0.0121 vs 
baseline]), respectively. Following 6 weeks of combination treatment with CILO+FIR (in 
addition to either VAS or FENO), median change from baseline in triglycerides was +41 mg/dL 
(16, 103 [P < 0.0001 vs baseline]) in the VAS group and −2 mg/dL (−42, 54 [P = 0.9206 vs 
baseline]) in the FENO group (Figure 1). In participants with baseline triglycerides ≥ 250 mg/dL, 
changes at Week 6 were +99 mg/dL (−29, 185) in the VAS group and −61 mg/dL (−128, −8) in 
the FENO group. 
Figure 1.
Study GS-US-384-3914 (Cohorts 12 and 13): Median Change From 
Baseline in Triglycerides by Visit and Treatment (VAS Versus FENO)
BL = baseline; CILO = cilofexor (GS-9674); FENO = fenofibrate; FIR = firsocostat (GS-0976); IQR = interquartile range; 
TG = triglyceride; VAS = icosapent ethyl (Vascepa®)
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* p<0.05 vs B by Wilcoxon signed-rank test. 

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Figure 2.
Study GS-US-384-3914 (Cohorts 12 and 13): Median Change From 
Baseline in Triglycerides by Visit, Treatment (VAS Versus FENO), 
and Pretreatment Baseline Triglyceride Level
BL = baseline; CILO = cilofexor (GS-9674); FENO = fenofibrate; FIR = firsocostat (GS-0976); IQR = interquartile range; 
TG = triglyceride; VAS = icosapent ethyl (Vascepa®)
During combination therapy, treatment-emergent Grade 3 triglyceride elevations 
(500-1000 mg/dL) were observed in 2 participants in each group, all with baseline triglycerides 
≥ 250 mg/dL. No Grade 3 or 4 triglyceride elevations were observed in participants with 
pretreatment triglycerides < 250 mg/dL. Combinations were otherwise safe and well tolerated. 
The majority of AEs were Grade 1 or Grade 2 and there were no discontinuations due to AEs. 
No pruritus was reported in either cohort. Overall, 2 SAEs were reported, including 1 participant 
with Grade 1 noncardiac chest pain in the VAS group and 1 participant with Grade 3 appendicitis 
in the FENO group which occurred 9 days after the last dose of study drug. Neither SAE was 
attributed to study drug by the investigator. No deaths were reported. Prior to initiating 
CILO+FIR, 1 participant in the VAS group with baseline triglycerides of 2.540 mg/dL 
discontinued VAS after 8 days due to a persistent triglyceride elevation > 500 mg/dL. 
1.5.2.2.
Study GS-US-454-4378 (ATLAS)
Study GS-US-454-4378 was a global, multicenter, randomized, placebo-controlled, Phase 2b 
study designed to evaluate the safety and efficacy of SEL, FIR, and CILO as monotherapies and 
in 2-drug combinations in participants with biopsy confirmed NASH and either bridging (F3) 
fibrosis or compensated cirrhosis (F4). Participants were randomized to 1 of 7 treatment groups: 
placebo, SEL 18 mg, CILO 30 mg, FIR 20 mg, SEL 18 mg + CILO 30 mg, SEL 18 mg + FIR 
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Shaded area indicates 2-week pre-treatment period with VAS or FENO monotherapy. 
CllO+FIR added to VAS or FENO between Weeks O and 6. 
* p<0.05 vs Bl by Wilcoxon signed-rank test. 

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20 mg, or CILO 30 mg + FIR 20 mg. Study drug was administered orally once daily for 
48 weeks. Of note, Phase 3 studies evaluating SEL as monotherapy in participants with advanced 
fibrosis due to NASH demonstrated lack of efficacy of SEL and led to sponsor discontinuation of 
the SEL monotherapy group in this study.
1.5.2.2.1.
Participant Disposition and Demographics
A total of 395 participants were randomized, 392 of which received at least 1 dose of study drug. 
Across all treatment groups, the majority of participants were female (64.5%) with a median 
(Q1, Q3) age of 60 (54, 66) years, and 71.9% had type 2 diabetes. The majority of participants 
had NASH Clinical Research Network (CRN) fibrosis stage F4 (56.4%) and NAS ≥ 6 (56.1%) at 
baseline. The percentage of participants with NAS ≥ 5 at baseline was 83.1%, including 86% 
with Grade 2 ballooning and 62% with Grade 3 lobular inflammation.
A total of 317 participants (80.9%) completed study drug and 75 participants (19.1%) 
prematurely discontinued study drug. Across all groups, the most common reason for study drug 
discontinuation was sponsor discontinuation of the SEL monotherapy group 
(8%, 33 participants).
1.5.2.2.2.
Safety Results
Overall, treatment with SEL, FIR, and CILO as single agents and 2-drug combinations for 
48 weeks was generally well tolerated. The 3 most commonly reported AEs across treatment 
groups were pruritus, upper respiratory tract infection, and nausea. In the CILO+FIR group, the 
3 most commonly reported AEs were pruritus, headache, and diarrhea. Most AEs were Grade 1 
or 2 in severity. The incidence of AEs leading to study drug discontinuation was consistent 
across groups, and ranged from 2.5% to 5.1%, including 3.8% in the CILO+FIR group and 2.6% 
in the placebo group. 
No specific trends in the frequency of Grade 3 or higher AEs were identified across treatment 
groups. The only Grade 3 or higher AE reported for > 1 participant in any treatment group was 
Grade 3 cellulitis. Across all groups, 45 participants (11.5%) had an SAE, including 8 
participants (10.3%) in the CILO+FIR group. The only SAE reported for > 1 participant was 
acute myocardial infarction (reported for 1 participant each in the FIR and CILO+FIR groups) 
and cellulitis. Only 1 participant (CILO+FIR group) had an SAE considered treatment related by 
the investigator (gastritis), which resolved within 3 days of onset and did not result in study drug 
discontinuation. Overall, no specific trends in type or onset of SAEs were observed. One death 
(CILO+SEL; due to cardiac arrest) was reported during the study that was not considered 
treatment related by the investigator.
Pruritus AEs were reported in 20% to 29% of all participants who received CILO alone or in 
combination versus 15% who received placebo; most (83%) were mild. In the CILO+FIR group, 
Grade 1 or 2 pruritus was reported in 28% of participants (16 of 22 cases Grade 1); there were no 
Grade 3 AEs or discontinuations due to pruritus.

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Most laboratory abnormalities were Grade 1 or 2. Overall, the most common Grade 3 or 
4 laboratory abnormality was increased triglycerides (hypertriglyceridemia; 3.6%, 14 of 
392 participants; 4% to 8% in participants treated with FIR vs 0% to 5% in participants not 
treated with FIR). The highest abnormality grade of hypertriglyceridemia was Grade 3. All 
14 participants with Grade 3 hypertriglyceridemia had Grade 1 or 2 elevated triglycerides at 
baseline, and for the majority of participants, the Grade 3 elevations decreased in severity to 
Grade 1 or 2 by Week 48. From baseline to Week 48, the least-squares mean (LSM) changes in 
triglycerides in participants treated with CILO+FIR was +44 mg/dL compared with 0 mg/dL in 
the placebo group.
Adverse events of Grade 1 or 2 hypertriglyceridemia were reported for 4 of the 14 participants 
with Grade 3 or 4 triglycerides, none of which led to study drug discontinuation. Two 
participants in the CILO+FIR group had Grade 3 ALT abnormalities, with 1 attributed to a 
concomitant medication (amoxicillin/clavulanic acid), and the other occurring 29 days after 
discontinuing study medication and 2 days after a repeat liver biopsy. There was no evidence of 
drug-induced liver injury (DILI) attributable to study medication in the study.
Compared with placebo, CILO+FIR was associated with increases from baseline to Week 48 in 
total cholesterol (LSM +17 mg/dL [95% CI: 5%-28%]; P = 0.0050) and VLDL (+8 mg/dL [95% 
CI: 4%-12%]; P < 0.0001), and reduced HDL(−4 mg/dL [95% CI: −7% to 1%]; P = 0.0121); 
changes in LDL cholesterol were not statistically significant (+9 mg/dL [95% CI: −1% to 18%]; 
P = 0.0795).
1.5.2.2.3.
Efficacy Results
The primary histologic endpoint at Week 48 was the proportion of participants who achieved 
≥ 1-stage improvement in fibrosis without worsening of NASH (defined as ≥ 1-grade increase 
from baseline in hepatocellular ballooning or lobular inflammation). The proportion of 
participants who met the primary histologic endpoint ranged from 11.8% to 20.9% in the active 
treatment groups compared with 10.5% in the placebo group. In all participants, the highest 
response rate was observed in the CILO+FIR group (20.9% [14 of 67 participants]; difference 
from placebo: 10.8%, P = 0.1658). Furthermore, in participants with cirrhosis (F4) at baseline, 
the highest response rate was observed in the CILO+FIR group (33.3% [12 of 36 participants]), a 
difference of 19.3% versus placebo (14.3% [3 of 21 participants]). 
NAS-related histologic endpoints at Week 48 included ≥ 2-point improvement in NAS, 
≥ 1-grade improvement in NAS hepatic steatosis, lobular inflammation, and hepatocellular 
ballooning, and NASH resolution without worsening of fibrosis. In the overall population, the 
proportion of participants with ≥ 2-point improvement in NAS ranged from 9.0% to 35.3% in the 
active treatment groups versus 10.5% in the placebo group. The highest response rate was 
observed in the CILO+FIR group, which was significantly higher compared with placebo (35.3% 
[24 of 68 participants]; difference from placebo: 25.5%; P = 0.0016). The combination of 
CILO+FIR also led to statistically significant increases in the proportions of participants with a 
≥ 1-grade reduction in steatosis (25.8% vs 5.9%, P = 0.0085), lobular inflammation (57.4% vs 
28.9%, P = 0.0036), and ballooning (29.4% vs 13.2%, P = 0.0433). The CILO+FIR group had 
the highest proportion of participants who achieved NASH resolution without worsening of 
fibrosis (4.5% [3 of 67 participants] vs 0% [0 of 38 participants] with placebo; P = 0.3454).

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The CILO+FIR group also had significant improvements in ALT (LSM change at Week 48: 
-18 U/L, P = 0.0333 vs placebo), AST (-12 U/L, P = 0.0497), cytokeratin 18 M30 fraction 
(CKl 8 M30) (-158 U/L, P = 0.0064), and estimated glomernlar filtrntion rate ( eGFR; 
4.5 mL/min, P = 0.0286) compared with placebo. Additionally, CILO+FIR led to a larger 
reduction in total bile acids (- 2.7 µmol/L) compared with placebo (P = 0.0047), as well as with 
either CILO or FIR monotherapy. 
1.5.2.2.4. 
Phaimacokinetic Results 
Using these PK data as well as intensive PK data in healthy paiiicipants, 
a pre nmnaiy popu at10n PK model was developed to describe the steady-state exposure of 
CILO, CILO metabolites GS-716070 and GS-1056756, FIR, and FIR metabolite GS-8343773 in 
paiiicipants with NASH. A previous Phase 1 study showed that CILO has no effect on the PK of 
FIR and, similarly, FIR had no effect on the PK of CILO (Study GS-US-402-2101). Plasma 
exposures of CILO and its metabolites (GS-716070 and GS-1056756) and FIR and its metabolite 
(GS-834773) were similai· across the applicable single-agent or combination treatment groups. 
Mean exposures of CILO and GS-716070 were moderately higher in pa1iicipants with NASH 
who received CILO 30 mg without regai·d to food (GS-US-454-4378) compai·ed with 
paiiicipants with NASH who received CILO 30 mg with food in a prior Phase 2 study 
(GS-US-402-1852). The higher mean exposure following administration of CILO without regard 
to food is expected given the known food effect. Additionally, modifications were made to the 
CILO tablet fonnulation to reduce PK vai·iability, which may have also contributed to 
differences in CILO PK between the 2 prior studies as described in IB. Mean FIR exposures 
were consistent with those observed in previous Phase 2 studies (GS-US-384-3914 and 
GS-US-426-3989). 
1.5.3. 
1.5.3.1. 
Clinical Studies Including CILO, FIR, and SEMA 
Study GS-US-454-5533 
Study GS-US-454-5533 was a randomized, open-label, proof-of-concept Phase 2 study that 
evaluated the safety, tolerability, and efficacy of SEMA administered as monotherapy and in 
combination with FIR, and/or CILO for 24 weeks in 108 paiiicipants with mild to moderate 
fibrosis due to NASH. Paiiicipants were randomized equally to 1 of 5 treatment groups: SEMA 
monotherapy, SEMA + FIR 20 mg once daily, SEMA + CILO 30 mg once daily, SEMA + CILO 
100 mg once daily, and SEMA + FIR 20 mg once daily+ CILO 30 mg once daily. In all groups, 
SEMA was administered SC once weekly with dose escalation from 0.24 mg to a 2.4 mg weekly 
target dose over the fast 16 weeks. The primaiy objective of the stud was to evaluate the safety 
and tolerability of the study drngs in paiiicipants with NASH. 
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1.5.3.1.1.
Participant Disposition and Demographics
A total of 108 participants were randomized, all of whom received at least 1 dose of study drug. 
Across all treatment groups, a majority of participants were female (68.5%), White (85.2%), with 
a median (Q1, Q3) age of 54 (48, 61) years. The majority of participants (54.6%) had type 2 
diabetes and median (Q1, Q3) BMI was 34.3 (30.9, 39.4) kg/m2. In the overall population, 
noninvasive tests of liver fibrosis and steatosis were consistent with mild to moderate fibrosis 
due to NASH, including median (Q1, Q3) ELF of 9.38 (8.91, 9.92), liver stiffness by transient 
elastography of 9.25 kPa (7.70, 12.00), and MRI-PDFF of 17.87% (11.97, 24.29).
Overall, 92 participants (85.2%), completed study drug. Reasons for discontinuation of study 
drug included AEs (8 participants, 7.4%), participant decision (6 participants, 5.6%), and lost to 
follow-up (2 participants, 1.9%). 
1.5.3.1.2.
Safety Results
Overall, treatment with SEMA as monotherapy or in combination with FIR and/or CILO, for 
24 weeks, was generally well tolerated. The tolerability of SEMA in combination with FIR 
and/or CILO was similar to that of SEMA monotherapy.
Across the treatment groups, the most commonly reported AEs were GI. The most commonly 
reported AEs by preferred term (PT) were nausea, diarrhea, constipation, and decreased appetite. 
The incidence of pruritus was low (4.6%); all events occurred in the treatment groups containing 
CILO, were Grade 1 in severity, and none led to discontinuation of study drug. The incidence of 
hypoglycemic episodes was also low (4.6%) with all events being Grade 1 or Grade 2 in severity, 
the majority of which (8/10) were assessed by the investigator as related to study drug.
Five participants (4.6%) had a total of 7 Grade 3 AEs. Of these, 2 participants (1.9%) had 4 
Grade 3 AEs assessed by the investigator as related to study drug. One participant in the SEMA 
monotherapy group had 3 Grade 3 treatment-related AEs of diarrhea, vomiting, and dehydration, 
and 1 participant in the SEMA + CILO 100 mg group had a Grade 3 treatment-related AE of 
pancreatitis. The Grade 3 treatment-related AEs of diarrhea, vomiting, and pancreatitis were the 
only SAEs reported.
Across treatment groups, the AEs leading to discontinuation of study drug were predominantly 
GI events. The incidence of AEs leading to discontinuation of study drug in the combination 
groups (range: 4.5% to 9.1%) was no higher than that reported for the SEMA monotherapy 
group (14.3%). There were no deaths, no pregnancies, and no AEs related to the pen injector 
device used for SEMA administration. No neoplasms, benign or malignant, were reported.

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Overall, 3 participants (2.8%) had Grade 3 or 4 laboratory abnormalities. One participant in the 
SEMA + FIR 20 mg group, who had a Grade 2 elevation in triglycerides at baseline, had Grade 3 
hypertriglyceridemia at Week 4, after which the participant remained on study drug with no 
further Grade 3 or 4 triglyceride elevations. Two participants in the SEMA+CILO 100 mg group 
had Grade 4 increases in creatine phosphokinase (CPK), both reported as unrelated by the 
investigator. For both participants, CPK values returned to baseline levels and there were no 
further elevations with continued administration of study drug. There was no evidence of 
hepatotoxicity attributable to study drug.
A dose-dependent increase in fasting LDL cholesterol level was observed with CILO treatment 
with median changes from baseline to Week 24 of 0 to +13 mg/dL for the 2 treatment groups 
containing CILO 30 mg and +18 mg/dL in the SEMA + CILO 100 mg group. 
Mild increases from baseline to Week 24 in fasting triglycerides were observed for the 
2 treatment groups containing FIR. The median increase from baseline to Week 24 in fasting 
triglycerides was lower for the SEMA + FIR 20 mg + CILO 30 mg group (10 mg/dL) compared 
with the SEMA + FIR 20 mg group (22 mg/dL).
1.5.3.1.3.
Efficacy Results
Compared with SEMA monotherapy, treatment with combinations led to greater reductions from 
baseline in liver steatosis, as measured by MRI-PDFF and controlled attenuation parameter 
(CAP). The greatest median reductions from baseline in these parameters were observed for the 
SEMA + FIR 20 mg + CILO 30 mg group and SEMA + FIR 20 mg group, respectively. 
Furthermore, the proportion of participants who achieved a ≥ 5% absolute reduction in 
MRI-PDFF at Week 24 was higher in the 4 combination treatment groups (range: 76.5% to 
94.4%) compared with the SEMA monotherapy group (64.7%). A similar proportion of 
participants in all treatment groups achieved a ≥ 30% relative reduction in MRI-PDFF at 
Week 24 (range: 76.5% to 90.5%). 
Reductions in liver stiffness as measured by transient elastography at Week 24, were similar or 
greater in the combination treatment groups as compared with the SEMA monotherapy group, 
with the greatest median reductions from baseline to Week 24 observed in the 2 treatment groups 
containing FIR. The proportion of participants with a ≥ 25% relative reduction in liver stiffness 
at Week 24, were 1.4- to 1.7-fold higher in the 4 combination treatment groups (50% to 60%) 
compared with the SEMA monotherapy group (35.7%). 
Treatment with combinations led to improvements in liver enzymes, including ALT and AST, 
that were similar to or greater than those observed with SEMA monotherapy. 
Reductions from baseline to Week 24 in ELF score were observed in all treatment groups, 
however no significant differences were observed between groups. Further, reductions from 
baseline in hepatocellular apoptosis (as measured by serum CK18 M30) and inflammation (as 
measured by serum CRP) were observed in all treatment groups. 

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At Week 24, similar relative reductions from baseline in body weight and BMI were observed 
across groups, including SEMA monotherapy and combinations. Overall, glycemic control was 
similarly improved in all groups, as reflected by median reductions from baseline to Week 24 in 
HbA1c (range: 0.6% to 1.0%), with greater reductions observed in participants with type 2 
diabetes. 
1.5.3.1.4.
Pharmacokinetic Results
A single PK blood sample was collected from all participants at any time during the study visits 
at Weeks 1, 4, 8, and 12. The plasma concentrations of FIR, CILO, and their respective 
metabolites were consistent with those observed in the previous NASH Phase 2 ATLAS study 
(GS-US-454-4378). These results suggest that the PK of FIR and CILO was not impacted when 
administered in combination with SEMA.
1.6.
Rationale for This Study
Among patients with NASH, those with cirrhosis are at the highest risk of liver-related morbidity 
and mortality, including progression to end-stage liver disease and HCC. Currently, there are no 
approved therapies for this patient population. Additionally, fibrosis stage is the primary 
determinant of overall and liver-related mortality, as well as liver-related morbidity in NASH 
{Angulo 2015, Ekstedt 2015, Yeh 2014}. Given the complex pathophysiology of NASH, 
combination regimens may offer superior efficacy compared with monotherapies, both on liver 
histology and other clinically relevant hepatic and metabolic parameters in this patient 
population. 
Semaglutide is a GLP-1 RA with multiple established beneficial effects, including weight loss, 
improvements in insulin sensitivity, and a reduction in cardiovascular risk in high-risk patients 
with type 2 diabetes {Marso 2016}. In a Phase 2 study in participants with NASH and F2-F3 
fibrosis, treatment with 0.4 mg SEMA once daily (considered equivalent to a weekly SEMA 
dose of 2.4 mg), resulted in a significantly higher proportion of participants achieving NASH 
resolution without worsening of fibrosis compared with placebo at Week 72 (59% vs 17%, 
P < 0.001). In this treatment group, a greater proportion of participants achieved fibrosis 
improvement ≥ 1-stage without worsening of NASH, however the difference was not 
significantly greater than with placebo (43% vs 33%, P = 0.48). Semaglutide also reduced body 
weight, with the greatest reduction versus placebo at Week 72 observed in the SEMA 0.4 mg 
group (−12.5% vs −0.6%). Additionally, compared with placebo, participants treated with 
SEMA had improvements in liver enzymes (eg, ALT, AST), and markers of hepatocellular 
injury, apoptosis, and fibrosis (eg, CK18 M30 and M65, ELF score, and liver stiffness by 
FibroScan) at Week 72. In a Phase 2 study in participants with cirrhosis due to NASH, a 2.4 mg 
weekly dose of SEMA by subcutaneous injection for 48 weeks was well tolerated but did not 
demonstrate efficacy as a monotherapy by NASH resolution or fibrosis improvement {Loomba 
2023}.
Cilofexor is a nonsteroidal FXR agonist that functions primarily in the small intestine to induce 
release of FGF19, which suppresses bile acid synthesis, lipogenesis, and gluconeogenesis. In a 
Phase 2 study, treatment with CILO alone for 24 weeks reduced hepatic steatosis and serum bile 

