Conditions: Nonalcoholic Steatohepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 109
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

Detailed description:

Arms:
arm 1: Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks arm 2: Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks arm 3: Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks arm 4: Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks arm 5: Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks

Interventions: intervention 1: Semaglutide intervention 2: Firsocostat intervention 3: Cilofexor
Intervention descriptions: intervention 1: Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly intervention 2: Tablets administered orally once daily intervention 3: Tablets administered orally once daily

Protocol document:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
PD 
PD 
Protocol Version/Date: 
GILEAU 
CLINICAL STUDY PROTOCOL 
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy ofMonotherapy and Combination Regimens in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
141683 
Not Applicable 
NCT03987074 
Nonalcoholic steatohepatitis (NASH) 
GS-US-454-5533 
Name: 
Telephone: 
Mobile: 
Fax: 
Email: 
Name: 
Telephone: 
Mobile: 
Fax: 
Email: 
Original: 
Amendment 1 : 
Amendment 2: 
PD 
PD 
PD 
PD 
YLJ 
PD 
PD 
PD 
PD 
YLJ 
17May2019 
16 August 2019 
22 October 2019 
This study will be conducted m1der US Food & Drug Administration IND regulations 
(21 CFR Part 312). 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this docmnent, particularly m1published 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 Co1mnittee. The infonnation 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 infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
infonned consent from those persons to whom the drug may be administered. 


Protocol GS-US-454-5533 
Gilead Sciences, Inc. 
Final 
Amendment2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 6 
PROTOCOL SYNOPSIS .............................................................................................................................................. 7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 18 
I. 
INTRODUCTION .............................................................................................................................................. 23 
1.1. 
Background ............................................................................................................................................ 23 
1.2. 
General Information for Semaglutide ..................................................................................................... 24 
1.2.1. 
General Information ............................................................................................................. 24 
1.2.2. 
Pre-Clinical Studies .............................................................................................................. 25 
1.2.3. 
Clinical Trials with Semaglutide .......................................................................................... 25 
1.3. 
General Information for Cilofexor ......................................................................................................... 27 
1.3.1. 
Cilofexor .............................................................................................................................. 27 
1.3 .2. 
Nonclinical Pharmacology and Toxicology ......................................................................... 27 
1.3.3. 
Clinical Trials ofCilofexor .................................................................................................. 29 
1.3.4. 
A Phase I, Open-Label, Parallel-Group, Adaptive, Single-Dose Study to 
Evaluate the Phannacokinetics and Pharmacodynamics ofCilofexor in 
Subjects with Normal and Impaired Hepatic Function 
(Study GS-US-402-3885) ..................................................................................................... 29 
1.4. 
General Information for Firsocostat ....................................................................................................... 34 
1.4.1. 
Firsocostat ............................................................................................................................ 34 
1.4.2. 
Nonclinical Pharmacology ................................................................................................... 34 
1.4.3. 
Nonclinical Toxicology ........................................................................................................ 35 
1.4.4. 
Nonclinical Pharmacokinetics .............................................................................................. 36 
1.4.5. 
Clinical Trials of Firsocostat ................................................................................................ 36 
1.4.6. 
Study GS-US-426-3988: A Phase I Open-Label, Parallel-Group, 
Single-Dose Study to Evaluate the Pharmacokinetics of Firsocostat or 
Fenofibrate in Subjects with Normal and Impaired Hepatic Function ................................. 39 
1.5. 
Rationale for This Study ........................................................................................................................ 42 
1.5.1. 
Rationale for Dose Selection of Semaglutide ....................................................................... 43 
1.5.2. 
Rationale for the Dose Selection of Cilofexor. ..................................................................... 44 
1.5.3. 
Rationale for the Dose Selection of Firsocostat ................................................................... 45 
1.5.4. 
Rationale for Study Population ............................................................................................ 45 
1.6. 
Compliance ............................................................................................................................................ 46 
2. 
OBJECTIVES ..................................................................................................................................................... 47 
3. 
STUDY DESIGN ................................................................................................................................................ 48 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
Study Design .......................................................................................................................................... 48 
Study Treatments ................................................................................................................................... 48 
Duration of Study ................................................................................................................................... 48 
End of Study ........................................................................................................................................... 49 
Post Stud Care ...................................................................................................................................... 49 
4. 
SUBJECT POPULATION .................................................................................................................................. 52 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 52 
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4.2.
Inclusion Criteria....................................................................................................................................52
4.3.
Exclusion Criteria...................................................................................................................................53
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................56
5.1.
Randomization .......................................................................................................................................56
5.2.
Description and Handling of Semaglutide 3.0 mg/mL...........................................................................56
5.2.1.
PDS290 pen-injector for Semaglutide for use in Clinical Trials..........................................57
5.2.2.
Storage and Handling...........................................................................................................58
5.2.3.
Shelf-life and in-use time for Semaglutide in PDS290 ........................................................58
5.3.
Description and Handling of Cilofexor (GS-9674)................................................................................58
5.3.1.
Formulation..........................................................................................................................58
5.3.2.
Packaging and Labeling .......................................................................................................58
5.3.3.
Storage and Handling...........................................................................................................58
5.4.
Description and Handling of Firsocostat (GS-0976)..............................................................................59
5.4.1.
Formulation..........................................................................................................................59
5.4.2.
Packaging and Labeling .......................................................................................................59
5.4.3.
Storage and Handling...........................................................................................................59
5.5.
Dosage and Administration....................................................................................................................60
5.5.1.
Management of Semaglutide Dose Escalation .....................................................................61
5.6.
Prior and Concomitant Medications.......................................................................................................62
5.7.
Accountability for Deuterated Water and Investigational Medicinal Product (IMP) and 
Devices...................................................................................................................................................64
5.7.1.
Investigational Medicinal Product and Device Return or Disposal......................................64
6.
STUDY PROCEDURES ....................................................................................................................................65
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................65
6.2.
Screening Assessments ..........................................................................................................................65
6.2.1.
Screening Visit .....................................................................................................................65
6.3.
Pretreatment Assessments......................................................................................................................67
6.3.1.
Day -14 Visit........................................................................................................................67
6.3.2.
Day -11 and Day -7 Visits (± 1 day) ....................................................................................68
6.4.
Treatment Assessments..........................................................................................................................69
6.4.1.
Day 1 Visit ...........................................................................................................................69
6.4.2.
Day 7 (Week 1) Visit (± 3 days) ..........................................................................................70
6.4.3.
Day 28 (Week 4) Visit (± 3 days) ........................................................................................71
6.4.4.
Day 56 (Week 8) Visit (± 3 days) ........................................................................................71
6.4.5.
Day 84 (Week 12) Visit (± 3 days) ......................................................................................72
6.4.6.
Day 112 (Week 16) Visit (± 3 days) ....................................................................................74
6.4.7.
Day 140 (Week 20) Visit (± 3 days) ....................................................................................74
6.4.8.
Day 154 (Week 22) Visit (± 1 day)......................................................................................75
6.4.9.
Day 157 (Week 22 Day 2) and Day 161 (Week 23) Visit (± 1 day) ....................................76
6.4.10.
Day 168 (Week 24) / End of Treatment Visit (± 3 days) .....................................................76
6.4.11.
Early Termination (ET) Visit ...............................................................................................78
6.4.12.
Unscheduled Visits...............................................................................................................79
6.5.
Posttreatment Assessments ....................................................................................................................79
6.5.1.
Telephone Follow-Up Visit (± 3 days).................................................................................79
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................80
6.7.
Assessments for Premature Discontinuation from Study.......................................................................81
6.8.
Interruption of Study Drug.....................................................................................................................82
6.9.
End of Study...........................................................................................................................................82
6.10.
Description of Assessments ...................................................................................................................82
6.10.1.
Clinical Laboratory Analytes ...............................................................................................82
6.10.2.
Creatinine Clearance/eGFR..................................................................................................83
6.10.3.
Child-Pugh (CP) Score.........................................................................................................83
6.10.4.
MRE and MRI-PDFF...........................................................................................................84