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acids in paiiicipants with NASH and mild to moderate fibrosis {Patel 2020}. Firsocostat is a 
liver-tai·geted, small molecule allosteric inhibitor of ACC that catalyzes the rate-limiting step in 
DNL and regulates ~-oxidation of fatty acids. In a Phase 2 study, tr·eatment with FIR alone for 
12 weeks reduced hepatic steatosis, liver biochemistry, and senun fibrosis markers in NASH 
paiiicipants with mild to moderate fibrosis {Loomba 2018} . In a subsequent Phase 2 study 
(GS-US-454-4378) in paiiicipants with advanced fibrosis due to NASH (56% with cnThosis), the 
safety and efficacy of CILO and FIR as monotherapies, or in combination (CILO+FIR) for 
48 weeks, was evaluated. Among all 7 tr·eatment groups in this study, the lai·gest propo1iion of 
paiiicipants meeting the primaiy endpoint of~ I-stage improvement in fibrosis without 
worsening of NASH was observed in the CILO+FIR group (20.9% vs 10.5% in placebo, 
P = 0.1658). Fmihe1more, significant iinprovement in NASH activity based on NAS components 
of steatosis, lobulai· inflammation, and hepatocellulai· ballooning were observed in the 
CILO+FIR group (all P < 0.05 vs placebo) and improvements in liver biochemistry (ALT, AST, 
total bilirnbin), markers of fibrosis (ELF, liver stiffness by FibroScan), and other biomai·kers 
(total bile acids, CK18, insulin, eGFR) were observed. The combination of CILO+FIR was well 
tolerated in these paiiicipants with advanced fibrosis. While the most common AE was prnritus 
(28% of CILO+FIR paiiicipants vs 15% of placebo paiticipants ), most cases were mild (83% 
Grade 1 ), and no paiiicipants discontinued study drng due to pnuitus. Over 48 weeks, tr·eatment 
with CILO+FIR was associated with increases in h'iglycerides, total and VLDL cholesterol, and 
reduced HDL cholesterol. 
In a subsequent Phase 2 study (GS-US-454-5533), the safety and tolerability of combinations of 
SEMA, CILO, and/or FIR were evaluated in paiticipants with mild to moderate fibrosis due to 
NASH over 24 weeks. Treatment with SEMA in combination with FIR 20 mg and CILO 30 mg 
was generally well tolerated. The most commonly repo1ted AEs were GI, and similai· rates of 
study diug discontinuation due to AEs were observed with combination therapies compared with 
SEMA monotherapy. Low rates of prnritus in groups adininistered CILO was observed, 
including 2 of21 paiticipants (9.5%) in the SEMA + CILO 30 mg+ FIR 20 mg group. In 
combination tr·eatment groups including CILO 30 mg, median change from baseline to Week 24 
in fasting LDL cholesterol was O to 13 mg/dL (SEMA + CILO 30 mg and SEMA + FIR 20 mg 
and CILO 30 mg, respectively). The addition of SEMA to FIR 20 mg pa1tially mitigated 
FIR-induced tr·iglyceride elevations as compai·ed with observations in prior studies {Loomba 
2018}, with a 10 to 22 m /dL increase in h'i 1 cerides observed in the ·ou s adininistered FIR 
20m 
Given that patients with cnThosis due to NASH have the highest risk of liver-related 
complications, and that no therapies have been approved for their tr·eatment, this patient 
population has a high unmet medical need. In light of the complex pathophysiology of NASH, 
the potential of weight loss to di·ive histologic improvement, and the relevance of long-tenn 
cardiovasculai· risk in NASH patients, combination regiinens including a GLP-1 RA with 
liver-tai·geted therapies (such as CILO and FIR) offer the potential for greater overall efficacy 
than a monotherapy approach. To evaluate the histologic benefits of SEMA, CILO/FIR, and then· 
combination in paiticipants with cinhosis due to NASH, this Phase 2 study has been designed as 
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an international, multicenter, randomized, double-blind, double-dummy, placebo-controlled 
study to evaluate the safety and efficacy of these treatments over 72 weeks. In total, 
approximately 440 participants with histologically confirmed, compensated cirrhosis due to 
NASH (F4 fibrosis by the NASH CRN classification) will be enrolled. Participants will be 
randomized in a 3:3:3:2 ratio to receive SEMA+CILO/FIR, CILO/FIR, SEMA, or PTM for 
72 weeks. Given the beneficial effects of SEMA on NASH resolution and metabolic parameters 
(body weight, glucose, lipids) in participants with F2-F3 fibrosis (Study NN9931-4296), as well 
as improvements in fibrosis and necroinflammatory activity with the combination of CILO+FIR 
in participants with F3-F4 fibrosis (Study GS-US-454-4378), it is hypothesized that a 
combination of SEMA+CILO/FIR will have additive benefits, leading to both NASH resolution 
and fibrosis improvement in NASH patients with cirrhosis. Considering the metabolic benefits of 
SEMA, including weight loss and improvements in lipids, the addition of SEMA to CILO/FIR is 
also hypothesized to mitigate elevations in serum lipids that have been observed with CILO/FIR 
treatment in prior studies.
The primary objective of this study is to evaluate whether the combination of SEMA with 
CILO/FIR causes fibrosis regression in this high-risk patient population. Efficacy will be 
determined based on changes in liver histology, with the primary efficacy endpoint of ≥ 1-stage 
improvement in fibrosis without worsening of NASH on liver biopsy at Week 72. Given the 
limitations of conventional histological assessment of liver biopsies, including the potential for 
sampling error, variability in pathological interpretation, and limited sensitivity for detection of 
treatment effects due to the ordinal nature of current classification systems, multiple noninvasive 
markers of fibrosis (ELF, liver stiffness by FibroScan), and automated, quantitative machine 
learning-based methods of histologic assessment will also be evaluated in this study.
1.7.
Rationale for Dose Selection of Semaglutide
The proposed target dose of SEMA 2.4 mg once weekly is based on an integrated evaluation of 
efficacy and safety as well as on exposure (Cavg and Cmax). Results from the Phase 2 dose-finding 
study (NN9536-4153) in participants with obesity showed that the SEMA 0.4 mg once-daily 
dose led to the greatest effect on weight loss while displaying an acceptable tolerability profile. 
Furthermore, data from the SEMA SC type 2 diabetes development program (SUSTAIN studies 
with once-weekly dosing and Study NN9535-4191 with once-daily SC dosing of up to 
0.3 mg/day) did not support the hypothesis that once-daily dosing provides better GI tolerability 
as compared with once-weekly dosing. 
Based on population PK modeling, it was estimated that a once-weekly maintenance dose of 
SEMA 2.4 mg would result in similar Cmax at steady state as that obtained by the once-daily 
0.4 mg SEMA dose in the Phase 2 dose-finding Study NN9536-4153. When comparing the 
simulated human exposure at 2.4 mg weekly to the animal exposures at the NOAEL, exposure 
ratios are above 1, indicating that exposure at 2.4 mg weekly is supported by nonclinical studies. 
Based on these data, a maintenance dose of SEMA 2.4 mg once weekly was chosen for the Phase 
3 weight management and NASH development programs. Based on experience from the SEMA 
type 2 diabetes and weight management development program, a similar fixed-dose escalation 
regimen was selected, with dose escalation every 4 weeks until the target dose of 2.4 mg is 
reached after 16 weeks.

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1.8.
Rationale for Dose Selection of CILO and FIR in Fixed-Dose 
Combination ± SEMA
The doses of CILO and FIR for evaluation in this study, 30 mg and 20 mg once daily, 
respectively, are supported by a combination of safety and efficacy data from Phase 1 and 
2 studies in healthy participants and participants with NASH as summarized below. Regarding 
combination dosing, available PK and safety data from Study GS-US-454-4378 in participants 
with advanced fibrosis due to NASH demonstrated no clinically meaningful changes in CILO 
and FIR exposure, or the safety profile of the individual therapies, when coadministered. 
Pharmacokinetic and safety data from Study GS-US-454-5533 in participants with mild to 
moderate fibrosis due to NASH demonstrated no clinically meaningful changes in CILO and FIR 
exposures or the safety profile of the individual therapies when administered in combination with 
SEMA.
A CILO dose of 30 mg once daily is supported by PK, PD, safety, and efficacy data from 
Phase 1 studies in healthy participants and participants with hepatic impairment (Studies 
GS-US-402-1851, GS-US-454-4315, GS-US-402-3885), and participants with advanced fibrosis 
due to NASH (Studies GS-US-384-3914, GS-US-454-4378). In PD studies, CILO doses ≥ 30 mg 
daily provided comparable intestinal FXR agonism as assessed by increases in FGF19 exposure, 
including in participants with advanced fibrosis due to NASH. In a Phase 2 dose-ranging study 
(GS-US-402-1852) in NASH participants with mild to moderate fibrosis, CILO 30 mg and 
100 mg administered once daily for 24 weeks showed dose- and exposure-dependent reductions 
in MRI-PDFF and liver biochemistry. At the 100-mg dose, an increased incidence of Grade 2 or 
3 pruritus (14.3% vs 1.8% with 30 mg), as well as greater increases in LDL cholesterol (LSM 
change from baseline to Week 24: +7 mg/dL with 100 mg vs 0 mg/mL with 30 mg) were 
observed. In the ATLAS study (GS-US-454-4378), which evaluated an optimized formulation of 
CILO 30 mg that would approximate exposures of 60 mg with the formulation used in Study 
GS-US-402-1852, the incidence of pruritus in participants treated with CILO was low and no 
pruritus-related treatment discontinuations in participants treated with CILO+FIR were observed. 
Moreover, CILO treatment was associated with improvements in hepatic fat, liver biochemistry, 
and liver stiffness by transient elastography. The data described above suggest that a 30 mg dose 
of CILO with the optimized formulation poses a relatively minimal risk for pruritus, which is 
dose-dependent, and is expected to have a lower risk of pruritus-related treatment 
discontinuation and elevations in LDL cholesterol than higher doses, while still providing 
adequate FXR activation to contribute to improvements in fibrosis and other NASH-related 
parameters when used in combination with FIR. While exposures of CILO are increased in mild 
hepatic impairment (1.8-fold), preliminary population PK data from Study GS-US-454-4378 
indicate no difference in CILO exposures in participants with F3 or F4 fibrosis. Additionally, 
CILO 30 mg was well tolerated over 12 and 48 weeks in participants with compensated cirrhosis 
due to NASH (Studies GS-US-384-3914, GS-US-454-4378). Data from the Phase 1 Study 
GS-US-402-3885 indicated that CILO and metabolite exposures increase significantly in 
participants with moderate Child-Pugh (CP) Class B and severe (CP Class C) hepatic 
impairment. These data support an approach wherein no CILO dose adjustment is required for 
participants with CP Class A cirrhosis; however, participants with clinical or biochemical (ie, CP 
Class B or C) evidence of hepatic decompensation will not be eligible for this study.

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A FIR dose of 20 mg once daily is supported by the safety, tolerability, and effects of FIR on 
DNL from Studies 0976-101, 0976-102, and 0976-103 as described in the FIR IB, and the safety 
and efficacy observed in participants with mild hepatic impairment (Study GS-US-426-3988) 
and NASH (Studies GS-US-426-3989, GS-US-384-3914, GS-US-454-4378). In the Phase 2 
Study GS-US-426-3989, FIR 5 mg and 20 mg doses were evaluated for 12 weeks in participants 
with mild to moderate fibrosis due to NASH. Both dose levels demonstrated similar safety 
profiles, but only the 20 mg dose showed statistically and clinically significant reductions in 
hepatic steatosis measured by MRI-PDFF. Firsocostat 20 mg also resulted in larger reductions in 
liver biochemistry (ie, ALT) and serum markers of fibrosis (ie, tissue inhibitor of 
metalloproteinase 1 and procollagen III amino terminal peptide). These data were consistent with 
reductions in liver biochemistry and serum markers of fibrosis observed in participants treated 
with FIR 20 mg alone in Study GS-US-454-4378. In this study, there were no meaningful 
differences in FIR exposures in participants with F4 and less than F4 fibrosis, or between 
participants who experienced AEs or laboratory abnormalities and those that did not. Based on 
these data, FIR exposures in participants with mild hepatic impairment (CP Class A) are 
expected to remain ≥ 22- and ≥ 105-fold lower than the FIR exposures observed at the NOAELs 
in the 39-week dog and 26-week rat toxicity studies, respectively. Based on PK data in 
participants with mild hepatic impairment and the overall safety profile of FIR, dose adjustments 
are not considered necessary for participants with compensated cirrhosis.
1.9.
Benefit-Risk Assessment for the Study
This study will provide information regarding the safety and efficacy of SEMA, CILO/FIR, and 
their combination in patients with compensated cirrhosis due to NASH. The potential benefits of 
SEMA as a monotherapy in participants with F2-F3 fibrosis due to NASH were demonstrated in 
the Phase 2 study (NN9931-4296). As described above, compared with placebo, SEMA led to 
the highest proportion of participants achieving NASH resolution without worsening of fibrosis, 
improvements in liver biochemistries, markers of liver fibrosis, body weight, glycemic control, 
and lipid parameters at Week 72. In participants with F4 fibrosis due to NASH, SEMA as a 
monotherapy in the Phase 2 study (NN9931-4492) failed to promote fibrosis improvement or 
NASH resolution at Week 48. However, participants receiving SEMA experienced greater 
improvements in liver steatosis by MRI-PDFF, change in ALT concentration, decreased 
bodyweight, reductions in HbA1c, triglycerides, and VLDL. The potential benefits of CILO and 
FIR in combination were demonstrated in a Phase 2 study (GS-US-454-4378) in participants 
with advanced fibrosis, including 56% with compensated cirrhosis (F4). As described above, 
CILO+FIR led to the highest proportion of participants achieving fibrosis regression without 
worsening of NASH after 48 weeks of treatment, and, compared with monotherapy or placebo, 
led to greater improvements in NAS parameters, liver biochemistry, markers of fibrosis (ELF, 
liver stiffness by FibroScan), and other relevant biomarkers (CK18 M30 and M65, total bile 
acids, insulin). Based on the above, as well as data from the Phase 2 Study GS-US-454-5533, 
which demonstrated that combinations, including SEMA+CILO+FIR, led to greater reductions 
in liver steatosis (MRI-PDFF, CAP), liver biochemistries (ALT, AST), and additional 
biomarkers (CK18 M30, FGF-21) compared with monotherapy, it is hypothesized that the 
combination of SEMA+CILO/FIR will translate to greater histologic and metabolic benefits in 
this patient population. Participants randomized to the placebo control group in this study may 

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benefit from frequent medical monitoring and close assessment of their NASH and associated 
pathologies during the duration of placebo treatment (eg, surveillance for HCC and management 
of cardiovascular risk). 
Potential risks of this study include the limited number of participants with cirrhosis due to 
NASH, as compared with those with noncirrhotic (F1-F3) NASH, in which SEMA’s safety and 
efficacy has been evaluated. In noncirrhotic NASH, SEMA was well tolerated over 72 weeks in 
a Phase 2 study (NN9931-4296) and in cirrhotic participants with NASH over 48 weeks in a 
Phase 2 study (NN9931-4492) in which there was no increased rate of GI AEs in participants 
with more versus less advanced fibrosis, and no increased rate of discontinuation due to AEs in 
the high-dose SEMA arm compared with the placebo arm. The PK of SEMA are similar in 
cirrhotic and noncirrhotic participants. To mitigate the potential risk of poor tolerability due to 
GI AEs, with SEMA, participants will be counseled on expected GI AEs during SEMA dose 
escalation and lifestyle strategies to aid in their mitigation (Section 6.8.12). As the majority of GI 
AEs attributed to SEMA are experienced during dose escalation, visits are scheduled every 4 
weeks through Week 16 to enable close monitoring. In cases of poor tolerability, participants 
may delay SEMA dose escalation (Section 5.5.2) and, if necessary, remain at a dose lower than 
the target. Additional safety considerations specific to SEMA include the observation of thyroid 
C-cell tumors in nonclinical carcinogenicity studies. These rodent C-cell tumors are caused by a 
nongenotoxic GLP-1 receptor mechanism to which rodents are particularly sensitive. Given that 
the GLP-1 receptor is not expressed in normal human thyroid and that medullary thyroid 
carcinoma has not been associated with SEMA in clinical studies, the clinical relevance of this 
observation is considered low. Nevertheless, participants with a personal or family history of 
multiple endocrine neoplasia type 2 or medullar thyroid carcinoma will be excluded from this 
study, and any participants who develop medullary thyroid carcinoma must discontinue study 
drug. Additional potential risks associated with the GLP-1 RA class, including SEMA, include 
gallbladder or hepatobiliary events and acute pancreatitis. Given this, participants with a recent 
history of symptomatic gallbladder or biliary tract disease are excluded, unless a 
cholecystectomy has been performed, and participants with a history of chronic or recent acute 
pancreatitis are excluded. Additionally, any participants who develop suspected acute 
pancreatitis must discontinue study drug (Section 3.5). 
An additional risk is the fact that CILO and FIR are new chemical entities studied in a limited 
number of participants with cirrhosis. However, the combination of CILO+FIR was well 
tolerated in participants with F3-F4 fibrosis over 48 weeks in the Phase 2 Study 
GS-US-454-4378. In this study, the AE of pruritus occurred in 28% of participants treated with 
CILO+FIR versus 15% of participants treated with placebo; however, the majority of cases 
(83%) were mild (Grade 1) and no participants discontinued due to pruritus. In the Phase 2 Study 
GS-US-454-5533, which evaluated SEMA in combination with CILO and/or FIR in participants 
with mild to moderate fibrosis due to NASH, combinations were generally well tolerated, with 
the most common AEs gastrointestinal in nature and no higher rate of discontinuation due to AE 
in combination groups versus SEMA alone. Furthermore, pruritus observed exclusively in CILO 
containing groups was limited, all Grade 1, and no participants discontinued due to pruritus. To 
mitigate the risk of treatment discontinuation due to pruritus, close monitoring for new or 

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worsening pruritus will be conducted and a pruritus management plan is included in this protocol 
(Section 7.7.5). 
In the Phase 2 Study GS-US-454-4378, CILO+FIR led to an increase in total and VLDL 
cholesterol, and a decrease in HDL cholesterol at Week 48. A nonsignificant increase in LDL 
cholesterol was also observed. Given these changes, as well as the frequency of cardiovascular 
risk factors in the NASH patient population, the cardiovascular risk profile of participants will be 
evaluated prior to treatment initiation and on an ongoing basis. Upon treatment initiation, lipids 
will be closely monitored and guidance has been provided in the protocol for initiation or dose 
modification of lipid lowering therapies as necessary (Section 7.7.4)
Regarding triglycerides specifically, prior studies of FIR have revealed asymptomatic Grade 3 or 
4 elevations in triglycerides that resolved spontaneously or with treatment with fibrates or fish 
oil. In Study GS-US-426-3988, participants who had abnormal triglycerides at baseline were 
more likely to be affected. Therefore, participants with baseline triglycerides greater than 
250 mg/dL were excluded from the subsequent Phase 2 combination study (GS-US-454-4378). 
This approach resulted in fewer Grade 3 or 4 triglyceride elevations in participants treated with 
FIR 20 mg daily. In the current study, participants with serum triglycerides over 250 mg/dL are 
excluded unless triglycerides can be optimized prior to Day 1 (eg, via conservative or 
pharmacologic management), per the discretion of the investigator. To mitigate the risks 
associated with on-treatment triglyceride elevations, lipids will be closely monitored throughout 
the study, with additional guidance regarding criteria for study drug withholding and initiation of 
triglyceride management (eg, treatment with fibrates), or study drug discontinuation provided in 
Section 7.7.4.
An additional risk of this study is the potential for drug-related hepatotoxicity, particularly in 
participants with underlying cirrhosis. In the Phase 2 combination study (GS-US-454-4378), 2 of 
78 participants treated with CILO+FIR experienced an ALT elevation > 5 times the upper limit 
of normal (ULN). However, 1 case was attributed to a concomitant treatment with 
amoxicillin/clavulanic acid, a common cause of hepatotoxicity, and the other case was noted 
29 days following completion of treatment and 2 days after a liver biopsy which did not suggest 
DILI. Further, when CILO and/or FIR were evaluated in combination with SEMA in the Phase 2 
Study GS-US-454-5533, treatment-emergent elevations in serum ALT were not observed. 
Nevertheless, in order to mitigate any potential risk of hepatotoxicity, close monitoring of liver 
biochemistry values will be performed and parameters for discontinuation of study drug, 
including liver test abnormalities and clinical criteria consistent with hepatic decompensation, 
have been defined and will be closely followed (Section 7.7.1). Importantly, for any participant 
who meets criteria for study drug withholding due to concern for DILI, the data monitoring 
committee (DMC) will be notified and resumption of study drug may only be considered after 
review of relevant safety data by the DMC.

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Additional risks to study participants include those attributable to study participation in general, 
including risks associated with frequent clinic visits, laboratory blood draws, and liver biopsy, 
and the potential discomfort associated with these procedures. Strategies to mitigate these risks 
include close monitoring of laboratory values as well as AEs. Parameters for discontinuation of 
study drug and/or notification of the DMC due to AEs and nonhepatic laboratory abnormalities 
are also defined and will be closely followed. Finally, an infectious disease pandemic may pose 
additional risks to study drug availability, the study visit schedule, and adherence to 
protocol-specified safety monitoring or laboratory assessments. Appendix 11.2 provides further 
details on the relevant risks and risk mitigation strategies.
Overall, the nonclinical and clinical data to date suggest a positive benefit/risk profile in support 
of further evaluation of SEMA, CILO/FIR, and their combination in participants with 
compensated cirrhosis due to NASH, a high-risk patient population without any available 
treatment options. Appropriate safety monitoring will be conducted throughout the study to 
further characterize the safety profiles of these treatment regimens in this patient population.
1.10.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.
A list of study interventions and their marketing authorization status is provided in 
Appendix 11.3. 
Auxiliary medicinal products/noninvestigational medicinal products are not used in this study.

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2_ 
OBJECTIVES 
The prima1y objective of this study is as follows: 
Final 
Amendment2 
• 
To evaluate whether the combination of SEMA with the FDC of CILO/FIR causes fibrosis 
improvement (according to the NASH CRN classification) without worsening of NASH 
( defined as a~ I-point increase in hepatocellular ballooning or lobular inflammation) in 
paiiicipants with compensated cinhosis due to NASH, as compared with placebo 
The secondaiy objectives of this study ai·e as follows: 
• 
To confnm the contribution of CILO/FIR to fibrosis improvement without worsening of 
NASH in paiiicipants treated with the combination of SEMA and CILO/FIR by comparing 
with pa1iicipants treated with SEMA alone 
• 
To evaluate whether the combination of SEMA with the FDC of CILO/FIR causes NASH 
resolution ( defined as lobulai· inflammation of O or 1 and hepatocellulai· ballooning of 0) in 
paiiicipants with compensated cinhosis due to NASH, as compared with placebo 
• 
To confnm the contribution of SEMA to NASH resolution in pa1iicipants treated with the 
combination of SEMA and CILO/FIR by compai·ing with paiticipants treated with CILO/FIR 
alone 
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3_ 
STUDY DESIGN 
3.1. 
Endpoints 
The prirmuy endpoint of this study is as follows: 
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• 
:::: I-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH ( defined as a:::: I-point increase in hepatocellular ballooning or lobular 
inflammation) at Week 72 in the SEMA+cILO/FIR versus placebo groups 
The secondaiy endpoints of this study ai·e as follows: 
• 
:::: I-stage improvement in fibrosis without worsening of NASH at Week 72 in participants 
treated with SEMA +CILO/FIR versus SEMA alone 
• 
NASH resolution ( defined as lobular inflammation of O or I and hepatocellulai· ballooning 
of 0) at Week 72 in the SEMA+CILO/FIR versus placebo groups 
• 
NASH resolution at Week 72 in paiiicipants ti·eated with SEMA+CILO/FIR versus 
CILO/FIR alone 
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3.2. 
Study Design 
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This is a Phase 2, randomized, double-blind, double-dummy, placebo-contrnlled study evaluating 
the efficacy and safety of SEMA, CILO/FIR, and their combination in paiiicipants with 
compensated cinhosis due to NASH. 
Paiiicipants meeting the study's ent:Iy criteria will be randomly assigned in a 3:3:3:2 ratio to 1 of 
3 active ti·eatment groups (SEMA+CILO/FIR, SEMA+PTM CILO/FIR, PTM 
SEMA+CILO/FIR) or placebo (PTM SEMA+PTM CILO/FIR), as shown in Figure 3 below. 
Randomization will be sti·atified by the presence or absence of type 2 diabetes as detennined by 
medical histo1y or based on screening laborato1y values if previously undiagnosed (ie, HbA1c 
:::: 6.5% or fasting plasma glucose:::: 126 mg/dL, confmned on repeat testing), and by ELF score 
(:::: 11.30 or < 11.30 during screening). 
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Figure 3. 
GS-US-454-6075 Study Schema 
(;n111p A 
SEM,\ I CJl .0 /FIR ( n 
120) 
Grnnp B 
SEMA ! 0 ml PTi\,I (n 
120) 
Group C 
lnjcclablc PTM I CILOiFlR (n 
120) 
Group D 
lnjcclahlc PTM 
Oral PTM (n 
80) 
8 Weeks 
72 Weeks 
W~ k 77. 
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Prim~ry En<lpninl (l lii:to lngy) 
• 
CILO = cilofexor (GS-9674); FIR = firsocostat (GS-0976); PTM = placebo-to-match; SEMA = semaglutide 
3.3. 
Study Treatments 
Paiiicipants meeting the study's ent:Iy criteria will be randomly assigned in a 3:3:3:2 ratio to 
1 of 3 active ti·eatment groups (SEMA+CILO/FIR, SEMA+PTM CILO/FIR, PTM 
SEMA +CILO/FIR) or placebo group (PTM SEMA + PTM CILO/FIR) as presented in 
Section 3.2. 
Details regarding the dosage fo1ms, packaging, and labeling of SEMA and CILO/FIR are 
provided in Sections 5.2 and 5.3, respectively. 
3.4. 
Duration of Treatment 
Paiiicipants will be ti·eated for 72 weeks. Total study duration will be up to 85 weeks, including 
up to 8 weeks for screening, a 72-week ti·eat:Inent period, and a 5-week follow-up period. 
3.4.1. 
Poststudy Care 
If Gilead Sciences (Gilead) discontinues development of the study diug, fmiher provision of 
study diug to pa1iicipants may be discontinued, independent of ti-eatment effect. No poststudy 
ti·eatment will be provided by Gilead or Novo Nordisk for pa1iicipants in this study. The 
long-te1m cai·e of all study pa1iicipants will remain the responsibility of their prima1y ti·eating 
physician. 
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3.5.
Discontinuation Criteria
It is strongly recommended to contact the medical monitor or designee to discuss whether a 
participant has met criteria for discontinuation of study drugs as soon as possible when any of the 
following conditions are observed. 
Study drugs must be discontinued in the following circumstances:
•
Any Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 AE, deemed life 
threatening and related to study drug(s) in the opinion of the investigator
•
Participant progression to decompensated cirrhosis, as defined by any of the following:
Grade 2 ascites (symptomatic; medical intervention indicated), graded using the CTCAE 
Toxicity Grading Scale 
HE of Grade 2 or above according to the West Haven Criteria (Appendix 11.4) requiring 
treatment
Portal hypertension–related upper GI bleeding identified by endoscopy and requiring 
hospitalization, including events of bleeding from esophageal varices, gastric varices, and 
portal hypertensive gastropathy 
•
CP score > 6 on 2 consecutive occasions, preferably within 72 hours, unless due to an 
alternative etiology (eg, Gilbert’s syndrome or therapeutic anticoagulation) (Section 6.8.5)
•
Liver transplantation or qualification for liver transplantation, defined as MELD score > 12 
on at least 2 consecutive occasions, preferably within 72 hours, unless due to an alternative 
etiology (eg, Gilbert’s syndrome or therapeutic anticoagulation)
•
Diagnosis of HCC or other hepatobiliary cancer
•
Fasting serum triglycerides > 1000 mg/dL confirmed on 2 consecutive occasions, preferably 
within 48 hours
•
Fasting serum triglycerides > 500 mg/dL, confirmed on 2 consecutive occasions, preferably 
within 48 hours, in participants on maximal dose of fibrate in the opinion of the investigator
•
Diagnosis of acute pancreatitis, including pancreatitis attributed to elevated serum 
triglycerides in the opinion of the investigator
•
Diagnosis of medullary thyroid carcinoma
•
Concomitant treatment with nonprotocol GLP-1 RAs
•
Surgical treatment for obesity

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•
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the 
participant may resume study dosing at the discretion of the investigator
•
Unacceptable toxicity (Section 7.7), or toxicity that, in the judgment of the investigator, 
compromises the participant’s ability to continue study-specific procedures or is considered 
to not be in the participant’s best interest
•
Participant request to discontinue for any reason
•
Significant participant noncompliance, in the judgment of the investigator
•
Significant protocol deviation that impacts participant safety in the opinion of the medical 
monitor or designee
•
Pregnancy during the study (Appendix 11.6)
•
Discontinuation of the study at the request of Gilead, regulatory agencies, or an institutional 
review board (IRB) or independent ethics committee (IEC) or ethics committee (EC)
3.6.
End of Study
The end of study is defined as when the last participant enrolled has completed the final visit in 
the study (including the follow-up visit) or is considered lost to follow-up. 
3.7.
Source Data
The source data for this study will be obtained from electronic data capture (EDC), central 
laboratory, local laboratory(ies), specialty laboratory(ies) (for PK, PD, biomarker, and/or biopsy 
data), central pathology laboratory, interactive response technology (IRT) system, and/or other 
vendors as designated by sponsor.
3.8.
Biomarker Testing 
3.8.1.
Biomarker Samples to Address the Study Objectives
The following biological specimens will be collected from all participants who have provided 
consent to participate in this study and may be used to evaluate the association of systemic 
and/or tissue-based biomarkers with study drug response (including efficacy and/or AEs), and to 
better understand the biological pathways of SEMA, CILO, and FIR and how they affect 
downstream markers of the regulation of these pathways. Biological specimens will also be used 
to increase the knowledge of diseases such as NASH, liver fibrosis, and inflammatory diseases, 
and/or the validation of a companion diagnostic for NASH. The specific analyses will include, 
but will not be limited to, the biomarkers and assays described in Table 1. Because biomarker 
science is a rapidly evolving area of investigation, and AEs in particular are difficult to predict, it 
may not be possible to specify prospectively all tests that may be done on the specimens 

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provided. The testing outlined below is based upon the current state of scientific knowledge. It 
may be modified during or after the end of study to remove tests no longer indicated and/or to 
add new tests based upon new state of the art knowledge. 
Liver tissue, blood, stool, and urine samples will be collected at the time points listed in 
Appendix 11.5 to measure biomarkers which may include but not be limited to those listed in 
Table 1. If a test will no longer be performed, sample collection may also be withdrawn to 
reduce burden on participants.
Samples collected for biomarker assessments will be destroyed no later than 15 years after the 
end of study or per country requirements. 
CCI
CCI

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CCI

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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
This study will enroll approximately 440 participants with compensated cirrhosis due to NASH.
4.1.1.
Participant Replacement
Participants who discontinue before the end of study will not be replaced.
4.2.
Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Men and women between 18 and 80 years of age, inclusive, based on the date of the 
screening visit
2) Willing and able to give informed consent prior to any study-specific procedures being 
performed
3) Cirrhosis (F4) due to NASH as defined by 1 of the following:
a) A historical liver biopsy within 180 days of screening that, in the opinion of the central 
pathologists, is evaluable and consistent with cirrhosis (F4) and NASH (defined as the 
presence of steatosis Grade ≥ 1, hepatocellular ballooning Grade ≥ 1, and lobular 
inflammation Grade ≥ 1, according to NAS)
OR
b) In participants without a qualifying historical liver biopsy, if FibroScan ≥ 9.9 kPa at 
screening, a screening liver biopsy may be performed. The screening liver biopsy must, 
in the opinion of the central pathologists, be evaluable and meet histologic criteria as 
specified in inclusion criterion 3a)
OR
c) In participants with a historical liver biopsy completed more than 180 days prior to 
screening that is consistent with cirrhosis (F4) and NASH, as determined by a local 
reader, a screening liver biopsy may be performed. The screening liver biopsy must, in 
the opinion of the central pathologists, be evaluable and meet histologic criteria as 
specified in inclusion criterion 3a)

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4) The following laboratory parameters at screening, as determined by the central laboratory:
a) eGFR ≥ 30 mL/min/1.73m2, as calculated by the Modification of Diet in Renal Disease 
(MDRD) equation to estimate CLcr
b) HbA1c ≤ 10% (or serum fructosamine ≤ 400 μmol/L if HbA1c is not quantifiable)
c) Hemoglobin > 10.6 g/dL
d) International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation
e) Total bilirubin ≤ 1.3  ULN (unless due to an alternative etiology such as Gilbert’s 
syndrome or hemolytic anemia)
f)
Serum albumin ≥ 3.5 g/dL 
g) Serum ALP ≤ 2  ULN
h) Platelet count ≥ 125,000/μL
i)
Serum triglyceride level ≤ 250 mg/dL. If initial screening value is > 250 mg/dL, 
triglycerides may be retested during the screening period. Fasting serum triglycerides 
must be confirmed to be ≤ 250 mg/dL prior to Day 1. Management of 
hypertriglyceridemia may be initiated or modified at investigator discretion during the 
screening period (Section 7.7.4.1) 
j)
ALT < 5  ULN
5) BMI ≥ 23 kg/m2 at screening
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1) Any history of decompensated liver disease in the opinion of the investigator, including 
clinically relevant ascites, HE, or variceal bleeding
2) CP score > 6 at screening, unless due to an alternative etiology such as Gilbert’s syndrome or 
therapeutic anticoagulation
3) MELD score > 12 at screening, unless due to an alternative etiology such as therapeutic 
anticoagulation
4) Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive)

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5) Chronic hepatitis C virus (HCV) infection (HCV antibody and HCV RNA positive). 
Participants cured of HCV infection less than 2 years prior to the screening visit are not 
eligible
6) Other causes of liver disease based on medical history and/or central pathologists’ review of 
liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders 
(eg, PBC, PSC, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, 
clinically significant iron overload, or alpha-1-antitrypsin deficiency
7) History of liver transplantation
8) Current or prior history of HCC
9) HIV infection
10) Weight loss > 10% within 180 days of screening, or > 5% between the date of the biopsy 
used for eligibility and the date of screening
11) Any weight reduction surgery or procedure in the 2 years prior to screening or malabsorptive 
weight loss surgery (eg, Roux-en-Y or distal gastric bypass) at any time prior to screening
12) History of intestinal resection that could result in malabsorption of study drug
13) Planned coronary, carotid, or peripheral artery intervention or unstable cardiovascular disease 
in the opinion of the investigator, including any of the following:
a) Unstable angina, myocardial infarction, coronary artery bypass graft surgery, or coronary 
angioplasty within 180 days prior to screening
b) Transient ischemic attack or cerebrovascular accident within 180 days prior to screening
c) Symptomatic valvular heart disease or hypertrophic cardiomyopathy
d) Symptomatic congestive heart failure
e) Uncontrolled or recurrent ventricular tachycardia or arrhythmia requiring an automatic 
implantable cardioverter defibrillator. Stable, controlled atrial fibrillation is allowed
f)
An emergency room visit or hospitalization for confirmed cardiovascular disease within 
180 days prior to screening
14) History of uncontrolled chronic pulmonary disease in the opinion of the investigator (eg, 
chronic obstructive pulmonary disease, interstitial lung disease) within 180 days prior to 
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15) Men who habitually drink greater than 21 units/week of alcohol or women who habitually 
drink greater than 14 units/week of alcohol (1 unit is equivalent to 12 oz/360 mL of beer, a 
4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor)
16) Positive urine drug screen for amphetamines, cocaine, or opiates (eg, heroin, morphine) at 
screening, unless due to a prescription medication (eg, oxycodone, methylphenidate) and the 
prescription and diagnosis are reviewed and approved by the investigator. Participants on 
stable methadone or buprenorphine maintenance treatment for at least 180 days prior to 
screening may be included in the study
17) Use of any prohibited concomitant medication prior to enrollment as described in Table 4:
a) Participants on vitamin E regimen ≥ 800 IU/day, or pioglitazone, must be on a stable 
dose in the opinion of the investigator for at least 180 days prior to the historical or 
screening liver biopsy
b) Participants taking antidiabetic medications must be on a stable dose, in the opinion of 
the investigator, for at least 90 days prior to the historical or screening liver biopsy
18) Participation in another investigational study of a drug or device within 30 days or within 
5 half-lives of the prior investigational agent (whichever is longer) prior to the date of 
screening and through the end of the study. Participation in a study of an investigational 
device may be approved by the medical monitor or designee
19) History of malignancy within 5 years of screening with the following exceptions:
a) Adequately treated carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin 
cancer
20) For participants with type 2 diabetes diagnosed prior to the date of the screening visit OR 
based on screening visit results (HbA1c ≥ 6.5% or fasting plasma glucose ≥ 126 mg/dL, 
confirmed on repeat testing), participants must have no evidence of uncontrolled and 
potentially unstable retinopathy or maculopathy as determined by a fundoscopic examination 
performed starting 90 days prior to screening visit date through Day 1. If there has been 
worsening of the participant’s visual function since a historical fundoscopic examination in 
the opinion of the investigator, then the fundoscopic examination must be repeated prior to 
Day 1 for eligibility. Pharmacological pupil dilation is a requirement unless using a digital 
fundus photography camera specified for nondilated examination.
21) Acute pancreatitis within 180 days prior to screening
22) History or presence of chronic pancreatitis
23) History of symptomatic gallbladder or biliary tract disease in the opinion of the investigator 
within 6 months prior to screening, unless a cholecystectomy has been performed

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24) Presence or history of type 1 diabetes 
25) Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullar 
thyroid carcinoma
26) Treatment with GLP-1 RAs (including SEMA) in the period from 90 days prior to the 
screening visit and from 90 days prior to the date of the historical qualifying liver biopsy (if 
applicable)
27) Female who is pregnant, breastfeeding, intends to become pregnant, or is of childbearing 
potential and not using an adequate contraceptive method as described in Appendix 11.6
28) Men who engage in heterosexual intercourse not using an adequate method of contraception 
as described in Appendix 11.6
29) Presence of any laboratory abnormality or condition that, in the opinion of the investigator, 
could interfere with or compromise a participant’s treatment, assessment, or compliance with 
the protocol and/or study procedures. This includes a history of substance abuse and/or 
psychiatric condition requiring hospitalization and/or emergency room visit within 2 years of 
screening
30) Known hypersensitivity to the study drug(s), metabolites, or formulation excipient(s)
31) For participants who have not completed a series of an authorized COVID-19 vaccination 
regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 reverse 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding, and Treatment Codes Access
This is a randomized, double-blind, double-dummy, placebo-controlled study. Participants 
meeting the study’s entry criteria will be randomly assigned in a 3:3:3:2 ratio to 1 of 3 active 
treatment groups or PTM as described in Section 3.2.
5.1.1.
Randomization
An IRT system will be used for centralized randomization, stratification, and treatment 
assignment. Investigative site personnel will obtain the participant’s identification number and 
study drug assignment from the IRT. Participants and all personnel directly involved in the 
conduct of the study will be blinded to treatment assignment. Randomization will be stratified by 
the presence or absence of type 2 diabetes as determined by medical history or based on 
screening laboratory values if previously undiagnosed (ie, HbA1c ≥ 6.5% or fasting plasma 
glucose ≥ 126 mg/dL, confirmed on repeat testing), and by ELF score (≥ 11.30 or < 11.30 during 
screening).
5.1.2.
Blinding
During the randomized phase, participants and all personnel directly involved in the conduct of 
the study will be blinded to treatment assignment. Study personnel who may be unblinded 
because of the nature of their functional or study role without additional documentation, as 
specified in Gilead procedural documents, include the following:
•
Individuals in Clinical Packaging and Labeling or Clinical Supply Management who have an 
Unblinded Inventory Manager role in an IRT for purposes of study drug inventory 
management 
•
Individuals in Patient Safety (PS) who review individual case data and/or group-level 
summaries contained within the safety database when they are involved in activities such as 
aggregate report generation, signal management, or expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs)
•
Individuals who are involved in bioanalytical/biomarker data transfer and sample/assay 
review.
The Bioanalytical File Administrator in either Bioanalytical Laboratory Clinical Data 
Management or Biomarker and Bioanalytical Operations who facilitates the transfer of 
bioanalytical (eg, PK, antidrug antibody) files between Gilead and bioanalytical 
laboratories 
Bioanalytical Chemistry scientists who monitor the development, validation, and 
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The personnel in bioanalytical laboratories involved in sample receipt, analysis, data 
review, and data transfer
Personnel (eg, Biomarker Sciences) not serving on the study management team who 
review assay results for samples collected per the study procedures
•
Regulatory Quality and Medical Governance personnel in Research and Development (R&D 
Q&MG) not serving on the study management team to support Quality Assurance activities 
and/or regulatory agency inspections
•
Biostatisticians and programmers employed by contract research organizations (CROs) who 
develop datasets and outputs for development of randomization schedule, DMC, IND safety 
reporting purposes
Should Gilead staff receive unblinded information, they will maintain the confidentiality of the 
unblinded information and will not communicate the information to blinded sites or participants 
as specified in Gilead standard operating procedures (SOPs) documents 
5.1.3.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the participant, the investigator may obtain the treatment assignment for that participant 
directly from IRT (refer to Investigator Site File or IRT unblinding instructions). In the event the 
IRT system is down, the investigator can reference the IRT Site User Manual for technical 
support details. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor or designee before breaking the blind. Treatment assignment should 
remain blinded unless that knowledge is necessary to determine participant’s emergency medical 
care. The rationale for unblinding must be clearly explained in source documentation along with 
the date on which the treatment assignment was obtained. The investigator is requested to inform 
the medical monitor or designee promptly in case of any treatment unblinding not discussed in 
advance.
Blinding of study treatment is critical to the integrity of this clinical study. Therefore, if a 
participant’s treatment assignment is disclosed to the investigator, the participant will have study 
treatment discontinued. All participants will be followed until study completion unless consent to 
do so is specifically withdrawn by the participant.
5.2.
Description and Handling of Semaglutide 
5.2.1.
Formulation
The drug product formulation for the SEMA solution for injection has the composition shown in 
Table 2. All ingredients other than the active drug substance are commonly used excipients. 
Semaglutide solution for injection is a colorless or almost colorless liquid, free from turbidity 
and essentially free from particulate matter.

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Table 2.
Composition of Semaglutide Solution for Injection
Name of ingredient
Function 
Pharmacopeia
Drug substance
Semaglutide
Active ingredient
Novo Nordisk A/S
Other ingredients
Disodium hydrogen phosphate, 
dihydrate 
Buffering agent
USP/Ph. Eur
Propylene glycol
Isotonic agent
USP/JP/Ph. Eur
Phenol
Preservative
USP/JP/Ph. Eur
HCl
pH adjustment
USP/JP/Ph. Eur
NaOH
pH adjustment
USP/JP/Ph. Eur
Water for injection
Solvent
USP/JP/Ph. Eur
JP = Japanese Pharmacopeia; Ph. EUR = European Pharmacopeia; USP = United States Pharmacopeia
Placebo-to-match SEMA has an identical formulation to the study drug product except that it 
does not contain any active ingredient.
5.2.2.
PDS290 Pen Injector for Semaglutide for Use in Clinical Studies
5.2.2.1.
Device Information
The PDS290 pen injector for SEMA/PTM SEMA is a dial-a-dose prefilled device integrated 
with a 3.0 mL cartridge filled with SEMA 3.0 mg/mL/PTM SEMA. The pen injector can deliver 
doses from 1 to 80 dose steps in increments of 1. The user can dial up and down in order to 
adjust a dose. The accuracy of dosing is ensured according to the international standard for 
needle-based injection systems, EN ISO 11608-1. 
The PDS290 pen injector for SEMA/PTM SEMA can be used multiple times until either the in-
use time (up to 8 weeks when stored at 8 to 30 °C) has passed or the cartridge is empty, 
whichever comes first. The pen injector works in conjunction with all variants of NovoTwist® 
and NovoFine® disposable needles. A new needle must be attached before and discarded after 
each injection.
Specific instructions for correct handling of the PDS290 pen injector for SEMA/PTM SEMA are 
included in the directions for use provided to study sites and to be provided directly to 
participants. Storage instructions are printed on the drug product label and are also provided in 
the Investigator Site File. Investigators must ensure that these instructions are strictly followed.
5.2.2.2.
Regulatory Status
The PDS290 pen injector for SEMA/PTM SEMA complies with relevant standards and 
regulations. Several other variants of PDS290 pen injectors have been approved worldwide since 
2010 for SC injection of insulins (under the brand name modifier FlexTouch®), growth hormone 
(under the brand name modifier FlexPro®) and GLP-1 products (Saxenda®, Ozempic®).

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5.2.2.3.
Existing Clinical Data
The adequate safety and performance of the PDS290 pen injector for SEMA (3.0 mg/mL) for the 
intended purpose are demonstrated through the literature review as well as the analysis of human 
factors engineering data and postmarketing safety data for the PDS290 pen injector family.
In the Phase 2 Study GS-US-454-5533, 108 participants were randomized to 1 of 5 treatment 
groups, all of which included SEMA administered with the PDS290 pen injector (3.0 mg/mL). 
Overall, no participants experienced any treatment-emergent pen injector related AEs over the 
24-week treatment period.
It is concluded that the PDS290 pen injector for SEMA (3.0 mg/mL) provides a favorable 
benefit-risk profile for administration of SEMA/PTM SEMA in NASH clinical studies.
5.2.3.
Storage and Handling
Semaglutide must be stored at 2 to 8 °C. Exposure to light and freezing must be avoided. Under 
these storage conditions, SEMA will retain full biological activity until the expiry date stated on 
the label. The SEMA solution should be inspected visually for particulate matter and 
discoloration prior to administration. The pen injector should be discarded if either is present. 
Only use the SEMA solution for injection if it has colorless or almost colorless appearance free 
from turbidity and essentially free from particulate matter.
5.2.4.
Shelf-life and In-use Time for Semaglutide in PDS290 
The shelf -life of SEMA in the PDS290 pen injector is up to 36 months when stored between 2 to 
8 °C. The study drug should not be used after the expiry date unless an extension of the expiry 
date has been notified and received in writing from Gilead. The in-use time is up to 8 weeks 
when stored at 8 to 30 °C. Do not refrigerate after first use of the pen injector. Exposure to 
excessive heat and light as well as freezing must be avoided during use.
5.3.
Description and Handling of CILO/FIR
5.3.1.
Formulation
CILO/FIR 30 mg/20-mg tablets are a FDC product containing 30 mg of CILO (free-form 
equivalent) and 20 mg of FIR. The tablets contain CILO tromethamine salt (GS-967402), FIR, 
and inactive ingredients mannitol, microcrystalline cellulose, crospovidone, magnesium stearate 
and film-coating materials polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow 
iron oxide, and red iron oxide. The CILO/FIR 30 mg/20-mg tablets are orange, capsule-shaped, 
debossed with "GSI" on 1 side and "7674" on the other side.
Placebo-to-match CILO/FIR 30 mg/20-mg tablets are identical in size, shape, color and 
appearance to the active CILO/FIR 30 mg/20-mg tablets and contain inactive ingredients lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and 
film-coating materials polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron 
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5.3.2.
Packaging and Labeling
CILO/FIR 30 mg/20 mg and PTM CILO/FIR 30 mg/20-mg tablets are packaged in white, 
high-density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, silica gel desiccant 
and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced liner. 
Study drug(s) to be distributed to sites in the US and other participating countries shall be labeled 
to meet applicable requirements of the US Food and Drug Administration (FDA), EU Guideline 
to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products) for CTD, or 
Annex 6 for CTR, as applicable, and/or other local regulations.
5.3.3.
Storage and Handling
CILO/FIR 30 mg/20-mg tablets and PTM CILO/FIR 30 mg/20-mg tablets should be stored 
below 30 °C (86 °F). Storage conditions are specified on the label. Until dispensed to the 
participants, all bottles of study drug should be stored in a securely locked area, accessible only 
to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling. 
5.4.
Labeling of Study Drug
Study drug to be distributed to sites in the US and other participating countries shall be labeled to 
meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing Practice - 
Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.5.
Dosage and Administration of CILO/FIR and SEMA
The administration of study drug will be recorded in the source documentation and in the 
electronic case report form (eCRF).
Study drug dosing and administration will occur as follows:
•
Group A: SEMA 3.0 mg/mL administered SC with prefilled pen injector once weekly and 
1 CILO/FIR 30 mg/20-mg tablet administered orally once daily, both without regard to food
•
Group B: SEMA 3.0 mg/mL administered SC with prefilled pen injector once weekly and 
1 PTM CILO/FIR 30 mg/20-mg tablet, administered orally once daily, both without regard to 
food

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•
Group C: PTM SEMA 3.0 mg/mL administered SC with prefilled pen injector once weekly 
and 1 CILO/FIR 30 mg/20-mg tablet administered orally once daily, both without regard to 
food
•
Group D: PTM SEMA 3.0 mg/mL administered SC with prefilled pen injector once weekly 
and 1 PTM CILO/FIR 30 mg/20-mg tablet administered orally once daily, both without 
regard to food
5.5.1.
Dosage and Administration of CILO/FIR
CILO/FIR 30 mg/20 mg and PTM CILO/FIR 30 mg/20-mg tablets will be provided by Gilead. 
Participants will take a CILO/FIR 30 mg/20-mg tablet (if applicable) at approximately the same 
time each day, with or without food, swallowed whole with water. Participants taking a 
concomitant acid reducing agent, including histamine 2 receptor antagonists, should be 
instructed to take the CILO/FIR 30 mg/20-mg tablet with food. For CILO/FIR 30 mg/20 mg, a 
dose will be considered missed if the participant cannot take the complete dose within 12 hours 
of their regular dosing time. If a participant misses a dose, the participant should take their next 
dose at the regular dosing time.
5.5.2.
Dosage and Administration of Semaglutide
Semaglutide 3.0 mg/mL in PDS290 pen injectors will be manufactured and provided by Novo 
Nordisk, Inc. Participants should be instructed to inject SEMA SC once weekly on the same day 
of the week throughout the study. Injections may be administered in the thigh, abdomen or upper 
arm, at any time of day irrespective of meals. Participants should be encouraged to inject in the 
same area throughout the study but changing between the left and right side is allowed. 
If a single dose of study drug is missed, it should be administered as soon as possible, provided 
the time to the next scheduled dose is at least 48 hours. If a single dose is missed and the next 
scheduled dose is less than 48 hours away, the participant should not administer a dose until the 
next scheduled dose. A single missed dose should not affect the previously scheduled dosing day 
of the week. 
If 2 or 3 consecutive doses are missed, the participant should be encouraged to restart study drug 
if considered safe per the investigator’s discretion and if the participant does not meet any of the 
discontinuation criteria. The study drug should be resumed as early as possible. The starting dose 
for resuming study drug is at the investigator’s discretion; however, if more than 3 consecutive 
doses are missed, consideration should be given to resuming study drug at a reduced dose. In 
case of questions related to resuming study drug, the investigator should consult the medical 
monitor or designee.