Protocol GS-US-454-5533 
Gilead Sciences, Inc. 
Final 
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6.10.5. 
6.10.6. 
6.10.7. 
6.10.8. 
6.10.9. 
6.10.10. 
6. 10.11. 
6.10.12. 
FibroScan® ........................................................................................................................... 85 
Electrocardiogram ................................................................................................................ 85 
Medical History .................................................................................................................... 85 
Physical Examination ........................................................................................................... 85 
Fundus Examination ............................................................................................................. 86 
Vital Signs ............................................................................................................................ 86 
Pregnancy Testing ................................................................................................................ 86 
Health Related ual i of Life HR oL Measures ............................................................. 87 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 88 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 88 
7. I. I. 
Adverse Events ..................................................................................................................... 88 
7 .1.2. 
Serious Adverse Events ........................................................................................................ 88 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 89 
7 .2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 90 
7 .2.2. 
Assessment of Severity ........................................................................................................ 90 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 91 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 92 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 93 
7.6. 
Toxicity Management ............................................................................................................................ 93 
7 .6.1. 
Observation for Drug Induced Liver lnju1y (DILi) .............................................................. 93 
7.6.2. 
Close Observation ................................................................................................................ 94 
7.6.3. 
CP Score ............................................................................................................................... 96 
7 .6.4. 
Hypertriglyceridemia ............................................................................................................ 96 
7.6.5. 
Pruritus Management ........................................................................................................... 97 
7.7. 
Special Situations Reports ...................................................................................................................... 97 
7.7.1. 
Definitions of Special Situations .......................................................................................... 97 
7.7.2. 
Instmctions for Reporting Special Situations ....................................................................... 98 
8. 
STA TIS TI CAL CONSIDERATIONS .............................................................................................................. I 00 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
8.9. 
8.10. 
Analysis Objectives and Endpoints ...................................................................................................... I 00 
8.1.1. 
Analysis Objectives ............................................................................................................ I 00 
8.1.2. 
Primar End oint ............................................................................................................... I 00 
.
ysis Conventions ........................................................................................................................... I I 
8.2.1. 
Analysis Sets ...................................................................................................................... IO I 
8.2.2. 
Interim Analysis ................................................................................................................. I 02 
Data Handling Conventions ................................................................................................................. I 02 
Demographic Data and Baseline Characteristics ................................................................................. I 02 
ir::,;:.:;, 
:o, 
8.6.1. 
Extent of Exposure ............................................................................................................. I 03 
8.6.2. 
Adverse Events ................................................................................................................... I 03 
8.6.3. 
Laboratory Evaluations ...................................................................................................... I 03 
Pharmacokinetic Analysis .................................................................................................................... I 04 
8.7.1. 
Other Safety Evaluations .................................................................................................... 104 
Biomarker Analysis .............................................................................................................................. 104 
Sample Size .......................................................................................................................................... 104 
Data Monitoring Committee ................................................................................................................ 104 
CONFIDENTIAL 
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9.
RESPONSIBILITIES........................................................................................................................................105
9.1.
Investigator Responsibilities ................................................................................................................105
9.1.1.
Good Clinical Practice........................................................................................................105
9.1.2.
Financial Disclosure...........................................................................................................105
9.1.3.
Institutional Review Board (IRB) Review and Approval...................................................105
9.1.4.
Informed Consent...............................................................................................................106
9.1.5.
Confidentiality....................................................................................................................106
9.1.6.
Study Files and Retention of Records ................................................................................106
9.1.7.
Case Report Forms.............................................................................................................108
9.1.8.
Investigational Medicinal Product Accountability and Return...........................................108
9.1.9.
Inspections..........................................................................................................................108
9.1.10.
Protocol Compliance..........................................................................................................109
9.2.
Sponsor Responsibilities ......................................................................................................................109
9.2.1.
Protocol Modifications.......................................................................................................109
9.2.2.
Study Report and Publications ...........................................................................................109
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................110
9.3.1.
Payment Reporting.............................................................................................................110
9.3.2.
Access to Information for Monitoring................................................................................110
9.3.3.
Access to Information for Auditing or Inspections ............................................................110
9.3.4.
Study Discontinuation........................................................................................................110
10.
REFERENCES .................................................................................................................................................111
11.
APPENDICES ..................................................................................................................................................114
Appendix 1.
Investigator Signature Page..................................................................................................115
Appendix 2.
Study Procedures Table........................................................................................................116
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE)............................................124
Appendix 5.
West Haven Criteria .............................................................................................................125
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-402-3885: Preliminary Cilofexor, GS-716070, and GS-1056756 PK 
Parameters Following a Single Dose of Cilofexor 30 mg or 10 mg in Subjects with 
Hepatic Impairment or Normal Hepatic Function ..................................................................32
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 Evaluating 
DDIs with Firsocostat (20 mg or 50 mg)................................................................................39
Table 1-3.
GS-US-426-3988: Preliminary Firsocostat and GS-834773 PK Parameters 
Following a Single Dose of Firsocostat 20 mg in Subjects with Mild or Moderate 
Hepatic Impairment or Normal Hepatic Function ..................................................................41
Table 5-1.
Composition of Semaglutide Solution for Injection...............................................................56
Table 5-2.
Semaglutide Dose Escalation Schedule..................................................................................61
Table 5-3.
List of Representative Disallowed and Use with Caution Medicationsa ................................63
Table 6-1.
Visit Windows........................................................................................................................80
Table 6-2.
Child-Pugh Classification of the Severity of Cirrhosis ..........................................................84
CCI


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LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................48
Figure 7-1.
On-Treatment ALT/AST Monitoring Requiring Close Observation......................................94
Figure 7-2.
On-Treatment Monitoring Requiring Withholding of Study Drugs .......................................95
Figure 7-3.
Algorithm for Monitoring and Treatment of Hypertriglyceridemia .......................................96


Protocol GS-US-454-5533 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Dr. 
Foster City, CA 94404 USA 
Final 
Amendment2 
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Mono therapy and Combination 
Regimens in Subjects with Nonalcoholic Steatohepatitis (NASH) 
141683 
Not Applicable 
NCT03987074 
Approximately 20 centers in the United States 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study drug(s) in subjects 
with NASH. 
I 
I 
I 
I 
I 
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Study Design:
This is a proof of concept, open-label study evaluating the safety, 
tolerability, and efficacy of monotherapy and combination regimens 
in subjects with NASH.
Subjects meeting the study’s entry criteria will be randomly assigned 
in a 1:1:1:1:1 ratio to 1 of 5 treatment groups, with approximately 
20 subjects in each group, as shown in the figure below:
Randomization will be stratified by the presence or absence of 
type 2 diabetes mellitus, as determined by medical history or based 
on the Screening laboratory values if previously undiagnosed 
(hemoglobin A1c [HbA1c] ≥ 6.5%).
Number of 
Subjects Planned:
Approximately 100 Subjects
Target Population:
Males and non-pregnant, non-lactating females between 18-75 years 
of age with NASH as assessed by historical liver biopsy, and/or 
noninvasive tests.
Duration of 
Treatment:
Subjects will be treated for up to 24 weeks 
Duration of Study:
Participation in the study can last up to 35 weeks, which includes a 
2-week Screening period, a 2-week Pre-Treatment period, a 24-week 
Treatment period, and a 7-week Follow-Up period. 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Diagnosis and 
Main Eligibility 
Criteria:
Key Inclusion Criteria:
1) Males and females between 18-75 years of age; inclusive based 
on the date of the Screening Visit;
2) Willing and able to provide informed consent prior to any study 
specific procedures being performed;
3) Subjects must meet all of the following conditions (a-d) OR (e):
a.
Clinical diagnosis of nonalcoholic fatty liver disease 
(NAFLD);
b. Screening FibroTest® < 0.75, unless all previous historical 
liver biopsies do not reveal cirrhosis. In subjects with 
Gilbert’s syndrome or hemolysis, FibroTest® will be 
calculated using direct bilirubin instead of total bilirubin;
c.
Screening MRI-PDFF with ≥ 10% steatosis, as assessed by 
the central reader. Historical MRI-PDFF within 4 weeks of 
the date of the Screening Visit may be used if deemed 
acceptable by the central reader;
d. Screening FibroScan® with liver stiffness ≥ 7 kPa. Historical 
FibroScan® within 4 weeks of the date of the Screening Visit 
is acceptable;
OR
e.
An historical liver biopsy within 6 months of the date of the 
Screening Visit consistent with NASH (defined as the 
presence of steatosis, inflammation, and ballooning) with 
stage 2-3 fibrosis according to the NASH Clinical Research 
Network (CRN) classification (or equivalent). Report will be
reviewed by the Medical Monitor;
4) Subject has the following laboratory parameters at the Screening 
Visit, as determined by the central laboratory:
a.
Alanine aminotransferase (ALT) ≤ 5 x ULN;
b. Estimated glomerular filtration rate (eGFR) ≥ 30 
milliliter/minute (mL/min), as calculated by the MDRD study 
equation;
c.
HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 μmol if HbA1c 
is unable to be resulted);
d. International normalized ratio (INR) ≤ 1.2, unless due to 
therapeutic anti-coagulation therapy;
e.
Platelet count ≥ 100,000/μL;
f.
Total bilirubin < 1.3 x ULN unless alternate etiology such as 
Gilbert’s syndrome present;