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5.5.3.
Management of Semaglutide Dose Escalation
After randomization, SEMA will be initiated with a starting value of 8 (0.24 mg) as shown on 
the dose counter of the prefilled pen injector for the first 4 weeks (4 doses), and subsequently the 
value will be increased every 4 weeks. All participants must aim to reach the recommended 
target dose of SEMA 2.4 mg once weekly.
Table 3.
Semaglutide Dose-Escalation Schedule
Product
Dose
Volume
Value Shown in the 
Dose Counter
Duration (by Study Visit)
Semaglutide 
3.0 mg/mL PDS290
0.24 mg
80 μL
8
Day 1* up to Week 4
Semaglutide 
3.0 mg/mL PDS290
0.50 mg
170 μL
17
Week 5 up to Week 8
Semaglutide 
3.0 mg/mL PDS290
1.0 mg
340 μL
34
Week 9 up to Week 12
Semaglutide 
3.0 mg/mL PDS290
1.7 mg
570 μL
57
Week 13 up to Week 16
Semaglutide 
3.0 mg/mL PDS290
2.4 mg
800 μL
80
Week 17 up to Week 72
*
Participant will take first dose of study drug on-site at Day 1. 
If a participant does not tolerate the planned 4-week dose-escalation regimen due to GI AEs or 
for other reasons as judged by the investigator, the participant may stay longer at any dose level. 
It is recommended that the investigator aim for a maximum of 1 extra week on any dose level 
below the target dose level. If the dose escalation is delayed, the investigator should evaluate 
weekly if the dose can be escalated to the next planned level until the target dose of 2.4 mg once 
weekly is reached.
If a participant does not tolerate the recommended target dose of 2.4 mg once weekly, the 
participant may stay at the lower dose level. This is only permitted if the participant would 
otherwise discontinue study drug completely and if it is considered safe for the participant to 
continue on study drug, per the investigator’s discretion. It is recommended that the participant 
makes at least 1 additional attempt to escalate to the recommended target dose of 2.4 mg once 
weekly, per the investigator’s discretion.
It is recommended that the investigator contact the medical monitor or designee in case of 
persistent deviations from the planned escalation.

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5.6.
Prior and Concomitant Medications
All concomitant medication will be recorded in the source documents and eCRFs. This includes 
medications taken within 30 days prior to screening and any taken during the study to the end of 
the follow-up period.
The following medications are prohibited:
•
Any investigational medication within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to screening and through the end of study is 
prohibited. Participation in an investigational study of a device may be approved by the 
medical monitor or designee
•
Any compound that is approved or under investigation for the treatment of NASH, or another 
liver disease associated with liver fibrosis such as PBC or PSC (eg, obeticholic acid, 
resmetirom, pegbelfermin, aldafermin), excluding antidiabetic medications, within 30 days or 
within 5 half-lives of the compound (whichever is longer) prior to screening and throughout 
the study 
•
Any medication or supplement prescribed for weight loss within 30 days prior to screening 
and throughout the study
Participants on a vitamin E regimen ≥ 800 IU/day or on pioglitazone must be on a stable dose, in 
the opinion of the investigator, for at least 180 days prior to the historical or screening liver 
biopsy. Participants taking antidiabetic medications must be on a stable dose, in the opinion of 
the investigator, for at least 90 days prior to the historical or screening liver biopsy. If possible, 
the doses of these medications should remain stable through the end of treatment.
Treatment with GLP-1 RAs, including SEMA, is prohibited in the period 90 days prior to the 
date of the qualifying historical or screening liver biopsy. Treatment with nonstudy-related 
GLP-1 RAs is prohibited from 90 days prior to the date of screening through the end of study. 
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters organic anion transporting polypeptide 1B1 or 1B3, potent or moderate 
inducers of CYP2C8, or potent inducers of CYP3A4) with drug(s) may result in PK interactions 
resulting in increases or decreases in exposure of study drug(s).
Examples of medications that are prohibited or which require special administration 
considerations are listed below in Table 4.

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Table 4.
Examples of Prohibited Medications and Agents Requiring Special 
Administration Considerations From 30 Days Prior to Day 1 Through 
End of Treatmenta
Drug Class
Prohibited
Agents Requiring 
Special Administration 
Considerations
Immunosuppressants
Chronic systemic corticosteroidsb, tacrolimus, 
sirolimus, cyclosporine, mycophenolate, 
methotrexate
—
Acid reducing agents
—
Antacidsc, histamine 2 
receptor antagonistsd,
proton pump inhibitorsd
Antibiotics
Clarithromycin, erythromycin
Azithromycine
Anticonvulsantsf
Phenobarbital, phenytoin, carbamazepine, 
oxcarbazepine
—
Antimycobacterialsf
Rifampin, rifabutin, rifapentineg, isoniazid
—
Bile acid sequestrantsh
—
Cholestyramine, 
colestipolg, colesevelemg, 
colestilan
Endothelin receptor agonists
Bosentan
—
Herbal/natural supplementsf
—
St John’s Wort, echinacea, 
Chinese herb sho-saiko-to 
(or xiao-shai-hu-tang)
Otherf
Glycyrrhetinic acidi (active ingredient of 
British licorice)
Gemfibrozilg, modafinil
a
Not all of these example medications may be approved where the study is being conducted; please refer to local product 
information.
b
Intra-articular, topical, nasal, or inhaled routes are allowed. Chronic systemic use of corticosteroids equivalent to prednisone 
> 10 mg/day for > 2 weeks is not allowed. Use for ≤ 2 weeks total is allowed.
c
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours (before 
or after) oral study drug administration.
d
Participants taking an acid reducing agent (including histamine 2 receptor antagonists) should take oral study drug with 
food.
e
Chronic azithromycin therapy is prohibited.
f
May result in an increase or decrease in the concentration of study drug.
g
Not approved in Japan.
h
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) oral study drug administration.
i
Glycyrrhizae Radix is a traditional herbal medicine commonly prescribed in Japan as an anti-inflammatory agent and 
contains glycyrrhetinic acid, which confers a mineralocorticoid excess state (sodium retention and potassium wasting).
Please refer to current World Health Organization guidelines for a complete list of medications from prohibited classes listed 
above.

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5.6.1.
Participants Treated With Insulin at Screening
Throughout the study, insulin dose should be titrated at the discretion of the investigator. For the 
individual participant, increasing the insulin dose before 2 weeks after the end of the final dose 
escalation should be avoided, unless required to control acute hyperglycemia and acute diabetic 
complications.
5.6.2.
Participants With Screening HbA1c ≤ 8.0% Treated With Insulin 
Participants with screening HbA1c ≤ 8.0% treated with SEMA in combination with insulin may 
have an increased risk of hypoglycemia. The risk of hypoglycemia can be lowered by reducing 
the dose of insulin, and a dose reduction at randomization and throughout the study should be 
considered at the discretion of the investigator.
5.6.3.
Participants Treated With Sulfonylureas at Screening
Participants treated with SEMA in combination with a sulfonylurea may have an increased risk 
of hypoglycemia. The risk of hypoglycemia can be lowered by reducing the dose of sulfonylurea, 
and a dose reduction at randomization and throughout the study should be considered at the 
discretion of the investigator.
5.7.
Accountability for Investigational Medicinal Product and Devices
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug and devices, including empty containers. This includes acknowledgment of receipt of each 
shipment of study drug and devices (quantity and condition). All used and unused study drug and 
devices (including empty containers) dispensed to participants must be returned to the site.
Each study site must keep accountability records that capture:
•
The date received and quantity of study drug/devices
•
The date, participant number, and the study drug/device kit number dispensed
•
The date, quantity of used and unused study drug/devices returned, along with the initials of 
the person recording the information

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5.7.1.
Investigational Medicinal Product and Device Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate SOP for drug destruction as determined by Gilead, the site may destroy used 
(empty or partially empty) and unused study drug supplies in accordance with that site’s 
approved SOP. A copy of the site’s approved SOP will be obtained for the electronic trial master 
file. If study drug is destroyed at the site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead. 
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability 
during an on-site monitoring visit.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each participant enrolled in the study (from screening 
through the follow-up visit) are presented in tabular form in Appendix 11.5 and described in the 
text that follows. 
The investigator must document any deviation from the protocol procedures and notify Gilead or 
the CRO.
6.1.
Participant Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study wide at any time. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Participants will be screened within 8 weeks before randomization to determine eligibility for the 
study. The screening period may be extended with the explicit approval of the medical monitor 
or designee. 
Screening laboratory tests may be repeated once within the screening period, at the discretion of 
the investigator, prior to administration of study drug. Lipid management may be initiated, and 
repeat testing of triglycerides is permitted at the discretion of the investigator as noted in 
Section 7.7.4.
Participants should be instructed to fast (no food or drink, except water), from midnight (00:00) 
or earlier, as appropriate, on the evening prior to obtaining blood samples to ensure an 
approximate 8-hour fast prior to the sample collection.
The following will be performed and documented at screening:
•
Obtain written informed consent before initiation of any screening procedures 
•
Review inclusion and exclusion criteria
•
Obtain screening number from IRT
•
Obtain medical history including, but not limited to, information related to the following: 
type 2 diabetes, NAFLD, NASH, and any history of hepatic decompensation

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•
Perform fundoscopic examination for participants with type 2 diabetes diagnosed prior to the 
date of the screening visit OR based on screening visit results (HbA1c ≥ 6.5% or fasting 
plasma glucose ≥ 126 mg/dL, confirmed on repeat testing). If there has been worsening of 
the participant’s visual function since an historical fundoscopic examination in the opinion of 
the investigator, then the fundoscopic examination must be repeated prior to Day 1 for 
eligibility. If a qualifying historical fundoscopic examination is available, this assessment is 
not required to be repeated at screening
•
Perform liver biopsy or provide liver tissue from historical liver biopsy (per inclusion 
criterion 3) for central pathologists’ evaluation
•
Complete physical examination (PE)
•
Assessment of ascites and HE
•
Record vital signs, body weight, and height
•
Measure hip and waist circumference
•
Conduct electrocardiogram (ECG)
•
Calculation of the CP and MELD scores
•
Abdominal ultrasound for evaluation of presence of HCC, gallstones, or other hepatobiliary 
disease, if applicable (Section 6.8.13). A historical ultrasound within 90 days of the screening 
visit is acceptable
•
Measure liver stiffness using FibroScan
•
Provide lifestyle counseling 
•
Obtain blood samples for 
Chemistry panel, including creatine kinase (CK)
Hematology panel
Coagulation panel 
Lipid panel
Glycemic panel

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Fasting plasma glucose (fasting plasma glucose ≥ 126 mg/dL should be confirmed on 
repeat testing if type 2 diabetes is previously undiagnosed as determined by medical 
history)*
HbA1c (HbA1c ≥ 6.5% should be confirmed on repeat testing if type 2 diabetes is 
previously undiagnosed as determined by medical history)*
* Note that if a participant with previously undiagnosed type 2 diabetes has confirmed fasting 
glucose or HbA1c above the protocol-specified criteria for diabetes, treatment should be 
initiated in accordance with guidelines from the American Diabetes Association {American 
Diabetes Association 2020a, American Diabetes Association 2020b} or other society, per 
investigator discretion.
eGFR by MDRD
ELF test 
HIV-1, HBV, and HCV serology 
Biomarkers 
Serum pregnancy test (only for women of childbearing potential)
Serum follicle-stimulating hormone (FSH) test (only for women who are < 54 years old 
and have stopped menstruating for ≥ 12 months but do not have documentation of 
ovarian hormonal failure) 
•
Collect urine samples for:
Drug screen for amphetamines, cocaine, and opiates (eg, heroin, morphine)
Biomarkers
•
Provide stool sample collection kit
•
Record all concomitant medications that the participant has taken within 30 days prior to 
screening
•
SARS-CoV-2 RT-PCR test in participants who have not completed a series of an authorized 
COVID-19 vaccination regimen prior to screening
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs, as well as any AEs related to protocol-mandated procedures on the Adverse 
Events eCRF. All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history, are to be considered medical history. See 
Section 7, Adverse Events and Toxicity Management, for additional details.

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Participants meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic within 8 weeks after screening for randomization into the study.
6.2.2.
Day 1 Visit
Participants returning to the clinic for randomization on Day 1 should be instructed to fast (no 
food or drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the 
evening prior to the Day 1 visit to ensure an approximate 8-hour fast prior to the blood sample 
collection the next morning.
After review of inclusion and exclusion criteria to confirm continued eligibility, participants will 
be randomized to study drug assignment and receive their participant identification number via 
the IRT prior to their first dose of study drug.
Prior to dosing at the Day 1 visit, the following will be performed and documented:
•
Collect PROs (Functional Assessment of Chronic Illness Therapy [FACIT] Fatigue 
Questionnaire, NASH-CHECK, Patient Global Impression of Severity [PGIS] for Fatigue 
and Pain, and 36-Item Short Form Survey [SF-36]). It is recommended that PROs be 
completed prior to any other study procedures being performed 
•
Symptom-driven PE
•
Assessment of ascites and HE 
•
Record vital signs and body weight
•
Measure hip and waist circumference
•
Calculation and review of the CP and MELD scores
•
Provide lifestyle counseling
•
Obtain blood samples for:
Chemistry panel 
■
(qualifying eGFR by MDRD)
Hematology panel
Coagulation panel 
Lipid panel
Glycemic panel
HbA1c 

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ELF test 
-
Biomarkers 
• 
Collect urine samples for: 
-
Pregnancy test ( only for women paiiicipants of childbearing potential) 
-
Biomai·kers 
• 
Collect stool sample for biomai·kers 
• 
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• 
Record all concomitant medications the paiiicipant has taken since the previous visit 
• 
Record any SAEs and all AEs related to protocol-mandated procedures occmTing since the 
screening visit 
• 
Dispense study dmg to the paiiicipant and provide instmction on appropriate dosing and 
administration; paiiicipant will take the Day 1 dose of study chug on site 
• 
Counseling regai·ding impo1iance of continued adherence to study procedures 
(Section 6.8.15) 
6.3. 
Randomization 
Randomization will be stratified by the presence or absence of type 2 diabetes as detennined by 
medical histo1y or based on screening laborato1y values if previously undiagnosed (ie, 
HbA1c 
6.5% or fasting plasma glucose~ 126 mg/dL, confnmed on repeat testing), and by ELF 
score (~ 11.30 or < 11.30 during screening). 
6.4. 
Treatment Assessments 
Week 4 through Week 72 assessments will be perfonned as described at the time points 
indicated in the Study Procedures Table (Appendix 11.5). 
6.5. 
Unscheduled Visits 
Unscheduled assessments may be perfo1med at the discretion of the investigator. 
Paiiicipants who will have any laborato1y assessments perfonned should be instrncted to fast 
(no food or ch·ink, except water), sta1iing from midnight (00:00) or earlier, as appropriate, on the 
evening prior to the visit to ensure an approximate 8-hour fast prior to the blood sample 
collection the next morning. 
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Additional assessments may be performed at the discretion of the investigator or as 
recommended by the medical monitor or designee. At a minimum, the following will be 
performed and documented:
•
Symptom-driven PE
•
Assessment of ascites and HE
•
Record vital signs and body weight
•
Obtain blood samples for:
Chemistry panel
o
(eGFR by MDRD)
Hematology panel
Coagulation panel 
•
Record all concomitant mediations that the participant has taken since the previous visit
•
Record any SAEs and all AEs occurring since the previous visit 
In cases where the unscheduled visit is performed for the primary purpose of safety evaluation 
(eg, SAE follow-up), collection of a single PK sample (anytime predose or postdose) is 
recommended. The timing of the PK sample in relation to the last dose of study drug should be 
documented.
If the unscheduled visit is performed for the sole purpose of the distribution of study drug, the 
assessments noted above do not need to be performed.
6.5.1.
Premature Discontinuation of Study Drug
If a participant discontinues study drug dosing (eg, as a result of an AE), every attempt should be 
made to keep the participant in the study and continue to perform the required study-related 
follow-up and procedures. If this is not possible or acceptable to the participant or investigator, 
the participant may be withdrawn from the study. Study drug discontinuation criteria are listed in 
Section 3.5.
Participants who prematurely discontinue study drug may return for an unscheduled visit at the 
discretion of the investigator or request of the medical monitor or designee for a safety 
evaluation. Participants should be encouraged to complete their remaining study visits in 
accordance with the Study Procedures Table (Appendix 11.5), if appropriate. 

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6.5.2.
Early Termination Visit
Participants who prematurely discontinue from the study should complete an ET visit within 
30 days of the last dose of study drug and a follow-up visit 5 weeks after the ET visit. 
Participants who previously discontinued study drug and continued to complete study visits 
should return for an ET visit even if it has been more than 30 days since their last dose of study 
drug.
Participants should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following must be performed and documented:
•
Symptom-driven PE (see Section 11.9.1 for France-specific text.)
•
Assessment of ascites and HE 
•
Record vital signs and body weight
•
Measure hip and waist circumference 
•
Calculation of the CP and MELD scores
•
Provide lifestyle counseling 
•
Obtain blood samples for:
Chemistry panel
■
(eGFR by MDRD)
Hematology panel
Coagulation panel 
Lipid panel
Glycemic panel
HbA1c
PK (single sample anytime predose or postdose; the timing of the PK sample in relation 
to the last dose of study drug should be documented)
•
Collect urine pregnancy test (only for women participants of childbearing potential per 11.6)

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• 
Record all concomitant medications that the paiiicipant has taken since the previous visit 
• 
Record any SAEs and all AEs occmTing since the previous visit 
• 
Review of study drng dosing compliance 
The following should be perfo1med unless completed within 12 weeks of ET visit: 
• 
Perfo1m abdominal ultrasound for presence of HCC, gallstones, or other hepatobilia1y 
disease 
• 
Measure liver stiffness by FibroScan 
The following can be perfonned and documented at the discretion of the investigator: 
• 
Collect PROs (F ACIT-Fatigue, NASH-CHECK, PGIS and Patient Global Impression of 
Change [PGIC] for Fatigue, PGIS and PGIC for Pain, SF-36). It is recommended that PROs 
be completed prior to any other study procedures being perfo1med 
• 
Perfo1m liver biopsy 
• 
Conduct ECG 
• 
Perfo1m fundus examination 
• 
Obtain blood samples for: 
-
ELF test 
-
Biomai·kers 
• 
Collect urine sample for: 
-
Biomai·kers 
See Section 11.9 .1 for France-specific text 
6.6. 
Follow-up Visit 
Paiiicipants will return for a follow-up visit 5 weeks after the Week 72 or ET visit. 
Paiiicipants should be instructed to fast (no food or drink, except water), staiiing from midnight 
(00:00) or eai·lier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning. 
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The following will be performed and documented at the follow-up visit:
•
Symptom-driven PE
•
Assessment of ascites and HE
•
Record vital signs and body weight
•
Measure hip and waist circumference
•
Calculation of the CP and MELD scores
•
Provide lifestyle counseling
•
Obtain blood samples for:
Chemistry panel
■
(eGFR by MDRD)
Hematology panel
Coagulation panel
Lipid panel
Glycemic panel
HbA1c
Biomarkers
•
Collect urine samples for:
Pregnancy test (only for women participants of childbearing potential per Appendix 11.6)
Biomarkers
•
Record all concomitant medications that the participant has taken since the previous visit
•
Record any SAEs and all AEs occurring since the previous visit

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6.7.
Study Visit Windows
Windows for study visits are presented in Table 5.
Table 5.
Study Visit Windows
Study Visit
Window
Screening visit
≤ 8 weeks prior to Day 1, window begins with the 
signing of the informed consent.
Day 1 
Day of randomization and the first dose of study drug. All study visits 
are calculated based on the Day 1 date.
Week 48 fundoscopic examination
± 14 days
Week 72 (including fundoscopic 
examination) 
−14 days
All study visits from Week 4 to Week 60 
± 3 days
ET visit
Within 30 days of last dose of study drug. Participants who 
previously discontinued study drug, continued to complete study 
visits and are discontinuing from the study should return for an ET 
visit even if it has been more than 30 days since their last dose of 
study drug.
Follow-up visit
5 weeks after Week 72 or ET visit (± 7 days).
ET = early termination
6.8.
Description of Study Assessments
6.8.1.
Clinical Laboratory Assessments
Fasting is required prior to all study visits.
6.8.1.1.
Chemistry Panel
Albumin, ALT, AST, ALP, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine 
(reflex to serum enzymatic creatinine, as applicable), lactate dehydrogenase, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, total protein, uric acid, and GGT.
6.8.1.2.
Hematology Panel
Hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count with 
differential (absolute and percentage) including lymphocytes, monocytes, neutrophils, 
eosinophils, basophils, and mean corpuscular volume.
6.8.1.3.
Coagulation Panel
Prothrombin time, partial thromboplastin time, and INR.