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g. Calcitonin ≤ 100 ng/L;
5) Body Mass Index (BMI) > 23 kg/m2 and body weight of > 60 kg;
6) A negative serum pregnancy test is required for female subjects
of childbearing potential as defined in Appendix 3.
7) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in Appendix 3.
Key Exclusion Criteria:
1) Documented weight loss > 5% within 6 months of the date of the 
Screening Visit; 
2) Any historical liver biopsy consistent with cirrhosis;
3) Pregnant or lactating females;
4) Alcohol consumption greater than 21 oz/week for males or 
14 oz/week for females (1oz/30 mL of alcohol is present in 
1 12oz/360 mL beer, 1 4oz/120 mL glass of wine, and a 
1oz/30 mL measure of 40% proof alcohol);
5) Positive urine screen for amphetamines, cocaine or opiates 
(ie, heroin, morphine) at Screening. Subjects on stable methadone 
or buprenorphine maintenance treatment for at least 6 months 
prior to the date of Screening Visit may be included in the study. 
Subjects with a positive urine drug screen due to prescription 
opioid-based or amphetamine-based medication are eligible if the 
prescription and diagnosis are reviewed and approved by the 
investigator;
6) Any history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding;
7) Other causes of liver disease, including but not limited to: 
alcoholic liver disease, hepatitis B, hepatitis C, autoimmune 
disorders (eg, primary biliary cholangitis [PBC], primary 
sclerosing cholangitis [PSC], autoimmune hepatitis), 
drug-induced hepatotoxicity, Wilson disease, clinically 
significant iron overload, or alpha-1-antitryspin deficiency 
requiring treatment;
8) History of liver transplantation;
9) History of hepatocellular carcinoma;
10) Weight reduction surgery in the past 2 years or planned during 
the study;


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11) Chronic hepatitis B (HBsAg positive);
12) Chronic hepatitis C (HCV RNA positive). Subjects cured of HCV 
infection less than 2 years prior to the date of the Screening Visit 
are not eligible;
13) HIV Ab positive;
14) Unstable cardiovascular disease as defined by any of the 
following:
a.
Unstable angina, myocardial infarction, coronary artery 
bypass graft surgery or coronary angioplasty within 6 months 
prior to the date of the Screening Visit;
b. Transient ischemic attack or cerebrovascular accident within 
6 months prior to the date of the Screening Visit;
c.
Symptomatic obstructive valvular heart disease or 
hypertrophic cardiomyopathy;
d. Symptomatic congestive heart failure;
e.
Uncontrolled or recurrent ventricular tachycardia or other 
arrhythmia requiring an automatic implantable cardioverter 
defibrillator (AICD). Stable, controlled atrial fibrillation is 
allowed;
f.
An emergency room visit or hospitalization for confirmed 
cardiovascular disease within 6 months prior to the date of the 
Screening Visit;
15) History of a malignancy within 5 years of the date of the 
Screening Visit with the following exceptions:
a.
Adequately treated carcinoma in situ of the cervix;
b. Adequately treated basal or squamous cell cancer or other 
localized non-melanoma skin cancer;
16) Presence of acute pancreatitis within the past 180 days prior to 
the date of the Screening Visit;
17) History or presence of chronic pancreatitis;
18) Presence or history of type 1 diabetes mellitus;


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19) For subjects with type 2 diabetes diagnosed prior to the date of 
the Screening Visit OR on Screening Visit labs 
(defined as HbA1c ≥6.5%), subjects must have no evidence of 
uncontrolled and potentially unstable retinopathy or maculopathy 
as determined by: 
a.
A fundus exam performed in the 90 days prior to the date of 
the Screening Visit. If there has been worsening of the 
subject’s visual function since this historical fundus exam in 
the opinion of the investigator, then the fundus exam must be 
repeated;
OR
b. A fundus exam performed between the date of the Screening 
Visit and Enrollment (Day -14) 
Pharmacological pupil-dilation is a requirement in both of the 
above cases unless using a digital fundus photography camera 
specified for non-dilated examination;
20) Personal or first degree relative(s) history of multiple endocrine 
neoplasia type 2 or medullary thyroid carcinoma;
21) Treatment with GLP-1 RAs in the period from 90 days prior to 
the date of the Screening Visit;
22) Subjects on Vitamin E regimen ≥800 international units (IU)/day 
must be on a stable dose (defined as no changes in prescribed 
dose, new Vitamin E containing medications, or discontinuation)
for at least 180 days prior to the date of the Screening Visit and in 
the period between the date of the Screening Visit and Enrollment 
(Day -14);
23) Subjects on antidiabetic medications must be on a stable dose for 
at least 90 days prior to the date of the Screening Visit and in the 
period between the date of the Screening Visit and Enrollment 
(Day -14); 
24) Use of any prohibited concomitant medications as described in 
Section 5.6;
25) Any investigational medication or device within 30 days or 
within 5 half-lives of the prior investigational agent (whichever is 
longer) prior to the date of the Screening Visit throughout the 
study (e.g., obeticholic acid, elafibranor, and cenicriviroc) is 
prohibited;
26) Known hypersensitivity to the study drug, the metabolites, or 
formulation excipient.


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Study Procedures/
Frequency:
After signing the informed consent form (ICF), subjects will 
complete a Screening Visit which will include the following 
assessments: obtain written informed consent, obtain Screening 
number from IWRS, complete medical history; if applicable, review
of any historical liver biopsy report obtained within 6 months of the 
date of the Screening Visit; record all concomitant medications that 
the subject has taken within 30 days prior to Screening; physical 
examination (PE) including vital signs, body weight, and height; 
dilated fundus exam or digital fundus photography camera specified 
for non-dilated examinations (if required for subjects with type 2 
diabetes from medical history or from Screening Hemoglobin 
A1c ≥6.5% only), laboratory assessments, serum pregnancy test 
(for females of childbearing potential); blood and urine collection for 
biomarkers, urine drug screen, 12-lead ECG, FibroTest®, ELF™Test, 
FibroScan® ; documentation of all serious adverse events (SAEs) and 
adverse events (AE) related to Screening procedures; MRI-PDFF and 
MRE examinations. 
All subjects determined eligible for the study based on the 
inclusion/exclusion criteria will then enroll into Pretreatment to begin 
Cycle 1 of the Kinetic Biomarkers. Subjects will consume deuterated 
water starting on Day -14 through Day -8 to determine the effects of 
study drug(s) on kinetic parameters of de novo lipogenesis (DNL), 
fibrogenesis, and inflammation. The first dose of approximately 
45 mL deuterated water will be administered under the supervision of 
investigative site personnel and monitored for at least 30 minutes 
after for any side effects. Kinetic biomarker samples will be obtained 
on Day -14, Day -11, Day -7, and Day 1. 
Eligible subjects will be randomized on Day 1 to receive treatment 
for 24-weeks with one of the following study drugs: semaglutide; 
firsocostat (FIR; GS-0976) and semaglutide; cilofexor (CILO; 
GS-9674) and semaglutide; or firsocostat, cilofexor, and semaglutide. 
On-treatment study assessments will include but are not limited to:

Symptom driven PE, vital signs, weight, chemistry, hematology, 
coagulation panel, and eGFR at Day 1 and at Weeks 1, 4, 8, 12, 
16, 20 and 24 

FibroScan®, MRI-PDFF, MRE, and FibroTest® at Weeks 12 and 
24

ELF™Test at Weeks 12 and 24

12-lead ECG at Week 24


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and Mode of 
Administration: 
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• 
Pregnancy testing (females of childbearing potential only) at 
Day 1 and at Weeks 4, 8, 12, 16, 20 and 24 
I 
• 
Insulin and Lipids collection at Day 1, Weeks 4, 8, 12 and 24 
• 
Hemoglobin Ale (HbAlc) collection at Weeks 12 and 24 
• 
Single PK sampling at Weeks 1, 4, 8 and 12 
I 
• 
Quality of Life (QoL) questio1maires: Chronic Liver Disease 
Questio1maire-Nonalchoholic Fatty Liver Disease 
[CLDQ-NAFLD], and EuroQol five dimensions [EQ-5D] at 
Day 1 and at Weeks 12 and 24 
Subjects will return on Day 154 to begin Cycle 2 of the Kinetic 
Biomarkers. Subjects will drink approximately 45 mL of deuterated 
water three times per day starting on Day 154 through Day 160. 
Kinetic biomarker samples will be obtained on Day 154, Day 157, 
Day 161 and Day 168. 
Subjects will complete a Telephone Follow-Up visit 7 weeks after the 
last dose of study drugs. During this visit, subjects will report on 
concomitant medications and any adverse events which have 
occurred since their Week 24 visit. During the Telephone Follow-Up 
visit, female subjects of childbearing potential that received at least 
one dose of study drug will report the results of the study-provided 
urine pregnancy test. 
Name: Semaglutide (0.24 2.4mg) 
Dosage fonn: Solution for injection 
Route of administration: Subcutaneous 
Dosing instructions: Once weekly 
Delivery device: 3 mL PDS290 pre-filled pen-injector 
Name: Cilofexor 
Dosage fonn: 30 mg or 100 mg tablet 
Route of administration: Oral 
Dosing instructions: Once daily 
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Name: Firsocostat 
Dosage form: 20 mg tablet 
Route of administration: Oral 
Dosing instructions: Once daily
Dose, and Mode of 
Administration:
Semaglutide: Dose escalation of semaglutide should take place 
during the first 16 weeks after randomization. All subjects must aim 
to reach the recommended target dose of semaglutide subcutaneous 
(s.c.) 2.4 mg once-weekly. Recommended dose escalation is as 
follows:

Weeks 1 through 4: 0.24 mg s.c. once weekly 

Weeks 5 through 8: 0.5 mg s.c. once weekly 

Weeks 9 through 12: 1 mg s.c. once weekly 

Weeks 13 through 16: 1.7 mg s.c. once weekly 

Weeks 17 through 24: 2.4 mg s.c. once weekly.
Cilofexor:  One 30 mg or one 100 mg tablet administered orally
once daily without regard to food
Firsocostat:  One 20 mg tablet administered orally once daily without 
regard to food
Criteria for 
Evaluation:
Safety:
Safety will be assessed during the study through the reporting of 
AEs, and by clinical laboratory tests and vital sign assessments at 
various time points during the study. Concomitant medication usage 
will also be assessed throughout the study.
Pharmacokinetics:
The PK of study drug(s) and relevant metabolite(s) may be evaluated, 
as applicable. PK samples may also be used to measure 
protein-binding of study drug(s) and/or its metabolites. Plasma 
concentrations of study drug(s) will be provided in a listing. 
Statistical Methods:
Primary 
Endpoint:
The primary endpoint is the safety and tolerability of study drug(s) in 
subjects with NASH.