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6.8.1.4.
Glycemic Panel
Insulin, homeostasis model assessment of insulin resistance (HOMA-IR) based on fasting 
glucose and insulin, and C-peptide.
6.8.1.5.
Lipid Panel
Triglycerides, total cholesterol, HDL, non-HDL, LDL, and VLDL by Friedewald calculation.
6.8.1.6.
Additional Tests
HbA1c (reflex to serum fructosamine, as applicable), HIV-1 (reflex to HIV-1 RNA, if applicable), 
HBV (HBsAg) and HCV (reflex to HCV RNA, as applicable) serology, eGFR as calculated by 
MDRD, urine drug screen (for amphetamines, cocaine, opiates), serum pregnancy test, FSH, 
reflex direct LDL (if triglycerides are > 400 mg/dL), CK, and 
.
6.8.1.7.
Biomarkers
Including but not limited to CRP, NMR LipoProfile®, ELF score, CK18 M30, CK18 M65, 
Pro-C3, CTXIII, total serum bile acids, apolipoproteins, SomaSignal NASH tests, and, 
potentially, levels of hepatic genes and proteins. Bile acids and the representation of microbial 
populations may also be tested in stool samples.
6.8.1.8.
Urine Samples
Microalbumin, creatinine, microalbumin/creatinine ratio; at screening for amphetamines, 
cocaine, methadone, and opiates; urine pregnancy test (reflex to serum beta human chorionic 
gonadotropin), and stored for 
.
6.8.1.9.
Pharmacokinetic Assessments
6.8.1.9.1.
Single PK Sampling
Single PK plasma samples will be collected and archived for PK analysis of CILO and FIR (and 
their metabolites, as applicable). Samples will be collected at Week 4 (15 minutes to 3 hours 
postdose), Week 24 (anytime postdose), Week 48 (predose), Week 60 (15 minutes to 3 hours 
postdose), Week 72 (predose), the ET visit (anytime), and at unscheduled visits (anytime) that 
are performed for the purpose of safety evaluation (eg, SAE follow-up). For PK sampling at 
Weeks 4, 48, 60, and 72, participants should be reminded not to take their oral study drug until 
advised to do so at their clinic visit.
6.8.1.10.
Blood Sample Collection
In the course of the assessments outlined above which require collection of blood samples, a total 
of at least 12 blood sample collections will be required throughout the study. Approximate total 
blood volume collected at each visit and overall is outlined below.
CCI
CCI

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•
Screening, Day 1, and Week 24: 81.8 mL
•
Week 4 and Week 60: 14.8 mL
•
Week 8, Week 16, and Week 36: 8.8 mL
•
Week 12: 75.8 mL
•
Week 48 and Week 72: 87.8 mL
•
ET: 89.3 mL
•
Follow-up: 73.3 mL
Approximate total blood volume of 552.8 mL may be drawn for study purposes from screening 
through Week 72, and approximate total blood volume of 626.1 mL may be drawn from 
screening through follow-up.
6.8.2.
Physical Examination
A complete PE should include source documentation of general appearance, and the following 
body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; chest 
(excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, nails; 
musculoskeletal; neurological.
The focus of a symptom-driven PE will be determined by the investigator based on participant 
complaint. For example, if a participant complains of a cough, a respiratory examination should 
be performed. If consistent with pneumonia (eg, rales or crackles are identified), then an AE 
would be documented.
Assessments to evaluate for the presence of ascites and HE should be performed at every visit.
Measurements for height, body weight, and hip and waist circumference will be collected at 
specified time points.
See Section 11.9.1 for France-specific text.
6.8.3.
Fundoscopic Examination
For participants with type 2 diabetes diagnosed prior to the date of the screening visit OR based 
on a screening visit HbA1c ≥ 6.5%, participants must have no evidence of uncontrolled and 
potentially unstable retinopathy or maculopathy as determined by a fundoscopic examination 
performed within 90 days prior to screening visit through Day 1. If there has been worsening of 
the participant’s visual function since a historical fundoscopic examination in the opinion of the 
investigator, then the fundoscopic examination must be repeated prior to Day 1 for eligibility. 
Pharmacological pupil dilation is a requirement unless using a digital fundus photography 
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Fundoscopic examinations should be performed and interpreted by a qualified ophthalmologist 
or optometrist. The report must be reviewed by the investigator or medically qualified delegate, 
with documentation of the below criteria on the fundoscopic examination result report or in the 
participant's medical record:
•
Normal
•
Abnormal
Was the result clinically significant? (Yes/No)
If a fundoscopic examination matching this description has been performed within 90 days prior 
to the date of the screening visit, or between screening visit and Day 1, the procedure does not 
need to be repeated unless there has been worsening of visual function since the last examination 
in the opinion of the investigator. The results must be available prior to Day 1. 
If the dilated fundoscopic examination is performed before the participant has signed the 
informed consent form (ICF), it must be documented in the medical records that the reason for 
performing the procedure was not related to this study.
For participants with type 2 diabetes only, the fundoscopic examination will be repeated at 
Weeks 48 and 72, or ET visit, per investigator’s discretion.
6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:
•
Participant should sit for ≥ 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level
•
Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery
•
Measure and record the blood pressure to the nearest 2 mm Hg mark on the manometer or to 
the nearest whole number on an automatic device

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6.8.5.
Clinical Liver Assessments
MELD and CP scores will be derived from the central laboratory values obtained at each visit. 
Sites will use the central laboratory values to calculate CP at each visit, including screening, to 
assess eligibility and at subsequent visits to identify CP > 6 requiring confirmation and treatment 
discontinuation (Section 3.5). Assessment of ascites and HE will be determined by the site at all 
visits, as described in Table 6, and will be entered into the eCRFs. Dialysis in the preceding 
week will also be determined by the site at each visit. Hepatic encephalopathy will be assessed 
using the West Haven Criteria (Appendix 11.4).
The MELD score calculation will be performed by the central laboratory. If the central 
laboratory is unable to perform the MELD score calculation, sites may use the central laboratory 
values to calculate the MELD score. MELD should be monitored by the site at each visit to 
identify potential criteria for liver transplantation, as described in study drug discontinuation 
criteria (Section 3.5). 
MELD will be calculated using the following formula:
MELD score = 10  ([0.378  ln (total bilirubin mg/dL)] + [1.12  ln (INR)] + [0.957  
ln (serum creatinine mg/dL)] + 0.643) 
•
Serum creatinine in μmol/L will be converted to mg/dL by multiplying by 0.01131. The 
resulting value will be rounded to 2 decimal places
If the serum creatinine is < 1.00 mg/dL, use 1.00 as the serum creatinine value
If the serum creatinine is > 4.00 mg/dL or if the participant has had 2 or more dialysis 
treatments within the preceding week, use 4.00 as the serum creatinine value
If the “Creatinine (Rate Blanked)” is resulted as “Icteric–Test Not Performed” by the 
central laboratory, use the serum enzymatic creatinine value
•
Total bilirubin in μmol/L will be converted to mg/dL by multiplying by 0.05848 and the 
resulting total bilirubin value to 1 decimal place
If the total bilirubin is < 1.0 mg/dL, use 1.0 as the total bilirubin value
•
If the INR is < 1.0, use 1.0 as the INR value
The online calculator https://www.mdcalc.com/meld-score-original-pre-2016-model-end-stage-
liver-disease may also be used

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Table 6.
Child-Pugh Classification of the Severity of Cirrhosis
Score
1
2
3
HE 
None
No encephalopathy and 
not on any treatment for 
HE
Medication-Controlled
Participant is lethargic, may 
have moderate confusion
 
Participant is receiving medical 
therapy for HE
Medication-Refractory
Marked confusion/incoherent, 
rousable but sleeping or comatose
Ascites
None
No ascites and not 
on treatment for ascites
Mild/Moderate
Abdominal distension 
 
Medication for ascites
Severe
(Diuretic-Refractory)
Visible clinically
Bilirubin (mg/dL)
< 2
2 to 3
> 3
Albumin (g/dL)
> 3.5
2.8 to 3.5
< 2.8
INR
< 1.7
1.7 to 2.3
> 2.3
HE = hepatic encephalopathy; INR = international normalized ratio
A CP score is obtained by adding the score for each parameter.
CP Class:
A = 5 to 6 points
B = 7 to 9 points
C = 10 to 15 points
Participants who have a CP score > 6 at any time during the study confirmed as soon as possible, 
preferably within 72 hours, (unless due to an alternative etiology such as Gilbert’s syndrome or 
therapeutic anticoagulation) must discontinue study drug (Section 3.5). 
6.8.6.
Estimated Glomerular Filtration Rate Using MDRD Equation
Estimated glomerular filtration rate will be calculated by the central laboratory. If the central 
laboratory is unable to perform the eGFR calculation, eGFR may also be calculated by the sites.
Estimated glomerular filtration rate is calculated by the MDRD equation (conventional units) 
{Levey 2006}
eGFR (mL/min/1.73 m²) = 175 × (Scr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if Black) 
Scr = serum creatinine (mg/dL)
6.8.7.
Genomic Testing
From participants who agree to participate and provide consent, blood samples will be collected 
at the Day 1 visit, Week 48, Week 72, and ET (if applicable) for genomic testing, including 
DNA methylation.

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6.8.8.
Pregnancy Testing
All women of childbearing potential (as defined in Appendix 11.6) will have a serum pregnancy 
test at screening. Urine pregnancy testing will occur at Day 1 (prior to dosing) and every 4 weeks 
thereafter. Starting at the Week 4 visit, every 4 weeks (± 3 days) urine pregnancy testing may be 
performed at home in between clinic visits, where possible, or in clinic, if at home pregnancy 
tests are unavailable. In the event of a positive urine pregnancy result, participants will be 
instructed to stop study drug immediately (if applicable), inform their study physician, and return 
to the clinic as soon as possible for a serum pregnancy test.
6.8.9.
PRO Measures
It is recommended that these questionnaires, as possible, be completed prior to any other study 
assessments at each visit. The participant should read the questionnaires and record the answers 
independently.
6.8.9.1.
FACIT-Fatigue (Version 4)
The FACIT-Fatigue PRO measure is a 13-item questionnaire designed to measure fatigue and 
lifestyle-related consequences of fatigue, with all responses reported on a scale of 0 to 4. 
Participants are directed to respond to each question based on their experience in the previous 
7 days. 
6.8.9.2.
NASH-CHECK (Version 1.0)
The NASH-CHECK is a 28-item PRO measure designed to measure symptoms and 
health-related quality of life including day-to-day activities, emotions, and lifestyle in 
participants with NASH. Symptoms of NASH are reported on a scale of 0 to 10, with 
participants asked to report the severity of the symptom at its worst over the previous 7 days. 
Participants are directed to respond to additional questions related to day-to-day activities, 
emotions and lifestyle based on quality of life in the prior 7 days. 
6.8.9.3.
Patient Global Impression of Severity (PGIS) Fatigue
For the PGIS Fatigue, participants will be asked to rate their overall impression of their fatigue 
during the past week on a 4-point scale from “none” to “severe”. The PGIS Fatigue will be used 
as an anchor to support the interpretation of the FACIT-Fatigue questionnaire and 
NASH-CHECK fatigue items.
6.8.9.4.
Patient Global Impression of Change (PGIC) Fatigue
For the PGIC Fatigue, participants will be asked to rate their overall impression of how their 
fatigue has changed since they started taking the study medication, on a 7-point scale from “very 
much improved” to “very much worsened”. The PGIC Fatigue will be used as an anchor to 
support the interpretation of the FACIT-Fatigue and NASH-CHECK fatigue items.

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6.8.9.5.
PGIS Pain
For the PGIS Pain, participants will be asked to rate their overall impression of their upper 
abdominal (stomach) pain during the past week on a 4-point scale from “none” to “severe”. The 
PGIS Pain will be used as an anchor to support the interpretation of the NASH-CHECK upper 
abdominal (stomach) pain item.
6.8.9.6.
PGIC Pain
For the PGIC Pain, participants will be asked to rate their overall impression of how their upper 
abdominal (stomach) pain has changed since they started taking the study medication, on a 
7-point scale from “very much improved” to “very much worsened”. The PGIC Pain will be used 
as an anchor to support the interpretation of the NASH-CHECK upper abdominal (stomach) pain 
item.
6.8.9.7.
SF-36 (Version 1.0)
The SF-36 consists of 36 questions to measure functional health and well-being from the 
participant’s point of view, and comprises 8 health domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health). These 
health domain scales contribute to the physical health and mental health summary measures.
6.8.10.
Liver Stiffness Measured by Transient Elastography (FibroScan)
The acceptable elastographic method is vibration-controlled transient elastography (FibroScan). 
FibroScan examinations will be performed at the screening visit and Weeks 24, 48, and 72. The 
median liver stiffness in kPa, interquartile range/median value (IQR/M), and success rate 
(number of valid shots/total number of shots) will be recorded. Where available, the median CAP 
and the IQR of CAP values will be recorded. For ET visits, a FibroScan assessment should be 
performed unless performed within 12 weeks of the ET visit.
For individual participants, the same probe should be used for all assessments. Probe size should 
be determined based on the machine probe size recommendation at the screening assessment. 
The same probe size should then be used at all subsequent assessments. If the machine being 
used does not recommend a probe size, an extra-large probe should be used at all examinations if 
available. If an extra-large probe is not available and/or a valid result cannot be obtained, an 
examination with the medium probe should be performed and the result recorded. At least 
3 hours fasting is recommended prior to all FibroScan assessments.
All FibroScan assessments should be performed with SmartExam turned off. If this is not 
possible, then data files must be saved and sent to Echosens for reprocessing into the standard 
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6.8.11.
Liver Biopsy
All possible attempts should be made to acquire a liver biopsy specimen of at least 2.0 cm in 
length to ensure accurate staging of fibrosis and other histological parameters. If a screening or 
Week 72 liver biopsy is deemed unevaluable by the central pathologists, it may be repeated. 
If a historical biopsy is used to determine eligibility, it must have been done within 180 days of 
the screening visit. All liver biopsies will be sent to a central laboratory and will be evaluated by 
central pathologists. For inclusion, historical or screening liver biopsy samples must be deemed 
evaluable and consistent with cirrhosis (F4) and NASH (defined as the presence of steatosis 
Grade ≥ 1, hepatocellular ballooning Grade ≥ 1, and lobular inflammation Grade ≥ 1, according 
to NAS) in the opinion of the central pathologists. 
Week 72 liver biopsy results will be blinded to the investigator and participant. 
If a liver biopsy is performed per standard of care outside of protocol-mandated assessments, all 
possible attempts should be made to submit the biopsy specimen to the central pathologists for 
evaluation. 
Please refer to the Investigator Site File for additional information.
6.8.12.
Lifestyle Counseling
Lifestyle modifications such as weight loss via diet and increased exercise can be effective in the 
treatment of NASH. All participants will receive counseling, provided by the investigator or a 
qualified health professional, regarding lifestyle modifications including the maintenance of a 
healthy diet and participation in regular exercise. Appendix 11.7 provides lifestyle 
recommendations developed by the American College of Cardiology/American Heart 
Association {Arnett 2019}. Weight loss surgeries or procedures may not be performed during 
the study.
6.8.13.
Abdominal Ultrasound 
Abdominal ultrasound for evaluation of presence of HCC, gallstones, or other hepatobiliary 
disease will be performed at the screening visit. A historical ultrasound within 90 days of the 
screening visit is acceptable. On-study abdominal ultrasounds should be performed at Weeks 24, 
48, and 72. For ET visits, an abdominal ultrasound should be performed unless performed within 
12 weeks of the ET visit.
6.8.14.
Electrocardiogram
Standard 12-lead ECG assessments will be performed. The investigator will review the ECGs for 
any clinically significant abnormalities to ensure participant safety. Abnormal ECG findings that 
are considered clinically significant by the investigator and meet the definition of an AE should 
be reported and recorded in the AE eCRF page.

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6.8.15.
Counseling Regarding Adherence to Study Procedures 
Participants should be encouraged at each visit to remain in the study and adhere to study 
procedures. Participants who prematurely discontinue study drug are encouraged to return for an 
unscheduled visit at the discretion of the investigator or request of the medical monitor or 
designee for a safety evaluation. Participants who prematurely discontinue study drug should be 
encouraged to complete their remaining study visits in accordance with the Study Procedures 
Table (Appendix 11.5), if appropriate. Site-specific plans will be developed to include relevant 
participant retention strategies. 
6.9.
Sample Storage
Stored biological samples may be used by Gilead or its research partner(s) for future testing to 
provide additional data to answer questions that relate to the main study. At the end of this study, 
these samples may be retained in storage by Gilead for a period of up to 15 years. If participants 
provide additional specific consent for optional future research, residual PK, and biomarker 
samples may be used for exploratory future research. Residual samples will be destroyed no later 
than 15 years after end of study or per country requirements. 

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study participant administered any study 
drug, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a study drug, whether or not the AE is considered related to the study drug. 
Adverse events may also include pretreatment or posttreatment complications that occur as a 
result of protocol-specified procedures or special situations (Section 7.1.5).
An AE does not include the following:
•
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported
•
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen
•
Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)
•
Overdose without clinical sequelae (Section 7.1.5)
•
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-associated procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs
7.1.2.
Serious Adverse Events
An SAE is defined as an event that results in the following:
•
Death
•
A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe)
•
In-patient hospitalization or prolongation of existing hospitalization (not including 
hospitalization for elective surgery)

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•
Persistent or significant disability/incapacity
•
A congenital anomaly/birth defect
•
A medically important event or reaction: such events may not be immediately 
life-threatening- or result in death or hospitalization but may jeopardize the participant or 
may require intervention to prevent one of the other outcomes constituting SAEs. Medical 
and scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse
•
A hypoglycemic episode is considered an SAE if it meets any criteria above of it requires the 
assistance of another person to correct (eg, to administer carbohydrate)
7.1.3.
Serious Adverse Drug Reaction
A serious adverse drug reaction (SADR) is defined as any SAE that is considered causally 
related to the medicinal product at any dose administered.
7.1.4.
Adverse Events of Special Interest
7.1.4.1.
Hypoglycemic Episodes
Hypoglycemic episodes must be reported as an AE on the AE eCRF according to Section 7.3.2. 
Additionally, participants with type 2 diabetes must be instructed to measure their blood glucose 
in connection with symptoms of hypoglycemia. Plasma glucose values ≤ 70 mg/dL 
(≤ 3.9 mmol/L) should be reported as a hypoglycemic episode. This information and other 
relevant clinical data must be reported on a hypoglycemic episode eCRF. If the hypoglycemic 
episode meets seriousness criteria, the event must be reported on the eCRF and to Gilead PS as 
an SAE (Section 7.4.1.1).
7.1.4.2.
Other Adverse Events of Special Interest
Additional adverse events of special interest (AESI), including both serious and nonserious AEs, 
will require submission of additional information on an event specific eCRF. These events 
include acute pancreatitis, acute gallbladder disease, malignant neoplasm (not including localized 
basal or squamous cell cancer or other localized non-melanoma skin cancer or carcinoma in situ 
of the cervix), diabetic retinopathy, and any case where a participant meets criterion for study 
drug withholding as specified in Section 7.7.3. 
7.1.4.3.
Liver-Related Clinical Events
Additional information for participants experiencing clinically significant liver events should be 
reported on an event specific eCRF. These events include clinically significant ascites, 

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complications of ascites such as spontaneous bacterial peritonitis, hepato-pleural effusion or 
others, variceal hemorrhage, hepatic encephalopathy, worsening of MELD score to ≥ 15 
(confirmed on repeat testing), liver transplantation, or liver-related death. Participants who 
discontinue study drug due to evidence of hepatic decompensation must be followed until they 
stabilize clinically.
7.1.5.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports
Special situation reports include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration or administration of a study drug while the medication is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE (which includes situations of missed dose), a medication error with an AE, an 
intercepted medication error, or a potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a 
participant.
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively which is above the maximum recommended dose 
per protocol or in the product labeling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine: any study drug with a false representation of (a) its identity, (b) 
its source, or (c) its history.

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7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:
•
No: evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).
•
Yes: there is reasonable possibility that the AE may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:
•
No: evidence exists that the AE has an etiology other than the study procedure.
•
Yes: the AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity 
The severity of AEs will be graded using the CTCAE Toxicity Grading Scale. For each episode, 
the highest grade attained (1, 2, 3, 4, or 5) should be reported as defined in the Toxicity Grading 
Scale (provided in the Investigator Site File).
7.3.
Investigator Reporting Requirements and Instructions 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable eCRFs: all SAEs and AEs related to protocol-mandated 
procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until at least 5 weeks after last administration of study drug and report them on the eCRFs as 
instructed.

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All AEs should be followed until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol-defined follow-up period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the participant first consents to 
participate in the study (ie, signing the ICF) and throughout the duration of the study, including 
the posttreatment follow-up visit, must be reported on the applicable eCRFs and to Gilead PS 
(Section 7.4.1). This also includes any SAEs resulting from protocol-associated procedures 
performed after the ICF is signed.
Any SAEs and deaths that occur after the posttreatment follow-up visit but within 5 weeks of the 
last dose of study drug, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if the investigator learns of any SAEs that occur after the protocol-defined follow-up 
period has concluded and the event is deemed relevant to the use of study drug or device, the 
investigator should promptly document and report the event to Gilead PS.
7.3.4.
Study Drug Special Situations Reports
All study drug special situations reports (SSRs) that occur from study drug initiation and 
throughout the duration of the study, including the posttreatment follow-up visit, must be 
reported to Gilead PS (Section 7.4.2). Adverse events and SAEs resulting from SSRs must be 
reported in accordance to the AE and SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing the informed 
consent) and throughout the duration of the study, including the posttreatment follow-up visit, 
must be reported to Gilead PS utilizing the paper SSR (Section 7.4.2.2).
7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, for special situations that result in AEs due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.

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7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports
7.4.1.
Serious Adverse Event Reporting Process
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety Report 
Form eCRF.
7.4.1.1.
Electronic Serious Adverse Event Reporting Process 
Site personnel will record all SAE data on the applicable eCRFs and from there transmit the SAE 
information to Gilead PS within 24 hours of the investigator’s knowledge of the event from ICF 
signature throughout the duration of the study, including the protocol-required posttreatment 
follow-up period. 
If it is not possible to record and transmit the SAE information electronically, record the SAE on 
the paper SAE reporting form and transmit within 24 hours:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to PS.
7.4.2.
Special Situations Reporting Process 
7.4.2.1.
Electronic Special Situations Reporting Process for Study Drug 
Site personnel will record all SSR data on the applicable eCRFs and from there transmit the SSR 
information within 24 hours of the investigator’s knowledge to Gilead PS from study drug 
initiation throughout the duration of the study, including the protocol-required posttreatment 
follow-up period. 

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If for any reason it is not possible to record the SSR information electronically, record the SSR 
on the paper special situation reporting form and transmit within 24 hours to:
Gilead PS
Email: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SSR reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to PS. 
7.4.2.2.
Reporting Process for Gilead Concomitant Medications
Special situations that involve Gilead concomitant medications that are not considered study 
drug must be reported within 24 hours of the investigator’s knowledge of the event to Gilead PS 
utilizing the paper special situations report form to:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, special situations that result in AEs due to a non-Gilead concomitant 
medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies in female study participants and/or female partners of 
male participants who are identified after initiation of study drug and throughout the study 
(including the posttreatment follow-up period) and through 5 weeks after last study drug dosage 
to Gilead PS using the pregnancy outcome report form within 24 hours of becoming aware of the 
pregnancy. Contact details for transmitting the pregnancy report form are as follows:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477

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The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to Gilead PS 
using the pregnancy outcome report form. If the end of the pregnancy/partner pregnancy occurs 
after the study has been completed, the outcome should be reported directly to Gilead PS at the 
contact listed above.
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
All other premature terminations of pregnancy of the participant (eg, a spontaneous abortion, an 
induced therapeutic abortion due to complications or other medical reasons) must be reported 
within 24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome poststudy must 
be reported to the Gilead PS; however, if the SAE occurs in a partner, the pregnancy-related SAE 
will not be captured in eCRF but should be reported via the paper pregnancy outcome report 
form.
Refer to Appendix 11.6 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs (which may be in the form of line listings), 
SADRs, or SUSARs. In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead 
or a specified designee will notify worldwide regulatory agencies and the relevant IEC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter or a quarterly SAE line listing notifying them of 
relevant SUSAR reports associated with any study drug. The investigator should notify the IRB 
or IEC of SUSAR reports as soon as is practical, where this is required by local regulatory 
agencies, and in accordance with the local institutional policy.

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7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, x-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the CTCAE Toxicity Grading Scale. For 
AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
Information regarding handling of specific laboratory abnormalities in this study is provided in 
Section 7.7.
7.7.
Toxicity Management
7.7.1.
Monitoring for DILI
Baseline values for liver tests (ALT, AST, ALP, and total bilirubin) will be determined by the 
central laboratory by averaging the values obtained during screening and at Day 1. At baseline, 
some participants may have liver biochemistry levels above the ULN. Please refer to the 
Laboratory Manual or individual participant laboratory reports for gender- and age-specific 
reference ranges.
Unless the clinical context points towards an apparent etiology other than DILI or progressive 
liver disease, on-treatment elevations of ALT, AST, and/or ALP should be confirmed on repeat 
testing within 72 hours of initial results (or as soon as possible). Participants with repeat ALT, 
AST, or ALP elevations must be placed into close observation as shown in Figure 4 below.

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Figure 4.
On-Treatment Monitoring Requiring Close Observation
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
7.7.2.
Close Observation
Close observation includes the following:
•
Obtaining a more detailed history of symptoms and prior or concurrent disease, including the 
presence of any hepatic decompensation events including hepatic encephalopathy, clinically 
relevant ascites, variceal bleeding, and spontaneous bacterial peritonitis
•
Obtaining a history of concomitant drug use (including nonprescription medications, herbal 
and dietary supplement preparations, and recreational drugs), alcohol use, and special diets
•
Obtaining a history of exposure to environmental chemical agents
•
Ruling out other causes of liver disease as needed (eg, obtain viral hepatitis panel, imaging 
for evaluation of biliary tract disease) and if relevant in the opinion of the investigator
•
Monitoring liver biochemistries at least twice weekly. Frequency can decrease to once a 
week or less if abnormalities stabilize or study drug has been discontinued and the participant 
is asymptomatic
During a period of close observation for DILI, study drug may be continued at the discretion of 
the investigator and the medical monitor, or designee
Baseline ALT, AST, and ALP 
{average of all Screening & Day 1 values) 
Note: ALT, AST, and ALP are evaluated independently 
I 
I 
I 
Normal 
> ULN 
l 
l 
Is the ALT, AST, or ALP 
Is the ALT, AST, or ALP 
> 3 x ULN? 
> 2 x baseline or is the ALT 
or AST> 300 U/L? 
I 
I 
I Yes I 
I Yes I 
• 
Enter Participant Into Close Observation 

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7.7.3.
Study Drug Withholding
If on-treatment elevations of ALT, AST, ALP, total bilirubin, and/or INR meet the criteria 
specified in Figure 5, and are confirmed on repeat testing within 72 hours of results (or as soon 
as possible), and no cause other than progressive liver disease and/or DILI is immediately 
apparent, the participant must be placed into close observation as described in Section 7.7.2 and 
study drug must be withheld. 
Additionally, any participant who develops signs or symptoms of liver toxicity (eg, right upper 
quadrant pain, fever, nausea, vomiting, jaundice, rash, or eosinophilia > 5%) which are suspected 
by the investigator to be drug related, must be placed into close observation and study drug must 
be withheld, or permanently discontinued if the participant meets discontinuation criteria 
outlined in Section 3.5. In cases where close observation as outlined in Section 7.7.3 is not 
possible, study drug must be discontinued. Participants who discontinue study drug due to 
suspected hepatotoxicity must be followed until symptoms subside, any abnormal laboratory 
values have resolved or returned to baseline levels, until there is a satisfactory explanation for the 
changes observed, or for 90 days after drug discontinuation, whichever is longer.
Figure 5.
On-Treatment Monitoring Requiring Study Drug Withholding
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized 
ratio; TB = total bilirubin; ULN = upper limit of normal
a
Unless participant has Gilbert’s syndrome or other cause of unconjugated hyperbilirubinemia, in which case a direct 
bilirubin > 2  baseline value (average of screening and Day 1 values) will be used instead of total bilirubin.
b
If not on therapeutic anticoagulation (eg, warfarin). If on therapeutic anticoagulation, INR criteria is disregarded.
In all cases where a participant meets criteria for study drug withholding as outlined in Figure 5, 
additional information must be submitted on an event of special interest eCRF, as described in 
Section 7.1.4.2. Additionally, if study drug is withheld due to meeting criteria in Figure 5 the 
case will be reported to the DMC and study drug may not be reintroduced prior to review by the 
DMC and subsequent approval of the medical monitor, or designee. In cases where study drug is 
Baseline ALT, AST, and ALP 
(average of all Screening & Day 1 values) 
Note: ALT, AST, and ALP are evaluated independently 
Normal 
(!, ULN) 
" 
While on-treatment does t he subject meet any one of these 
criteria: 
• Symptoms of drug-related hepatotoxicity 
• ALTorAST > 8xULN 
• ALT or AST > 5 x ULN for 2 weeks 
• ALT, AST, or ALP >3 x ULN and [TB > 2 x ULN' or INR > 1.Sb] 
l 
Yes 
I 
Elevated 
(> ULN) 
t 
While on-treatment does the subject meet any one of these 
criteria: 
• Symptoms of drug-related hepatotoxicity 
• ALT or AST > 50 U/L 
• [ALT or AST> 3 x Baseline or 300 U/L] and [TB > 2 x ULN' or 
INR > l.Sb] 
• [ALP > 2 x Baseline] and [TB > 2 x ULN' or INR > 1.Sb] 
I 
Yes 
Withhold Study Drug and Enter Participant into Close Observation 

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resumed and clinical or laboratory criteria outlined in Figure 5 are again met, study drug must be 
permanently discontinued.
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the medical monitor or designee. Whether or not considered treatment related, all participants 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or are considered irreversible, or 
until there is a satisfactory explanation for the changes observed. 
All clinically significant Grade 3 or 4 laboratory abnormalities, including laboratory parameters 
not included in Figure 4 or Figure 5, should be confirmed on repeat testing as soon as possible, 
and preferably within 72 hours of the initial results. For AEs associated with laboratory 
abnormalities, the event should be graded based on the clinical severity in the context of the 
underlying conditions, which may or may not agree with the grading of the laboratory 
abnormality. 
Any questions regarding toxicity management should be directed to the medical monitor or 
designee.
7.7.4.
Lipid Management
7.7.4.1.
Triglycerides
If a participant has fasting serum triglycerides > 250 mg/dL during screening, management of 
hypertriglyceridemia may be initiated and/or modified at investigator discretion in accordance 
with standard of care as described below. Repeat testing may be performed during the screening 
window after triglyceride management. Prior to Day 1, fasting serum triglycerides must be 
confirmed to be ≤ 250 mg/dL for the participant to be eligible for the study.
Standard of care management of hypertriglyceridemia includes, but is not limited to, lifestyle 
counseling and treatment with a fibrate (eg, FENO), and/or VAS, and/or a statin. In the Phase 2 
Study GS-US-384-3914, FENO 145 mg once daily was well tolerated and mitigated increases in 
serum triglycerides in participants with NASH treated with CILO+FIR (Section 1.5.2.1.1).
On-treatment elevations of fasting serum triglycerides > 500 mg/dL should be confirmed on 
repeat testing as soon as possible, preferably within 48 hours, and all study drugs should be 
withheld upon confirmation of levels > 500 mg/dL. In these cases, to manage observed 
triglyceride elevations, participants may initiate or dose escalate (if possible) fibrate therapy. 
Participants may resume study drug if fasting serum triglycerides are subsequently confirmed to 
be < 250 mg/dL after at least 2 weeks of fibrate therapy, if deemed safe in the opinion of the 
investigator. If after resumption of study drugs, serum triglycerides are again confirmed 
> 500 mg/dL and the participant is already on a maximal dose of fibrate, the participant must 
discontinue study drugs permanently (Section 3.5).

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Treatment with statins may be associated with muscle injury (ie, myopathy); this risk is 
increased in participants concurrently treated with a fibrate. If a participant is receiving treatment 
with both a fibrate and a statin, serum CK should be measured at study visits and appropriate 
clinical evaluation, including interruption of statin therapy, should be initiated if muscle injury is 
suspected {Brewster 2007, Kashani 2006, Rosenson 2017}. Myopathy should be considered in 
any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of 
serum CK. Participants should be advised to promptly report unexplained muscle pain, 
tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and 
symptoms persist after interruption of statin therapy.
Any questions regarding triglyceride management, including management of suspected 
myopathy, should be directed to the medical monitor or designee.
7.7.4.2.
Low-Density Lipoprotein Cholesterol
If at any time while on treatment, a participant has a persistent increase above baseline in fasting 
serum LDL cholesterol, initiation or dose modification of a statin (or other lipid lowering 
medication), should be considered. Questions regarding LDL changes and considerations of lipid 
modifying therapy should be directed to the medical monitor or designee. Appendix 11.8 
presents recommendations from academic societies on assessing cardiovascular risk that may be 
used to guide management.
7.7.5.
Pruritus Management 
The development or worsening of pruritus during the study is a consideration for participants 
with liver disease. Management of pruritus may include nonpharmacologic interventions 
(eg, skin moisturization, minimized heat exposure, avoidance of skin irritants, scratch reduction), 
oral antihistamines, and/or bile acid sequestrants. Bile acid sequestrants must be taken more than 
4 hours before or after oral study drug dosing, as described in Table 4. Administration of oral 
study drug with a light-fat meal may also be beneficial. 
7.7.6.
Child-Pugh Score
If a participant has an increase in their CP score to > 6, this should be confirmed with repeat 
testing as soon as possible, preferably within 72 hours. If confirmed, and an etiology for these 
findings other than progressive liver disease cannot be identified (eg, therapeutic 
anticoagulation), the participant must discontinue study drug (Section 3.5).
7.7.7.
MELD Score
If a participant has an increase in their MELD score to > 12, this should be confirmed with repeat 
testing, preferably within 72 hours. If confirmed, and an etiology for these findings other than 
progressive liver disease cannot be identified (eg, therapeutic anticoagulation), the participant 
must discontinue study drug (Section 3.5).

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STATISTICAL CONSIDERATIONS 
Final 
Amendment2 
This section provides a high-level description of the planned analyses, assessed statistical power 
with assumptions, and any applicable multiplicity adjustments. Additional details of the 
statistical methods will be provided in the statistical analysis plan, including any deviations from 
the original statistical analyses planned. 
8.1. 
Analysis Objectives and Endpoints 
Objectives are listed in Section 2. Endpoints are listed in Section 3.1 
8.1.1. 
Analysis Objectives 
The primaiy objective of this study is as follows: 
• 
To evaluate whether the combination of SEMA with the FDC of CILO/FIR causes fibrosis 
improvement in pa1ticipants with compensated cnThosis due to NASH as compared with 
placebo 
The secondaiy objectives of this study ai·e as follows: 
• 
To confnm the contribution of CILO/FIR to fibrosis improvement in pa1ticipants treated with 
the combination of SEMA and CILO/FIR by comparing with paiticipants treated with SEMA 
alone 
• 
To evaluate whether the combination of SEMA with the FDC of CILO/FIR causes NASH 
resolution ( defined as lobular inflammation of O or 1 and hepatocellular ballooning of 0) in 
paiticipants with compensated cnThosis due to NASH, as compared with placebo 
• 
To confnm the contribution of SEMA to NASH resolution in paiticipants treated with the 
combination of SEMA and CILO/FIR by compai·ing with paiticipants treated with CILO/FIR 
alone 
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I 
I 
I 
I 
I 
I 
8.1.2. 
8.1.2.1. 
Endpoints 
Prima1y Endpoint 
The primaiy endpoint is: 
Final 
Amendment2 
• 
I-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH ( defined as a~ I-point increase in hepatocellular ballooning or lobular 
inflammation) at Week 72 in the SEMA+cILO/FIR versus placebo groups 
8.1.2.2. 
Secondaiy Endpoints 
The secondaiy endpoints of this study ai·e as follows: 
• 
I-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH at Week 72 in SEMA+CILO/FIR versus pa1ticipants treated with 
SEMAalone 
• 
NASH resolution ( defined as lobulai· inflammation of O or 1 and hepatocellular ballooning 
of 0) at Week 72 in the SEMA+CILO/FIR versus placebo groups 
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NASH resolution at Week 72 in SEMA +CILO/FIR versus participants treated with 
CILO/FIR alone 
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8.2.
Planned Analyses
8.2.1.
Final Analysis
The final analysis will be performed at Week 72, after all participants have completed the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized. The analysis of the primary endpoint defined in Section 8.1.2.1 will 
be conducted at the time of the final analysis and will be tested at the 2-sided 0.05 significance 
level (Figure 6).
8.2.2.
Multiplicity Adjustments
The multiple testing strategy for the primary endpoint and the secondary endpoints is described 
below and presented graphically in Figure 6. 
Figure 6.
Multiple Testing Strategy
CILO = cilofexor (GS-9674); firsocostat = FIR (GS-0976); NASH = nonalcoholic steatohepatitis; SEMA = semaglutide
/' Primary Endpoint: Overall Effect of ' 
Fibrosis Improvement without 
Worsening of NASH: 
SEMA+CILO/FIR vs Placebo 
'-
P < 0.05? 
Yes 
/ 
Cl LO/FIR Contribution to Fibrosis ' 
Improvement without Worsening 
of NASH: 
SEMA+CILO/FIR vs SEMA 
'-
P < 0.05? 
Yes 
/ 
\ 
Overall Effect of NASH Resolution: 
SEMA+CILO/FIR vs Placebo 
P < 0.05? 
'-
Yes 
/ 
'\ 
SEMA Contribution to NASH 
Resolution: 
SEMA+CILO/FIR vs CILO/FIR 
P < 0.05? 
'-

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The family-wise type I error rate (FWER) will be controlled through the following sequential 
testing procedure at a 2-sided significance level of 0.05 (equivalent to 1-sided 0.025).
First, the primary endpoint will be tested at a 2-sided significance level of 0.05. The primary 
objective will be considered achieved if the superiority of SEMA+CILO/FIR versus placebo for 
the primary endpoint as described below is met.
1) The overall effect of the primary histologic efficacy endpoint of fibrosis improvement 
without worsening of NASH will be compared between the SEMA+CILO/FIR and placebo 
groups at Week 72 at a 2-sided significance level of 0.05. Superiority of SEMA+CILO/FIR 
versus placebo will be demonstrated through the test of the null hypothesis of equal 
responder proportions against the alternative hypothesis of a higher proportion in the 
SEMA+CILO/FIR group.
If the primary objective is achieved, the secondary efficacy endpoints will be tested sequentially 
in the following order at a 2-sided significance level of 0.05. If superiority is achieved for a 
secondary endpoint, the next secondary endpoint will be evaluated; otherwise, testing of the 
remaining secondary endpoint(s) will cease.
1) The contribution of CILO/FIR to fibrosis improvement ≥ 1-stage without worsening of 
NASH will be evaluated by comparing the SEMA+CILO/FIR and SEMA groups for this 
endpoint at a 2-sided significance level of 0.05. Superiority of SEMA+CILO/FIR versus 
SEMA will be demonstrated through the test of the null hypothesis of equal responder 
proportions against the alternative hypothesis of a higher proportion in the SEMA+CILO/FIR 
group.
2) The overall effect of NASH resolution will be compared between the SEMA+CILO/FIR and 
placebo groups at Week 72 at a 2-sided significance level of 0.05. Superiority of 
SEMA+CILO/FIR versus placebo will be demonstrated through the test of the null 
hypothesis of equal responder proportions against the alternative hypothesis of a higher 
proportion in the SEMA+CILO/FIR group. 
3) The contribution of SEMA to NASH resolution will be evaluated by comparing the 
SEMA+CILO/FIR and CILO/FIR groups for this endpoint at a 2-sided significance level of 
0.05. Superiority of SEMA+CILO/FIR versus CILO/FIR will be demonstrated through the 
test of the null hypothesis of equal responder proportions against the alternative hypothesis of 
a higher proportion in the SEMA+CILO/FIR group.

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8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Full Analysis set (FAS) which includes 
all participants who were randomized into the study and received at least 1 dose of study drug.
Participants who receive study drug other than that to which they were randomized will be 
analyzed according to the treatment group to which they were randomized.
8.3.1.2.
Safety
The primary analysis set for safety analyses will include all participants who received at least 
1 dose of study drug. Participants who received study drug other than that to which they were 
randomized will be analyzed according to the study drug received. All data collected during 
treatment plus 35 days after last dose of study drug will be included in the safety summaries.
8.3.1.3.
Pharmacokinetics
The PK Analysis Set includes concentration data from the single samples drawn at each visit.
The PK Analysis Set will include all randomized participants who took at least 1 dose of study 
drug and for whom concentration data of analytes CILO, FIR, and their respective metabolites, 
as applicable, are available. The PK Analysis Set will be used for analyses of population PK.
8.3.1.4.
Biomarkers
The Biomarker Analysis Set will include data from participants in the Safety Analysis Set who 
have the necessary baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest.
8.3.2.
Data Handling Conventions
Participants with missing data on the primary, secondary, and 
 at 
Week 72 will be imputed using reference-based multiple imputation method. The handling of 
intercurrent events for the primary, secondary, and 
 
 
Where appropriate, safety data for participants who did not complete the study will be included 
in summary statistics. For example, if a participant received study drug, the participant will be 
included in a summary of AEs according to the treatment received; otherwise, if the participant is 
not dosed then they will be excluded from the summary. If safety laboratory results for a 
participant are missing for any reason at a time point, the participant will be excluded from the 
calculation of summary statistics for that time point. If the participant has no available value 
before the first dosing time, then the participant will be excluded from the calculation of 
summary statistics for the predose value and the change from predose values.
CCI
CCI

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Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. 
Values for missing vital signs data (except for body weight and blood pressure) will not be 
imputed; however, a missing baseline result will be replaced with a screening result, if available.
8.4.
Demographic and Baseline Characteristics Analysis
Demographic and baseline measurements will be summarized using standard descriptive 
methods. Demographic summaries will include sex, race/ethnicity, age, body weight, height, and 
BMI.
Baseline data will include a summary of randomization stratification groups (presence or absence 
of diabetes; ELF score ≥ 11.30 or < 11.30), and other disease characteristic variables. 
Any discrepancies between the IRT randomization stratification groups and the group assigned 
based on data entered in the database will be listed. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The following hybrid estimand of composite and treatment policy strategies (Table 7) will be 
used as the primary estimand for the primary histologic endpoint. Treatment policy strategy will 
be used to handle all intercurrent events except all-cause mortality and any liver-related clinical 
events that occur prior to the Week 72 liver biopsy, which will be handled by a composite 
strategy.

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Table 7.
Estimand Strategy for Primary Histologic Endpoint
Primary Endpoint
Hybrid Composite/Treatment Policy Strategy
Population
All participants in the FAS as defined in Section 8.3.1.1 who had nonmissing baseline 
fibrosis (only for the primary outcome below) and NAS components used in the 
definition of the endpoints.
Patient-level outcomes 
to be measured
A binary response of ≥ 1-stage fibrosis improvement without worsening of NASH 
(defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation) 
at Week 72 in the SEMA+CILO/FIR vs placebo groups based on the reading of 
baseline and postbaseline biopsies by the central pathologists.
Measure of intervention 
effect and handling of 
intercurrent events
Composite policy estimand: participants who experienced a liver-related clinical 
eventa or died due to any cause (all-cause mortality) prior to the Week 72 liver biopsy 
are assumed to be nonresponders for the primary endpoint.
Treatment policy estimand: the value of outcome measure is used regardless of the 
occurrence of intercurrent events other than death or a liver-related clinical eventa 
prior to the Week 72 liver biopsy (ie, dose interruption/reduction, protocol deviation, 
or premature study drug discontinuation).
Population level 
summary measure
Difference in proportions of ≥ 1-stage fibrosis improvement without worsening of 
NASH responders between SEMA+CILO/FIR and placebo groups. 
Main estimators
A stratified Mantel-Haenszel test will be used to compare the difference in proportions 
of participants who meet the primary endpoint at Week 72 between SEMA+CILO/FIR 
and placebo, adjusting for baseline diabetes status and ELF score (≥ 11.30 or < 11.30). 
Participants who experienced a liver-related clinical event or died due to any cause 
(all-cause mortality) prior to the Week 72 liver biopsy are considered nonresponders. 
Participants who had missing data at Week 72 due to reasons other than death or a 
liver-related clinical eventa will be handled by reference-based imputation, ie, a 
method of multiple imputation that is informed by data from placebo participants. It is 
thereby assumed that participants in either treatment group without an observed 
outcome have the same chances of meeting the endpoint as participants in the placebo 
group with an observed outcome. 
CILO = cilofexor (GS-9674); ELF = enhanced liver fibrosis; FAS = Full Analysis Set; FIR = firsocostat (GS-0976); MELD = 
Model for End-Stage Liver Disease; NAS = nonalcoholic fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; 
SEMA = semaglutide
a
Liver-related clinical events include evidence of progression to decompensated cirrhosis, liver transplantation, or 
qualification for liver transplantation on basis of MELD score (Section 7.1.4.3).
8.5.2.
Secondary Analyses
The same estimand strategy as described for the primary endpoint will be used for the secondary 
endpoints. To demonstrate the contribution of CILO/FIR to fibrosis improvement without 
worsening of NASH, Table 8 describes the estimand strategy for the secondary endpoint of 
≥ 1-stage fibrosis improvement without worsening of NASH at Week 72 in the 
SEMA+CILO/FIR versus SEMA groups.

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Table 8. 
Estimand Strategy for Secondary Endpoint 1: Fibrosis Improvement 
Without Worsening of NASH at Week 72 in the SEMA+CILO/FIR 
Versus SEMA Groups
Secondary Endpoint 1
Hybrid Composite/Treatment Policy Strategy
Population
All participants in the FAS as defined in Section 8.3.1.1 who had nonmissing baseline 
fibrosis and NAS components used in the definition of the endpoints.
Patient-level outcomes 
to be measured
A binary response of ≥ 1-stage fibrosis improvement without worsening of NASH at 
Week 72 in the SEMA+CILO/FIR vs SEMA groups, based on the reading of baseline 
and postbaseline biopsies by the central pathologists.
Measure of intervention 
effect and handling of 
intercurrent events
Composite policy estimand: participants who experienced a liver-related clinical 
eventa or died due to any cause (all-cause mortality) prior to the Week 72 liver biopsy 
are assumed to be nonresponders for the secondary endpoint.
Treatment policy estimand: The value of outcome measure is used regardless of the 
occurrence of intercurrent events other than death or a liver-related clinical eventa 
prior to the Week 72 liver biopsy (ie, dose interruption/reduction, protocol deviation, 
or premature study drug discontinuation).
Population level 
summary measure
Difference in proportions of ≥ 1-stage fibrosis improvement without worsening of 
NASH responders between the SEMA+CILO/FIR and SEMA groups.
Main estimators
A stratified Mantel-Haenszel test will be used to compare the difference in proportions 
of participants who meet fibrosis improvement without worsening of NASH at 
Week 72 between the SEMA+CILO/FIR and SEMA groups, adjusting baseline 
diabetes status and ELF score (≥ 11.30 or < 11.30). Participants who experienced a 
liver-related clinical event or died due to any cause (all-cause mortality) prior to the 
Week 72 liver biopsy are considered nonresponders. Participants who had missing 
data at Week 72 due to reasons other than death or a liver-related clinical eventa will 
be handled by reference-based imputation. 
CILO = cilofexor (GS-9674); ELF = enhanced liver fibrosis; FAS = Full Analysis Set; FIR = firsocostat (GS-0976); MELD = 
Model for End-Stage Liver Disease; NAS = nonalcoholic fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; 
SEMA = semaglutide
a
Liver-related clinical events include evidence of progression to decompensated cirrhosis, liver transplantation, or 
qualification for liver transplantation on basis of MELD score (Section 7.1.4.3).
To evaluate the overall effect of NASH resolution, Table 9 describes the estimand strategy for 
the secondary endpoint of NASH resolution at Week 72 in the SEMA+CILO/FIR versus placebo 
groups.