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Efficacy Analysis: 
The biological activity of study drug(s) will be evaluated using 
radiologic endpoints and biomarker variables. Because efficacy 
endpoints will be evaluated for exploratory purposes, fonnal 
statistical comparisons will not be made for these endpoints. Instead, 
descriptive statistics (n, mean, standard deviation [SD], median, 
CONFIDENTIAL 
P1 quartile [Q 1 ], 3rd quartile [Q3], minimum, and maximum) will be 
provided by treatment group. 
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Safety Analysis: 
Safety endpoints will be analyzed by the number and percent of
subjects with events or abnormalities for categorical values or 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for continuous values by treatment group.
Pharmacokinetic 
Analysis:
Plasma concentrations of study drug(s) and relevant metabolite(s), as 
applicable, will be listed.
Kinetic Biomarker 
Analysis:
The kinetic biomarkers will be analyzed to evaluate the 
pharmacodynamic (PD) effects of study drug(s). The assessment will 
involve the analysis of DNL values; specifically, the change 
(absolute and relative) from baseline between the post-dose and 
pre-dose deuterated water loading periods.
Sample Size:
Due to the exploratory nature of this study, the sample size was not 
determined by any formal power calculation. The number of subjects 
in each treatment group was decided based on clinical experience 
with other similar proof of concept studies.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ACC
acetyl-CoA carboxylase
AE
adverse event
AICD
automatic implantable cardioverter defibrillator
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma/serum concentration versus time curve
AUC2-12hr
partial area under the plasma/serum concentration versus time curve from time 2 to 
time 12
AUC24hr
area under the plasma/serum concentration versus time curve from time zero to time 24
AUCinf
area under the plasma/serum concentration versus time curve extrapolated to infinite 
time, calculated as AUC0 last + (Clast/z)
AUClast
area under the plasma/serum concentration versus time curve from time zero to the last 
quantifiable concentration
BAP
Biomarker Analysis Plan
BCRP
breast cancer resistance protein
BMI
body mass index
BUN
blood urea nitrogen
CAP
controlled attenuation parameter
CFR
Code of Federal Regulations
CI
confidence interval
Clast
last observed quantifiable plasma/serum concentration of the drug
CLDQ-NAFLD
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease
Cmax
maximum observed plasma/serum concentration of drug
CP
Child-Pugh
CPK
creatine phosphokinase
CRN
Clinical Research Network
CRO
contract research organization 
CRP
c-reactive protein
CsA
single dose cyclosporine
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome
CYP3A
cytochrome P4503 A
CYP3A4
cytochrome P4503 A4
CYP7A1
cytochrome P450 7A1
DDI
drug-drug interaction
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee


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DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
DRSP
Drospirenone
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
Example
eGFR
estimated glomerular filtration rate
ELF™
Enhanced Liver Fibrosis 
EQ-5D
EuroQol five dimensions
F2
Moderate Fibrosis
F3
Bridging Fibrosis
F4
Compensated Cirrhosis
FDA
(United States) Food and Drug Administration
FFD
Fast food diet
FGF19
fibroblast growth factor 19
FSH
follicle stimulating hormone
FXR
farnesoid X receptor
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
gastrointestinal 
GLP-1 RA
glucagon-like peptide-1 receptor agonist
GMR
geometric mean ratio
GSI
Gilead Sciences, Inc.
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
Hepatocellular Carcinoma
Hct
Hematocrit
HCV
hepatitis c virus
HCV Ab
hepatitis c virus antibody
HCV RNA
hepatitis c virus ribonucleic acid
HDPE
high-density polyethylene
HE
hepatic encephalopathy
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HIV Ab
human immunodeficiency virus antibody
HIV RNA
human immunodeficiency virus ribonucleic acid
HLGT
high-level group term


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HLT
high-level term
HOMA-IR
homeostatic assessment of insulin resistance
HR
hazard ratio
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ID
Identification
IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
institutional review board
IU
international units
IUD
intrauterine device
IV
Intravenous
IWRS
Interactive web response system
kg
Kilogram
kPa
Kilopascal
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LEAN
Liraglutide Efficacy and Action in NASH
LLT
lower-level term
MCV
mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MD
multiple dose
MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mL
Milliliter
mm
Millimeter
mmHg
millimeter of Mercury
MRE
magnetic resonance elastography
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
MRP2
multidrug resistance-associated protein 2
N
Number
NAFLD
nonalcoholic fatty liver disease
NaNO2
sodium nitrite
NAS
NAFLD Activity Score
NASH
nonalcoholic steatohepatitis
NOAEL
no observed adverse event level


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NTCP
sodium-taurocholate cotransporting polypeptide
OATP
organic anion-transporting polypeptide
OAD
oral antidiabetic drug
OL
Open-Label
PBC
primary biliary cholangitis / probenecid
PD
pharmacodynamic
PDGF
platelet-derived growth factor
PE
physical exam
P-gp
Permeability-glycoprotein
PIIINP
procollagen III amino terminal peptide
PK
pharmacokinetic 
PRO
patient-reported outcomes
PSC
primary sclerosing cholangitis
PT
prothrombin time / Preferred Term
PTT
partial thromboplastin time
PVE
Pharmacovigilance & Epidemiology
QD
once daily
QTc
QT interval corrected for heart rate
RBC
red blood cell count
RIF
Rifampin
RNA
ribonucleic acid
ROS
reactive oxygen species
SADR
serious adverse drug reaction
SAE
serious adverse event
s.c.
subcutaneous 
SD
standard deviation
SD
single dose
SEMA
Semaglutide
SOC
System Organ Class
SOP
standard operating procedure
SREBP-1c
sterol regulatory element binding protein-1c
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
treatment-emergent adverse event
T2D
type 2 diabetes
TIMP-1
tissue inhibitor of metalloproteinase 1
Tmax
time (observed time point) of Cmax
UGT
UDP-glucuronosyltransferase
ULN
upper limit of the normal range
US
United States


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VAS
Visual Analog Scale
VLDL
very-large density lipoprotein
VORI
Voriconazole
WBC
white blood cell count


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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 diabetes mellitus 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 ranges from 6% to 37% worldwide {Ong 2007, Vernon 
2011} with a recent reported pooled global prevalence of 25% {Younossi 2016}.
Nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD 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 ~15 million 
adults, have NASH. Furthermore, as NASH is a manifestation of the metabolic syndrome, risk 
factors for cardiovascular disease frequently coexist in these patients {Dietrich 2014, Faramawi 
2008, Voulgari 2010}. Given the absence of any approved therapies and the increasing 
prevalence of NASH co-morbidities, NASH is expected to represent an increasingly large unmet 
medical need. 
As noted previously, NASH is primarily thought to occur as the result of the metabolic 
syndrome: the impact of obesity, insulin resistance, and dyslipidemia. Fatty liver, or simple 
steatosis is not sufficient to cause liver injury. Rather, it is the presence of inflammation and 
hepatocellular injury on the background of steatosis that defines NASH and may result in the 
progression to cirrhosis and its complications. The “2-hit” hypothesis of NASH suggests that in 
the setting of steatosis and metabolic dysfunction, increased oxidative stress and the generation 
of reactive oxygen species (ROS) likely mediate the inflammatory changes in the liver 
(steatohepatitis) that may lead to progressive fibrosis {Dowman 2010, Koek 2011, Sumida 
2013}. The major pathways in NASH disease progression include those involved in metabolic 
dysfunction in the hepatocyte, and activation of hepatic stellate cells and macrophages leading to 
progressive inflammation and liver fibrosis. Advanced fibrosis and cirrhosis are characterized by
extensive collagen deposition and remodeling of the extracellular matrix. Additionally, evidence 
suggests that lipotoxic intermediates of fatty acids likely contribute to the etiology of NASH 
{Neuschwander-Tetri 2010}.


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Over time, NASH may result in progressive liver fibrosis, ultimately leading to cirrhosis in 
10-20% of affected patients. Advanced fibrosis (bridging fibrosis or cirrhosis) 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. Decompensated liver disease, as defined by the 
development of one of the above complications, has a high mortality and the only known 
effective treatment is liver transplantation. With the increasing prevalence of obesity and 
obesity-related diseases, NASH is expected to become the leading indication for liver 
transplantation and the leading etiology of HCC among liver transplant recipients in the US 
{Afzali 2012, Wong 2014}.
1.2.
General Information for Semaglutide
1.2.1.
General Information
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently in development 
for weight management and non-alcoholic steatohepatitis. Semaglutide at once weekly doses of 
0.5 mg and 1.0 mg has been approved as an adjunct to diet and exercise for the management of 
Type 2 diabetes 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 semaglutide molecule is primarily obtained by increased albumin 
binding, which is facilitated by a large fatty acid-derived chemical moiety. 
Please refer to the Investigator’s Brochure (IB) for additional information on semaglutide, 
including:

In vitro activity

Nonclinical in vivo efficacy studies

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology

Clinical pharmacokinetics and pharmacodynamics

Safety in healthy subjects, subjects with obesity and subjects with type 2 diabetes (T2D)


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1.2.2.
Pre-Clinical Studies
Nonclinical efficacy data have shown that semaglutide lowers blood glucose, food intake and 
body weight in animal models of diabetes and obesity. Furthermore, semaglutide attenuated the
development of atherosclerosis and had an anti-inflammatory action in the cardiovascular (CV)
system. 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 duration, respectively. In all three 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 semaglutide. Non-lethal 
thyroid C-cell tumours observed in rodents are a class effect for the GLP-1 receptor agonists. In 
2-year carcinogenicity studies in rats and mice, semaglutide caused thyroid C-cell tumours at 
clinically relevant exposures. The C-cell changes in rodents are caused by a nongenotoxic,
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 to be low, but cannot be 
completely excluded. 
Semaglutide adversely affected embryo fetal 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 foetal 
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.
Refer to the Semaglutide IB for additional details.
1.2.3.
Clinical Trials with Semaglutide 
As part of the T2D development program, semaglutide once weekly was evaluated in 9 Phase 
3a/b trials (including a 2-year cardiovascular outcomes trial [CVOT]). Across all Phase 3a/b 
efficacy trials, both semaglutide 0.5 mg and 1.0 mg were superior in lowering glycosylated 
hemoglobin (HbA1c) and body weight as compared with placebo (both as monotherapy and in 
combination with insulin) or compared with the respective marketed comparators. CV safety of 
semaglutide was established in the CVOT with an estimated hazard ratio (HR) for semaglutide 
vs. placebo of 0.74 [0.58; 0.95] 95%CI corresponding to a reduced risk of major adverse 
cardiovascular events (MACE) by 26% vs. placebo.