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Table 9. 
Estimand Strategy for Secondary Endpoint 2: NASH Resolution at 
Week 72 in the SEMA+CILO/FIR Versus Placebo Groups
Secondary Endpoint 2
Hybrid Composite/Treatment Policy Strategy
Population
All participants in the FAS as defined in Section 8.3.1.1 who had nonmissing baseline 
NAS components used in the definition of the endpoints.
Patient-level outcomes 
to be measured
A binary response of NASH resolution (defined as lobular inflammation of 0 or 1 and 
hepatocellular ballooning of 0) at Week 72 in the SEMA+CILO/FIR vs placebo 
groups, based on the reading of baseline and postbaseline biopsies by the central 
pathologists.
Measure of intervention 
effect and handling of 
intercurrent events
Composite policy estimand: experienced a liver-related clinical eventa or died due to 
any cause (all-cause mortality) prior to the Week 72 liver biopsy are assumed to be 
nonresponders for the secondary endpoint.
Treatment policy estimand: the value of outcome measure is used regardless of the 
occurrence of intercurrent events other than death or a liver-related clinical eventa 
prior to the Week 72 liver biopsy (ie, dose interruption/reduction, protocol deviation, 
or premature study drug discontinuation).
Population level 
summary measure
Difference in proportions of NASH resolution responders between SEMA+CILO/FIR 
and placebo groups.
Main estimators
A stratified Mantel-Haenszel test will be used to compare the difference in proportions 
of participants who meet NASH resolution at Week 72 between SEMA+CILO/FIR 
and placebo, adjusting for baseline diabetes status and ELF score (≥ 11.30 or < 11.30). 
Participants who experienced a liver-related clinical event or died due to any cause 
(all-cause mortality) prior to the Week 72 liver biopsy are considered nonresponders. 
Participants who had missing data at Week 72 due to reasons other than death or a 
liver-related clinical eventa will be handled by reference-based imputation. 
CILO = cilofexor (GS-9674); ELF = enhanced liver fibrosis; FAS = Full Analysis Set; FIR = firsocostat (GS-0976); MELD = 
Model for End-Stage Liver Disease; NAS = nonalcoholic fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; 
SEMA = semaglutide
a
Liver-related clinical events include evidence of progression to decompensated cirrhosis, liver transplantation, or 
qualification for liver transplantation on basis of MELD score (Section 7.1.4.3).
To demonstrate the contribution of SEMA to NASH resolution, Table 10 describes the estimand 
strategy for the secondary endpoints of NASH resolution at Week 72 in the SEMA+CILO/FIR 
versus CILO/FIR groups.

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Table 10.
Estimand Strategy for Secondary Endpoint 3: NASH Resolution at 
Week 72 in the SEMA+CILO/FIR Versus CILO/FIR Groups
Secondary Endpoint 3
Hybrid Composite/Treatment Policy Strategy
Population
All participants in the FAS as defined in Section 8.3.1.1 who had nonmissing baseline 
NAS components used in the definition of the endpoints.
Patient-level outcomes 
to be measured
A binary response of NASH resolution at Week 72 in the SEMA+CILO/FIR vs 
CILO/FIR groups, based on the reading of baseline and postbaseline biopsies by the 
central pathologists.
Measure of intervention 
effect and handling of 
intercurrent events
Composite policy estimand: experienced a liver-related clinical eventa or died due to 
any cause (all-cause mortality) prior to the Week 72 liver biopsy are assumed to be 
nonresponders for the secondary endpoint.
Treatment policy estimand: the value of outcome measure is used regardless of the 
occurrence of intercurrent events other than death or a liver-related clinical eventa 
prior to the Week 72 liver biopsy (ie, dose interruption/reduction, protocol deviation, 
or premature study drug discontinuation).
Population level 
summary measure
Difference in proportions of NASH resolution responders between SEMA+CILO/FIR 
and CILO/FIR groups.
Main estimators
A stratified Mantel-Haenszel test will be used to compare the difference in proportions 
of participants who meet NASH resolution at Week 72 between SEMA+CILO/FIR 
and CILO/FIR, adjusting for baseline diabetes status and ELF score (≥ 11.30 
or < 11.30). Participants who experienced a liver-related clinical event or died due to 
any cause (all-cause mortality) prior to the Week 72 liver biopsy are considered 
nonresponders. Participants who had missing data at Week 72 due to reasons other 
than death or a liver-related clinical eventa will be handled by reference-based 
imputation. 
CILO = cilofexor (GS-9674); ELF = enhanced liver fibrosis; FAS = Full Analysis Set; FIR = firsocostat (GS-0976); MELD = 
Model for End-Stage Liver Disease; NAS = nonalcoholic fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; 
SEMA = semaglutide
a
Liver-related clinical events include evidence of progression to decompensated cirrhosis, liver transplantation, or 
qualification for liver transplantation on basis of MELD score (Section 7.1.4.3).
8.5.3.
Sensitivity Analysis
Sensitivity analyses on the primary and secondary histologic endpoints will be described in the 
statistical analysis plan. 

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8.6. 
Safety Analysis 
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Safety will be assessed during the study through the reporting of AEs, clinical laborato1y tests, 
and vital sign assessments at various time points during the study. Concomitant medication usage 
will also be assessed throughout the study. 
All safety data collected on or after the date that study drng was first administered up to the date 
of last dose of study drng plus 3 5 days will be summarized by treatment group ( according to the 
study drng received). Data for the pretreatment will be included in data listings if applicable. In 
addition to cumulative incidence propo1iions, exposure-adjusted incidence rates will be provided 
for GI and prnritus-related AEs, as well as selected AEs of special interest (as described in 
Section 7.1.3). 
8.6.1. 
Extent of Exposure 
A paiiicipant's extent of exposure to study drng data will be generated from the study drng 
administration data. Exposure data will be summai·ized by treatment group. 
8.6.2. 
Adverse Events 
Clinical and laborato1y AEs will be coded using the MedDRA. System organ class (SOC), high-
level group te1m, high-level tenn, PT, and lower-level te1m will be attached to the clinical 
database. Adverse event severity will be graded using the CTCAE. 
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Events will be summarized on the basis of the date of onset for the event. Treatment-emergent 
adverse events (TEAEs) will be defined as 1 or both of the following:
•
Any AEs with an onset date on or after the study drug start date and no later than 35 days 
after permanent discontinuation of study drug
•
Any AEs leading to premature discontinuation of study drug
Summaries (number and percentage of participants) of TEAEs by SOC and PT will be provided 
by treatment group. Treatment-emergent adverse events will also be summarized by relationship 
to study drug and severity. In addition, TEAEs leading to premature discontinuation of study 
drug and study will be summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no). 
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum) by treatment group and study visit along with the corresponding 
change from baseline values 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE. 
The incidence of treatment-emergent laboratory abnormalities, defined as values that increase at 
least 1 toxicity grade from baseline at any time after baseline up to and including the date of last 
dose of study drug plus 35 days, will be summarized by treatment group. If baseline data are 
missing, any graded abnormality (ie, at least a Grade 1) will be considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the participant has 
been discontinued from treatment for at least 35 days will be included in a data listing.
8.6.4.
Other Safety Evaluations
Vital sign measurements and 12-lead ECG will be summarized by treatment group and listed by 
participant.
8.7.
Pharmacokinetic Analysis 
Plasma concentrations of CILO, FIR, and their respective metabolites, as applicable, will be 
listed, if available. Data from this study may be combined with data from other studies in a 
population PK meta-analysis. 

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Biomarker Analysis 
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Descriptive statistics of biomarker results and change from baseline will be provided at each 
sampling time by dose group. Point estimates and 95% Cls may be calculated. 
8.9. 
Sample Size 
The power calculation is based on the estimated propo1tions of paiticipants in the 
SEMA+CILO/FIR group to achieve the prima1y endpoint at Week 72 as compared with the 
placebo group. Assuming the proportion of paiticipants in the SEMA+cILO/FIR and placebo 
groups to achieve fibrosis improvement ~ I-stage without worsening of NASH at Week 72 is 
35% and 12%, respectively, with a sample size of 120 paiticipants in the SEMA+CILO/FIR 
group and 80 pa1ticipants in the placebo group, the study has 97% power to detect a difference at 
a 2-sided significance level of 0.05. 
If the primaiy endpoint is achieved, the contribution of CILO/FIR to fibrosis improvement 
I-stage without worsening of NASH will be evaluated by compai·ing the SEMA+CILO/FIR 
and SEMA groups for this endpoint. Assuming the propo1tion of paiticipants to achieve 
I-stage fibrosis improvement without worsening of NASH at Week 72 is 35% and 20% in the 
SEMA+CILO/FIR and SEMA groups, respectively, with a sample size of 120 paiticipants in 
each group, the study has 74% power to detect a difference at a 2-sided significance level of 
0.05. 
If the contribution of CILO/FIR to fibrosis improvement ~ I-stage without worsening of NASH 
is demonstrated, the overall effect of NASH resolution will be evaluated by compai·ing the 
SEMA+CILO/FIR versus placebo groups. Assuming the propo1tion of paiticipants in the 
SEMA+CILO/FIR and placebo groups to achieve NASH resolution at Week 72 is 45% and 10%, 
respectively, the study has > 99% power to detect a difference at a 2-sided significance level of 
0.05. 
If the superiority of SEMA +CILO/FIR versus placebo for the overall effect of NASH resolution 
is achieved, the contribution of SEMA to NASH resolution will be evaluated by compai·ing the 
SEMA+CILO/FIR and CILO/FIR groups for this endpoint. Assuming the propo1tion of 
paiticipants to achieve NASH resolution at Week 72 is 45% and 15% in the SEMA+CILO/FIR 
and CILO/FIR groups, respectively, with a sample size of 120 pa1ticipants in each group, the 
study has 99% power to detect a difference at a 2-sided significance level of 0.05. 
The power calculations described above ai·e based on Peai·son's chi-squai·e test using a nonnal 
approximation. 
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8.10.
Data Monitoring Committee
An external DMC that consists of 2 hepatologists and a statistician will review the progress of 
the study, perform interim, and as necessary, ad hoc reviews of safety data, and provide 
recommendation to Gilead whether the nature, frequency, and severity of AEs associated with 
study treatment warrant the early termination of the study in the best interests of the participants, 
whether the study should continue as planned, or whether the study should continue with 
modifications. 
The DMC will convene after at least 55 participants have completed their Week 4 visit and 
approximately every 6 months thereafter to monitor the study for safety events.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, and meeting schedule.
In the course of ongoing safety monitoring, if at any point any of the below criteria are met, an 
urgent meeting of the DMC will be held to determine whether the study should proceed as 
planned, proceed with modification, or be terminated:
•
≥ 2 participants develop CTCAE Grade 4 pancreatitis (life threatening) deemed related to 
study drug(s) by the investigator
•
≥ 2 participants develop the same CTCAE Grade 4 unexpected AE (by PT) deemed related to 
study drug(s) by the investigator
•
Any participant develops a CTCAE Grade 5 unexpected AE (death) deemed related to study 
drug(s) by the investigator
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.

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9.
INVESTIGATOR RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (ICH) E6(R2) addendum to its guideline for GCP and applicable laws and 
regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with sponsor or proprietary interests in the study drug during 
the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree 
to notify sponsor of any change in reportable interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date when the last participant 
completes the protocol-defined activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study participant activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the participant after initial IRB/IEC approval, with the exception of those necessary 
to reduce immediate risk to study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB- or IEC-approved ICF for documenting written informed consent. 
Each ICF (or assent as applicable) will be appropriately signed and dated by the participant or 
the participant’s legally authorized representative, the person conducting the consent discussion, 
and an impartial witness (if required by IRB or IEC or local requirements). 

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9.1.5. 
Confidentiality 
Final 
Amendment2 
The investigator must ensure that paiiicipants' anonymity will be strictly maintained and that 
their identities are protected from unauthorized paiiies. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of bi1ih) will be recorded on any fo1m 
or biological sample submitted to Gilead, IRB, IEC, or the laborato1y. Laborato1y specimens 
must be labeled in such a way as to protect paiiicipant identity while allowing the results to be 
recorded to the proper pa1i icipant. Refer to specific laborato1y instructions. Note: the investigator 
must keep a screening log with details for all pa1i icipants screened and emolled in the study, in 
accordance with the site procedures and regulations. Paiiicipant data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
IB, this protocol, CRFs/eCRFs, study dmg info1mation, and any other study info1mation, remain 
the sole and exclusive prope1iy of Gilead during the conduct of the study and thereafter. This 
info1mation is not to be disclosed to any third paiiy ( except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator fmi her agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third pa1iy or othe1wise into the 
public domain. 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator's study file and 
(2) paiiicipant clinical source documents. 
The investigator's study file will contain the protocol/amendments, CRFs/eCRFs, IB, IEC, and 
governmental approval with con espondence, the ICF(s), diug records, staff cmTiculum vitae and 
authorization fo1ms, and other appropriate documents and conespondence. 
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The required source data should include sequential notes containing at least the following 
information for each participant:
•
Participant identification
•
Documentation that participant meets eligibility criteria, ie, medical history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion criteria)
•
Documentation of the reason(s) a consented participant is not enrolled
•
Participation in study (including study number)
•
Study discussed and date of informed consent
•
Dates of all visits
•
Documentation that protocol-specific procedures were performed
•
Results of efficacy parameters, as required by the protocol
•
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return
•
Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE
•
Concomitant medication (start and end date; dose if relevant; dose changes)
•
Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator for at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 

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in case of an inspection. When source documents are required for the continued care of the 
participant, appropriate copies should be made for storage away from the site.
9.1.7.
Case Report Forms
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the EDC system unless otherwise directed. The eCRF casebook 
will only capture the data required per the protocol schedule of events and procedures, unless 
collected by a nonelectronic data capture vendor system (eg, central laboratory). 
The Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility are available. Data entry should be performed in accordance with the case 
report form Completion Guidelines provided by the sponsor. Subsequent to data entry, a study 
monitor may perform source data verification. System-generated or manual queries will be 
issued in the EDC system as data discrepancies are identified by the study monitor or Gilead 
personnel who routinely review the data for completeness, correctness, and consistency. The site 
investigator, site coordinator, or other designee is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the 
original entry, and providing the reason for the update (eg, data entry error). Original entries as 
well as any changes to data fields will be stored in the audit trail of the system. Regular oversight 
by the principal investigator of the data entered into the EDC system is expected to occur on an 
ongoing basis throughout the study to ensure quality and completeness. At a minimum, before 
any interim, final, or other time points (as instructed by Gilead), the investigator will apply 
his/her electronic signature to confirm that the forms have been reviewed and that the entries 
accurately reflect the information in the source documents. At the conclusion of the study, Gilead 
will provide the site investigator with a read-only archive copy of the data entered. This archive 
must be stored in accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigator Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Gilead. The investigator must submit all protocol modifications to the IRB 
or IEC in accordance with local requirements and receive documented IRB or IEC approval 
before modifications can be implemented.

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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) when 
applicable and in accordance with local regulatory requirements. Gilead will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. For 
studies with sites in countries following the EU Regulation No. 536/2014, a CSR will be 
submitted within 1 year (6 months for pediatric studies, in accordance with Regulation [EC] 
No. 1901/2006) after the global end of study (as defined in Section 3.6).
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical study agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any participant records needed to 
verify the entries in the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on-site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the medical monitor or designee immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead access to records, facilities, 
and personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Termination
Both Gilead and the investigator (for their clinical site) reserve the right to terminate the study at 
any time. Should this be necessary, both parties will arrange discontinuation procedures and 
notify the participants, appropriate regulatory authority(ies), and IRB or IEC. In terminating the 
study, Gilead and the investigator will ensure that adequate consideration is given to the 
protection of the participants’ interests.

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10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic 
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
American college of Cardiology. ASCVD Risk Estimator Plus. 2023:
American Diabetes Association. 5. Facilitating Behavior Change and Well-being to Improve 
Health Outcomes: Standards of Medical Care in Diabetes-2020. Diabetes care 
2020a;43 (Suppl 1):S48-S65.
American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes-2020. Diabetes care 2020b;43 (Suppl 
1):S98-S110.
Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et 
al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-
term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology 2015;149 (2):389-97 e10.
Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 
ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A 
Report of the American College of Cardiology/American Heart Association Task 
Force on Clinical Practice Guidelines. Circulation 2019;140:e596-e646.
Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, et al. Acetyl-CoA 
Carboxylase Inhibition Disrupts Metabolic Reprogramming During Hepatic 
Stellate Cell Activation [Journal Pre-Proof]. J Hepatol 2020.
Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the 
general population: implications for statin therapy. American heart journal 
2007;154 (4):655-61.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of Fatty 
Acids Stored in Liver and Secreted Via Lipoproteins in Patients with 
Nonalcoholic Fatty Liver Disease. J Clin Invest 2005;115 (5):1343-51.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up. Hepatology 2015;61 (5):1547-54.

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Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the Epidemic of Nonalcoholic 
Fatty Liver Disease Demonstrates an Exponential Increase in Burden of Disease. 
Hepatology 2018;67 (1):123-33.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, et al. Acetyl-CoA Carboxylase 
Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes 
Hypertriglyceridemia in Rodents [Accepted Article]. Hepatology 2018.
Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, et al. Risks Associated 
With Statin Therapy A Systematic Overview of Randomized Clinical Trials. 
Circulation 2006;114:2788-97.
Kim WR, Mannalithara A, Lee H, Osinusi AO, Aguilar Schall RE, Brainard DM. Survival 
Benefit of Direct‐Acting Antiviral Therapy in Patients with Decompensated 
Cirrhosis [Poster LB-27]. The Liver Meeting® 2017 - The 68th Annual Meeting 
of the American Association for the Study of Liver Diseases (AASLD); 2017 20-
24 October; Washington, D. C. 
Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased De Novo Lipogenesis Is a 
Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease. 
Gastroenterology 2014;146 (3):726-35.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation 
for estimating glomerular filtration rate. Ann Intern Med 2006;145 (4):247-54.
Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjaer MS, Krarup N, et al. Semaglutide 2.4 
mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a 
randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol 
2023;8 (6):511-22.
Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 Reduces 
Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver 
Disease. Gastroenterology 2018;155 (5):1463-73 e6.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 
2016;375 (19):1834-44.
Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate-Tracing Reveals 
Hepatic Stellate Cells As Dominant Contributors to Liver Fibrosis Independent of 
Its Etiology [Author Manuscript]. Nature communications 2013;4:2823.

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Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. 
Hepatology 2010;52 (2):774-88.
Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, et al. NASH Leading Cause of 
Liver Transplant in Women: Updated Analysis of Indications For Liver 
Transplant and Ethnic and Gender Variances. Am J Gastroenterol 2018;113 
(11):1649-59.
Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 
2007;11 (1):1-16, vii.
Patel K, Harrison SA, Elkashab M, Trotter JF, Herring R, Rojter S, et al. Cilofexor, a 
Nonsteroidal FXR Agonist, in Non-Cirrhotic Patients with Nonalcoholic 
Steatohepatitis: A Phase 2 Randomized Controlled Trial [Accepted]. Hepatology 
2020.
Rosenson RS, Miller K, Bayliss M, Sanchez RJ, Baccara-Dinet MT, Chibedi-De-Roche D, et al. 
The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): Revision for 
Clinical Use, Content Validation, and Inter-rater Reliability. Cardiovascular drugs 
and therapy / sponsored by the International Society of Cardiovascular 
Pharmacotherapy 2017;31:179-86.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy 
in chronic liver disease: 2014 Practice Guideline by the American Association for 
the Study of Liver Diseases and the European Association for the Study of the 
Liver. Hepatology 2014;60 (2):715-35.
Voulgari C, Tentolouris N, Papadogiannis D, Moyssakis I, Perrea D, Kyriaki D, et al. Increased 
left ventricular arrhythmogenicity in metabolic syndrome and relationship with 
myocardial performance, risk factors for atherosclerosis, and low-grade 
inflammation. Metabolism: clinical and experimental 2010;59 (2):159-65.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of 
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely 
middle-aged population utilizing ultrasound and liver biopsy: a prospective study. 
Gastroenterology 2011;140 (1):124-31.
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.

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Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of 
nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, 
incidence, and outcomes. Hepatology 2016;64 (1):73-84.

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11.
APPENDICES

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11.1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
CLINICAL STUDY PROTOCOL ACKNOWLEDGMENT
GS-US-454-6075: A Phase 2, Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of Semaglutide, and the 
Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Subjects 
With Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis (NASH)
Amendment 2, 26 October 2023
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Sr Director, Clinical Development
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD

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11.2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study. 
These risks can be summarized as follows:
1) Study drug supplies to participants and sites:
a) Participants may be unable to return to the site for a number of visits to get the study 
drug, or the site may be unable to accept any participant visits. Without study drugs, the 
participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: study drug supplies may be provided to the participant from the site 
without a clinic visit, once it is confirmed that the participant may safely continue on 
study drug as determined by the principal investigator (PI). A virtual study visit, via 
phone or video conferencing, must be performed prior to remote study drug resupply. At 
the earliest opportunity, the site will schedule in-person participant visits and return to the 
protocol’s regular schedule of assessments. A qualified courier may be utilized to ship the 
study drug from sites to study participants if permitted by local ethics committee 
(EC)/institutional review boards (IRB)/regulatory authority as applicable and with 
sponsor's approval.
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: the sites' study drug inventory should be closely monitored. Site staff 
should notify the sponsor or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. The sponsor will continue to monitor 
inventory at the study drug depot and study sites. Manual shipments will be triggered as 
necessary.
2) Participant safety monitoring and follow-up:
a) Participants may be unable or unwilling to come to the study site for their scheduled 
study visits as required per protocol.
Mitigation plan: for participants who may be unable or unwilling to visit the study site for 
their scheduled study visits as required per protocol, the PI or qualified delegate will 
conduct a virtual study visit, via phone or video conferencing, to assess the participant 
within target visit window date whenever possible. During the virtual study visit, the 
following information at minimum will be reviewed: 
i)
Confirm if participant has experienced any adverse events (AEs)/serious adverse 
events (SAEs)/special situations (including pregnancy) and follow-up on any 
unresolved AE/SAEs.

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ii) Review current list of concomitant medications and document any new concomitant 
medications.
iii) If applicable, confirm electronic diary questionnaires and PROs have been completed 
and transmitted.
iv) If applicable, confirm participants study drug supply is sufficient to last until the next 
planned visit date. If study drug resupply is needed it will be provided as described 
above in (1).
v) If applicable, remind participant to maintain current dosing and to keep all dispensed 
study drug kits for return at the next on-site visit.
b) Participants may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central laboratory analyses.
Mitigation plan: local laboratories may be utilized as appropriate to monitor participant 
safety until the participant can return to the site for their regular follow-up per protocol. 
Any laboratory assessments conducted at a local laboratory due to the pandemic will be 
documented accordingly and may be captured in the electronic data capture. Pregnancy 
testing may be performed using a home urine pregnancy test if local laboratory 
pregnancy testing is not feasible.
c) Participants may be unable or unwilling to attend the study visit to sign an updated 
informed consent form (ICF) version.
Mitigation plan: the site staff will follow their approved consent process and remain in 
compliance with local EC/IRB and national laws and regulations. Remote consent will be 
allowed if has been approved by the local EC/IRB. The consent process will be 
documented and confirmed by normal consent procedure at the earliest opportunity.
d) Participants may be at risk of potential worsening of diabetic retinopathy with 
semaglutide.
Mitigation plan: annual retinal examinations will be performed and interpreted by an 
ophthalmologist or optometrist, as recommended by the American Diabetes Association 
(ADA) guidelines (ADA Standards of Medical Care in Diabetes Guideline 11.16; ADA 
2020; Diabetes Care 2020 Jan; 43 (Supplement 1): S135-S151. 
https://doi.org/10.2337/dc20-S011).
3) Protocol and monitoring compliance:
a) Protocol deviations may occur, in case scheduled visits cannot occur as planned per 
protocol.
Mitigation plan: if it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 

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be recorded and explained as a protocol deviation. Any missed participant visits or 
deviation to the protocol due to the pandemic must be reported in the eCRF and described 
in the clinical study report (CSR). Any virtual study visits that are conducted in lieu of 
clinic visits due to the pandemic will be documented as a protocol deviation related to the 
pandemic.
b) Monitors may be unable to carry out source data review or source data verification 
(SDV), or study drug accountability or assess protocol and Good Clinical Practice 
compliance. This may lead to delays in SDV, an increase in protocol deviations, or under 
reporting of AEs.
Mitigation plan: the study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. The study monitor is to reference the Study 
Monitoring Plan for guidance on how to conduct a remote monitoring visit. The study 
staff is to save and document all relevant communication in the study files. The status of 
sites that cannot accept monitoring visits and/or participants on site, must be tracked 
centrally and updated on a regular basis.
4) Missing data and data integrity:
a) There may be an increased amount of missing data due to participants missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data.
Mitigation plan: implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with regulatory 
authorities’ guidance. Overall, the CSR will describe the impact of the pandemic on the 
interpretability of study data.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of participants who are 
enrolled in this study.
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of study drug(s) in study participants remains unchanged.

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11.3.
Marketing Authorization Status of Study Interventions
Study Intervention Name
Category
Authorized in ≥ 1 
Country 
Following EU 
Regulation No. 
536/2014
Authorized in ≥ 1 
ICH Country
Authorized by 
Swissmedic
CILO/FIR
Study drug
No
No
No
SEMA
Study drug
Yes
Yes
Yes
CILO = cilofexor (GS-9674); EU = European Union; FIR = firsocostat (GS-0976); ICH = International Council for 
Harmonisation; SEMA = semaglutide

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11.4.
West Haven Criteria
http://www.mdcalc.com/hepatic-encephalopathy-grades-stages/
Grade of Hepatic 
Encephalopathy
Description
Suggested Operative Criteria
Grade I
•
Trivial lack of awareness
•
Euphoria or anxiety
•
Shortened attention span
•
Impairment of addition or 
subtraction
•
Altered sleep rhythm
Despite oriented in time and space (see 
below), the patient appears to have some 
cognitive/behavioral decay with respect to his 
or her standard on clinical examination or to 
the caregivers
Grade II
•
Lethargy or apathy
•
Disorientation for time
•
Obvious personality change
•
Inappropriate behavior
•
Dyspraxia
•
Asterixis
Disoriented for time (at least 3 of the 
following are wrong: day of the month, day of 
the week, month, season, or year) ± the other 
mentioned symptoms
Grade III
•
Somnolence to semistupor
•
Responsive to stimuli
•
Confused
•
Gross disorientation
•
Bizarre behavior
Disoriented also for space (at least 3 of the 
following wrongly reported: country, state [or 
region], city, or place) ± the other mentioned 
symptoms
Grade IV
•
Coma
Does not respond even to painful stimuli
Adapted from {Vilstrup 2014}

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11.5.
Study Procedures Table
Screening
Day 1
Day 29
(Wk 4)
(± 3 d)
Day 57
(Wk 8)
(± 3 d)
Day 85
(Wk 12)
(± 3 d)
Day 113
(Wk 16)
(± 3 d)
Day 169
(Wk 24)
(± 3 d)
Day 253
(Wk 36)
(± 3 d)
Day 337
(Wk 48)
(± 3 d)
Day 421
(Wk 60)
(± 3 d)
Day 505
(Wk 72)
(−14 d)
ET
Follow
-up
(± 7 d)a
Written informed 
consent
X
Confirm eligibility 
X
X
Medical history 
X
Symptom-driven 
physical examination 
Xb
X
X
X
X
X
X
X
Xb
X
Xb
Xb
X
Assessment of ascites 
and hepatic 
encephalopathyc
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs including 
body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Hip and waist 
circumference 
X
X
X
X
X
X
X
Fundus examination
Xd
Xd
Xd
Xd,e
12-lead ECGf
X
X
Xe
Calculation of the CP 
and MELD scores
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver biopsyg
X
X
Xe
Abdominal ultrasound
X
X
X
X
Xh
FibroScan® 
X
X
X
X
Xh
PRO measures
Xi
X
X
X
Xe
Lifestyle counseling 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
Review of study drug 
dosing compliance 
X
X
X
X
X
X
X
X
X
X

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Screening
Day 1
Day 29
(Wk 4)
(± 3 d)
Day 57
(Wk 8)
(± 3 d)
Day 85
(Wk 12)
(± 3 d)
Day 113
(Wk 16)
(± 3 d)
Day 169
(Wk 24)
(± 3 d)
Day 253
(Wk 36)
(± 3 d)
Day 337
(Wk 48)
(± 3 d)
Day 421
(Wk 60)
(± 3 d)
Day 505
(Wk 72)
(−14 d)
ET
Follow
-up
(± 7 d)a
Counseling regarding 
adherence to study 
procedures
X
X
X
X
X
X
X
X
X
X
Participant fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry, 
hematology, and 
coagulation panelsk
X
X
X
X
X
X
X
X
X
X
X
X
X
Glycemic panel 
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
eGFR by MDRD
X
X
X
X
X
X
X
X
X
X
X
X
X
ELF test
X
X
X
X
X
X
Xe
SARS-CoV-2 RT-
PCR Testl
X
Pregnancy testingm
X
X
X
X
X
X
X
X
X
X
X
X
X
Follicle-stimulating 
hormonen
X
Single PK samplingo
X
X
X
X
X
X
Blood collection 
(biomarkers)
X
X
X
X
X
X
Xe
X
Urine collection 
(biomarkers)
X
X
X
X
X
X
Xe
X
Stool collection
(biomarkers)p
X
X
X
Urine drug screen
X
HIV-1, HBV, HCV 
serology
X

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Screening
Day 1
Day 29
(Wk 4)
(± 3 d)
Day 57
(Wk 8)
(± 3 d)
Day 85
(Wk 12)
(± 3 d)
Day 113
(Wk 16)
(± 3 d)
Day 169
(Wk 24)
(± 3 d)
Day 253
(Wk 36)
(± 3 d)
Day 337
(Wk 48)
(± 3 d)
Day 421
(Wk 60)
(± 3 d)
Day 505
(Wk 72)
(−14 d)
ET
Follow
-up
(± 7 d)a
CK = creatinine kinase; COVID-19 = coronavirus disease 2019; CP = Child-Pugh; CTCAE = Common Terminology Criteria for Adverse Events; d = days; ECG = 
electrocardiogram; eGFR = estimated glomerular filtration rate; ELF = enhanced liver fibrosis; ET = early termination; FSH = follicle-stimulating hormone; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HbA1c = hemoglobin A1c; HIV-1 = human immunodeficiency virus type 1; MDRD = Modification of Diet in Renal Disease equation; MELD = 
Model for End-Stage Liver Disease; PK = pharmacokinetic(s); PGIC = Patient Global Impression of Change; PRO = patient-reported outcome; RT-PCR = reverse transcriptase-
polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; Wk = week 
a
Participants will complete a follow-up visit 5 weeks after the Week 72 or ET visit.
b
Perform complete physical examination at screening visit only. See Appendix 11.9.1 for France-specific text.
c
Assessment is to be done in accordance with established standard practices at the site and if present, graded based on CTCAE or West Haven criteria (Appendix 11.4), 
respectively.
d
For participants with type 2 diabetes diagnosed prior to the date of the screening visit OR based on screening visit HbA1c ≥ 6.5%, participants must have no evidence of 
uncontrolled and potentially unstable retinopathy or maculopathy as determined by a fundoscopic examination performed starting 90 days prior to screening visit date through 
Day 1. If there has been worsening of the participant’s visual function since a historical fundoscopic examination in the opinion of the investigator, then the fundoscopic 
examination must be repeated prior to Day 1 for eligibility. Pharmacological pupil dilation is a requirement unless using a digital fundus photography camera specified for 
nondilated examination.
e
Assessments to be performed at the discretion of the investigator.
f
See Appendix 11.9.1 for France specific text.
g
Required for all participants at time of screening unless a qualifying liver biopsy is available per inclusion criterion 3. On-treatment liver biopsy required at Week 72. Early 
termination liver biopsy at the discretion of the investigator. 
.
h
Assessment to be performed at the ET visit, unless performed within 12 weeks prior to the ET visit.
i
PGIC Pain and Fatigue will not be assessed at Day 1.
j
Adverse events reporting during screening is limited to SAEs and adverse events related to study procedures.
k
If a participant is receiving treatment with both a fibrate and a statin, serum CK should be measured at study visits and appropriate clinical evaluation, including interruption 
of statin therapy, should be initiated if muscle injury is suspected.
l
For participants who have not completed a series of an authorized COVID-19 vaccination regimen prior to screening.
m
All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy testing will occur at Day 1 (prior to dosing) and on each treatment visit. 
Starting at the Week 4 visit, every 4 weeks (± 3 days) urine pregnancy testing may be performed at home in between clinic visits, where possible, or in clinic, if at home 
pregnancy tests are unavailable.
n
Serum FSH test (only for women who are < 54 years old and have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure)
o
Single PK sample at Week 4 (15 minutes to 3 hours postdose), Week 24 (anytime postdose), Week 48 (predose), Week 60 (15 minutes to 3 hours postdose), Week 72 
(predose), and ET visit (anytime). In cases where the unscheduled visit is performed for the primary purpose of safety evaluation (eg, SAE follow-up), collection of a single 
PK sample (anytime predose or postdose) is recommended. The timing of the PK sample in relation to the last dose of study drug should be documented. For PK sampling at 
Weeks 4, 48, 60, and 72, participants should be reminded not to take their oral study drug until advised to do so at their clinic visit.
p
Participants will be given a stool sample collection kit at the screening visit and Weeks 36 and 60. Stool sample collection should be completed by the participant in advance 
of the required study visits (Day 1 and Weeks 48 and 72).
q
CCI
CCI
CCI

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11.6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born participant is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal unless the 
participant is permanently sterile or has medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women < 54 years of age with amenorrhea of ≥ 12 months may also be considered 
postmenopausal if their follicle-stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female participant of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born participant is considered fertile after the initiation of 
puberty unless the participant is permanently sterile by bilateral orchidectomy or medical 
documentation.
2) Contraception Requirements for Female Participants
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Firsocostat (FIR; GS-0976) and semaglutide (SEMA) are contraindicated in pregnancy as a 
malformative effect has been demonstrated/suspected or is unknown taking into consideration 
class effect and/or strong suspicion of human teratogenicity/fetotoxicity in early pregnancy based 
on nonclinical data. Data from clinical pharmacokinetic (PK) interaction studies of FIR, 
cilofexor (CILO; GS-9674), and SEMA have demonstrated that there is no reduction in the 
clinical efficacy of hormonal contraception. 
Refer to the latest version of the respective investigator’s brochures (IBs) and Sections 1.2.2, 
1.3.2, and 1.4.2 of the protocol for additional information. 
b. Contraception Requirements for Female Participants of Childbearing Potential
The inclusion of female participants of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test at the Day 1 visit prior to 
randomization. Pregnancy tests will be performed at monthly intervals thereafter until the end of 
contraception requirement.

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Duration of required contraception for female participants in this clinical study should start from 
the screening visit until 8 weeks following the last dose of study drug.
Female participants must agree to 1 of the following contraceptive methods:
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle. 
Or
Consistent and correct use of 1 of the following methods of birth control listed below: 
•
Hormonal or nonhormonal intrauterine device 
•
Subdermal contraceptive implant*
•
Bilateral tubal occlusion (upon medical assessment of surgical success)
•
Vasectomy in the male partner (upon medical assessment of surgical success)
Or 
Female participants who wish to use a hormonally based method must use it in conjunction with 
a barrier method, preferably a male condom. Hormonal methods are restricted to those associated 
with the inhibition of ovulation. Hormone-based contraceptives and barrier methods permitted 
for use in this protocol are as follows:
•
Hormonal methods (each method must be used with a barrier method, preferably male 
condom)
Oral contraceptives (either combined or progesterone only)
Injectable progesterone*
Transdermal contraceptive patch*
Contraceptive vaginal ring*
•
Barrier methods (each method must be used with a hormonal method)
Male condom (with or without spermicide)
Female condom (with or without spermicide)
Diaphragm with spermicide*
Cervical cap with spermicide*

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Sponge with spermicide
*Not approved in Japan
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Female participants must also refrain from egg donation and in vitro fertilization during 
treatment and until the end of contraception requirement. If needed, female participants should 
be advised to seek advice about egg donation and cryopreservation of germ cells before 
treatment.
3)
Contraception Requirements for Male Participants
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a female partner from exposure of the male participant’s seminal fluid and poses a potential 
risk to an embryo/fetus. Therefore, male participants with female partners of childbearing 
potential must use condoms during treatment until 8 weeks after last dose of study drug. If the 
female partner of childbearing potential is not pregnant, additional contraception 
recommendations should also be considered.
Male participants must also refrain from sperm donation during treatment and until the end of 
contraception requirement.
4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5)
Procedures to be Followed in the Event of Pregnancy
Female participants will be instructed to notify the investigator if they become pregnant or 
suspect they are pregnant at any time from start of the study to 8 weeks after the last study drug 
dose. Study drug must be discontinued immediately.
Male participants whose partner has become pregnant or suspects she is pregnant from start of 
study to 8 weeks after the last study drug dose must also report the information to the 
investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.4.2.3.

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11.7.
Lifestyle Recommendations Included in the 2019 American College of 
Cardiology/American Heart Association Guideline on the Primary 
Prevention of Cardiovascular Disease
1) All adults should consume a healthy diet that emphasizes the intake of vegetables, fruits, 
nuts, whole grains, lean vegetable or animal protein, and fish and minimizes the intake 
of trans fats, red meat and processed red meats, refined carbohydrates, and sweetened 
beverages. For adults with overweight and obesity, counseling and caloric restriction are 
recommended for achieving and maintaining weight loss.
2) Adults should engage in at least 150 minutes per week of accumulated moderate-intensity 
physical activity or 75 minutes per week of vigorous-intensity physical activity.
3) For adults with type 2 diabetes, lifestyle changes, such as improving dietary habits and 
achieving exercise recommendations, are crucial.

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11.8.
Cardiovascular Risk Assessment for Participants With Nonalcoholic Fatty 
Liver Disease
There are a variety of commonly used cardiovascular disease (CVD) risk calculators that have 
been developed from studies in different populations. While all of the CVD risk calculators have 
advantages and disadvantages, no single risk calculator is appropriate for all participants. The 
choice to use a risk calculator should consider ease of use, applicability to a clinician’s 
participant population, and professional society recommendations. 
Some of the most commonly used calculators include: 
•
United States derived population cohorts:
Framingham general CVD risk score, 2008, Circulation. 2008;117:743-753 
■
10-year risk of coronary heart disease (CHD) death, nonfatal myocardial infarction 
(MI), angina, fatal and nonfatal ischemic/hemorrhagic stroke, transient ischemic 
attack (TIA), intermittent claudication, heart failure (HF)
https://www.framinghamheartstudy.org/fhs-risk-functions/cardiovascular-disease-
10-year-risk/
American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort 
hard CVD risk calculator (2013), Circulation. 2014;129:
S49–S73; update Circulation. 2019;140:e596–e646
■
10-year risk of the following hard atherosclerotic cardiovascular disease (ASCVD) 
events: CHD death, nonfatal MI, fatal and nonfatal stroke
http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/ {American 
college of Cardiology 2023}
•
European derived population cohort
SCORE CVD death risk score (2003), Eur Heart J. 2003;24(11):987; Eur Heart J. 
2007;28(19):2375. Epub 2007 Aug 28; Eur J Prev Cardiol. 2016 Jul;23(11):NP1-NP96.
■
10-year risk of CVD death (CHD, arrhythmia, HF, stroke, aortic aneurysm, and 
peripheral vascular disease)
https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-
Risk-Charts
•
England and Wales
QRISK and QRISK2: BMJ. 2007;335(7611):136. Epub 2007 Jul 5, 
BMJ. 2008;336(7659):1475. Epub 2008 Jun 23.
■
10-year risk of CHD death, nonfatal MI and stroke, fatal stroke, angina, coronary 
revascularization, TIA, intermittent claudication
https://qrisk.org/2017/

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11.9.
Country-Specific Requirements
11.9.1.
Additional Country-Specific Requirements for France
Reflects the changes to the global Amendment 1 protocol dated 25 June 2021 and reflected in 
Amendment 1.2 (France) dated 23 December 2021.
Country-Specific Requirements
Protocol 
Section
Ophthalmoscopic examination included as a required component of the complete physical 
examination.
Section 6.8.2
Study Procedures Table modified to include complete physical examination at Week 48, Week 
72, and the early termination visit in addition to Screening.
Appendix 11.5, 
Section 6.5.2
Study Procedures modified to include electrocardiogram assessments at the Week 24 and 
Week 48 visits in addition to Screening, Week 72, and the early termination visit.
Synopsis, 
Appendix 11.5, 
Section 6.5.2

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11.10.
Amendment History
A high-level summary of this amendment is provided in tabular form in the subsection below, 
with changes listed in order of importance. Minor changes such as the correction of typographic 
errors, grammar, or formatting are not detailed. 
Separate summary of change documents for earlier amendments are available upon request.
A separate tracked change (red-lined) document comparing Amendment 1 to this amendment 
will be made available upon the publication of this protocol.
11.10.1.
Amendment 2 (26 October 2023)
Rationale for Key Changes Included in Amendment 2
Affected Sections
Objectives:
•
Changed the primary objective to evaluate only whether the combination of 
SEMA with the fixed-dose combination (FDC) of CILO/FIR causes 
fibrosis improvement without worsening of NASH compared with placebo; 
NASH resolution is no longer evaluated as part of the primary objective. 
The rationale for this change is that increasingly fibrosis improvement is 
recognized as the biomarker most likely to predict clinical benefit in a 
cirrhotic NASH study population, and this change allows fibrosis 
improvement to be tested independently as the highest priority hypothesis.
•
Added a secondary objective to evaluate whether the combination of 
SEMA with the FDC of CILO/FIR causes NASH resolution in participants 
with compensated cirrhosis due to NASH, as compared with placebo.
Synopsis, Sections 2 and 
8.1.1
Endpoints:
•
Changed coprimary endpoints to a single primary endpoint of fibrosis 
improvement without worsening of NASH in order to test fibrosis 
improvement independently as the highest priority hypothesis, appropriate 
for a cirrhotic NASH study population.
•
Information for stastistical testing of the primary and secondary endpoints 
was changed to order analysis objectives in keeping with the changes to the 
endpoints, and for consistency with changes made in other sections.
Synopsis, Sections 1.6, 
3.1, 8.1.2, 8.2.2, 8.9, and 
throughout as needed
Estimand strategy was added and updated for primary/secondary endpoints 
based on the modifications made to the endpoints in the protocol.
Section 8.5
Statistical considerations section was updated to add “power calculation.”
Section 8.9
Dose escalation schedule for SEMA was updated.
Section 5.5.3
Text related to clinical studies of SEMA was updated to add the latest 
information. 
Sections 1.2.3.3, 1.6, and 
1.9
Text related to clinical and nonclinical studies of CILO, and FIR (individual and 
in combination) was updated with the latest information.
Sections 1.3.2, 1.3.3, 1.4.2, 
1.4.3, 1.5.2, and 1.9
Clarified that auxiliary medicinal products/noninvestigational medicinal products 
are not used in this study.
Section 1.10
A list of study interventions and their marketing authorization status was added.
Section 1.10, 
Appendix 11.3
Added SomaSignal NASH tests to the list of planned biomarkers.
Sections 3.8.1 and 6.8.1.7

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Rationale fo1· Key Changes Included in Amendment 2 
Text was updated to add "or other hepatobilia1y cancer" to the discontinuation 
criteria for more clarity. 
Blinding: information was updated regarding personnel who may be unblinded. 
The text was updated to add glycyl1'hetinic acid to the prohibited medications 
list: GlycyIThizae Radix is a traditional herbal medicine commonly prescribed in 
Japan as an anti-inflammato1y agent and contains glycyl1'hetinic acid, which 
confers a mineralocorticoid excess state (sodium retention and potassium 
wasting). Additional information was provided regarding agents requiring 
special administration considerations. Azithromycin was moved to agents 
requiring special administration considerations and noted that chronic use 
remains prohibited. 
New section regarding definition of serious adverse dmg reaction was added. 
Section for "Liver-Related Clinical Events" was added. 
Pregnancy reporting process and time period was updated. 
The text related to "repeating liver-related laboratory assessments (ALT, AST, 
ALP, GGT, total bilimbin, INR) within 72 hours of initial results ( or as soon as 
possible)" was removed from toxicity management. 
Added text to clarify that laboratory abno1malities that occur before the first dose 
of study dmg or after the pa1ticipant has been discontinued from treatment for at 
least 35 days will be included in a data listing. 
Clarified that if Gilead discontinues development of the study dtug, further 
provision of study dtug to participants may be discontinued. 
Clarified that for early termination (ET) visits, a FibroScan assessment should be 
perfo1med unless perfonned within 12 weeks of the ET visit. 
Clarified that for ET visits, an abdominal ultrasound should be perfonned unless 
perfo1med within 12 weeks of the ET visit. 
Text was updated to replace "Site Operations Manual" to "Investigator Site File" 
for alignment with study documents. 
Text was updated to clarify that the urine pregnancy testing may be perfonned at 
home in betv.re.en clinic visits, where possible, or in clinic, if at home pregnancy 
tests are unavailable. 
Text was updated to add visit window of± 3 days to home pregnancy testing to 
allow more flexibility. 
Contraception requirements were extended from 5 to 8 weeks: contraception 
requirements updated to specify that acceptable methods of contraception, for 
both female and male participants, should be continued through 8 weeks after the 
last dose of study dtug due to the long washout period for SEMA, in keeping 
with guidance from the Warnings and Precautions for Use listed in the SEMA 
investigator's brochure and labeling for commercially available fonnulations of 
SEMA. 
CONFIDENTIAL 
Page 151 
Final 
Amendment2 
Affected Sections 
Section 3.5 
Section 3.8.3 
Section 5.1.2 
Section 5.6 
Section 7.1.3 
Section 7.1.4.3 
Section 7.4.2.3 
Section 7.7.2 
Section 8.6.3 
Section 3.4.1 
Section 6.8.10, 
Appendix 11.5 
Section 6.8.13, 
Appendix 11.5 
Sections 5.1.3, 5.2.2.1, 
6.8.11, and 7.2.2 
Section 6.8.8, 
Appendix 11.5 
Section 6.8.8, 
Appendix 11.5 
Appendix 11.6 
26 October 2023 

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Rationale for Key Changes Included in Amendment 2
Affected Sections
Text was added to clarify volume of blood to be collected per participant at each 
visit and overall.
Section 6.8.1.10
Score description of the Child-Pugh classification of the severity of cirrhosis was 
updated for clarity.
Section 6.8.5
Text regarding study drug withholding was revised to clarify required 
observation for participants who discontinue study drug due to evidence of 
hepatic decompensation.
Section 7.7.3
Added country-specific requirements.
Appendix 11.9
Minor changes to correct typographic errors.
Throughout, as needed

Prot-GS-US-454-6075-amd-2
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Global Development
Lead (GDL) eSigned
26-Oct-2023
23:36:28
PPD