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The PK and PD properties of semaglutide s.c. administered once weekly was investigated as part 
of the T2D development program including a total of 16 clinical pharmacology trials. 
Semaglutide has PK properties compatible with once-weekly administration with a median time 
to maximum concentration (tmax) of 1-3 days and an elimination half-life (t½) of approximately 
1 week. The exposure of semaglutide in subjects with various degrees of impaired renal function 
and with various degrees of impaired hepatic function was similar to the exposure in subjects 
with normal renal function and normal hepatic function, respectively. No clinically relevant 
drug-drug interactions (DDIs) were observed between semaglutide 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 drugs 
are required. Semaglutide circulates in plasma, highly bound to plasma protein. Prior to 
excretion, semaglutide is metabolized and excreted in urine and feces, with only 3% of the 
administered dose excreted as intact semaglutide.
For the evaluation of semaglutide in weight loss, Novo Nordisk A/S has conducted one phase 2 
clinical dose finding trial of semaglutide s.c. treatment in subjects with obesity. 857 eligible 
subjects were randomised to a target daily dose of semaglutide 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 
or 0.4 mg, liraglutide 3.0 mg or corresponding placebo matching each of the active treatment 
arms. Overall, a dose-dependent decrease in body weight was observed from baseline at 
week 52, with the greatest weight loss (estimated mean change in body weight -13.84%) 
observed with the highest semaglutide dose tested (0.4 mg, once daily). Weight loss was
accompanied by consistent improvements in weight-related comorbidities, such as CV risk 
factors as well as in patient-reported outcomes (PRO). No unexpected safety findings were 
identified and the tolerability and safety profile was overall consistent with previous findings in 
the semaglutide s.c. development program for T2D and the GLP-1 RA class in general. The most 
frequently reported AEs were gastrointestinal (GI) disorders (mainly nausea).
Semaglutide did not increase the risk of severe or blood glucose (BG) confirmed symptomatic 
hypoglycemia when used as monotherapy or in combination with oral antidiabetic drugs (OADs) 
(excluding sulphonylurea), and only slightly increased the risk when used in combination with 
insulin and with sulphonylurea.
Allergic reactions and injection site reactions were generally infrequent, non-serious and of mild 
or moderate severity and reported by a similar proportion of subjects on semaglutide and placebo 
and comparator products (allergic reactions: 4 6%) and (injection site reactions ~1%).
Data from the CVOT in T2D showed that semaglutide treatment was associated with an 
increased risk of diabetic retinopathy complications in subjects with pre-existing diabetic 
retinopathy, albeit at low risk. This finding is believed to be attributable to the rapid initial 
improvement in BG levels with semaglutide, consistent with the early worsening phenomenon 
described with insulins. Patients with a history of diabetic retinopathy should be monitored for 
worsening and treated according to clinical guidelines. 
No causal association between semaglutide and any type of neoplasms has been seen in the 
clinical development program. The incidence of pancreatic cancer and breast neoplasms was low 
and appeared not to be different from placebo or other comparators.


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1.3.
General Information for Cilofexor
1.3.1.
Cilofexor
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. Thus cilofexor, by agonizing FXR, is 
expected to improve NASH. Please refer to the Investigator’s Brochure (IB) for additional 
information on cilofexor, including:

In vitro FXR agonism

Nonclinical in vivo efficacy studies

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology
1.3.2.
Nonclinical Pharmacology and Toxicology
In vivo pharmacology studies have demonstrated that cilofexor preferentially activates intestinal 
FXR and reduces liver fibrosis. In cynomolgus monkeys, there was an increase in circulating 
FGF19 levels after oral dosing of cilofexor but not after IV dosing despite greater exposure to 
cilofexor after IV dosing. These data suggest that intestinal FXR agonism by cilofexor causes 
FGF19 production, whereas low systemic free drug concentrations limit effects following IV 
administration of cilofexor. In addition, the oral administration of cilofexor to monkeys directly 
activated intestinal FXR, as measured by the expression of FXR-target genes in the ileum 
(FGF19, OSTα, and OSTβ mRNA). In a mouse model of NASH induced by a diet enriched in 
fat, cholesterol and sugar, cilofexor reduced hepatic steatosis and normalized bile acid levels in 
plasma. In a choline-deficient high fat diet /NaNO2 rat model of liver fibrosis that utilizes 
“2 hits” to mimic the metabolic and oxidative stress components of NASH in humans, cilofexor
dose dependently reduced both biochemical and histological measures of liver fibrosis. Overall, 
the results from these pharmacology studies demonstrate that cilofexor is a potent and selective 
agonist of intestinal FXR with the potential to benefit NASH patients by inducing FGF19 
production.
The oral bioavailability of cilofexor was low in the nonclinical species. cilofexor was extensively 
bound to plasma proteins in all species. In mice, [14C] cilofexor-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. No quantifiable radioactivity was detected in 
brain, suggesting [14C] cilofexor-derived radioactivity did not cross the blood: brain barrier. The 
primary cilofexor metabolic pathways in pooled cryopreserved hepatocytes were observed to be 
oxidative. Comparison of metabolism in hepatocytes from mice, rats, dogs, monkeys, and 
humans did not identify any metabolites unique to humans. The primary metabolic pathways of 
[14C] Cilofexor in vivo were oxidation and O-dealkylation in mice, rats, and monkeys; 
glutathione conjugation was observed in mice and rats; additionally, dechlorination was observed 


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in mice. Fecal elimination was a predominant route of elimination of [14C] cilofexor-derived 
radioactivity in both mice and monkeys.
Based on nonclinical assays, cilofexor has the potential to affect hepatic/intestinal uptake of 
organic anion-transporting polypeptide (OATP) substrates or metabolism of CYP2C8, CYP2C9, 
or CYP3A4 substrates when its concentrations are sufficiently high. However, low solubility, 
high protein binding (> 99.98%), and low systemic levels reduce the potential for cilofexor to 
cause drug-drug interactions (DDIs) via inhibition of metabolic enzymes and transporters. 
GS-716070, an inactive metabolite of cilofexor, was found to inhibit human OATP1B1, 
OATP1B3, and OATP2B1 with IC50 values of 0.94, 1.3, and 2.5 μM, respectively.
Cilofexor was a substrate for efflux transporters P-gp and breast cancer resistance protein 
(BCRP), as well as the uptake transporters OATP1B1, OATP1B3, OATP2B1, and sodium-
taurocholate cotransporting polypeptide (NTCP). Inhibitors or genetic polymorphisms affecting 
the activity of these transporters may affect cilofexor intestinal absorption and hepatic uptake.
Cilofexor and GS-716070 did not activate nuclear hormone receptors associated with the 
potential for induction of human drug-metabolizing enzymes and transporters (eg, PXR, CAR, 
AhR) in cell-based reporter assays. Thus, the liability of cilofexor and GS-716070 to cause DDIs 
through proteins regulated by these nuclear receptors is low.
Based on nonclinical assays, GS-1056756 (the R-enantiomer of M13), an inactive, major 
circulating metabolite of cilofexor has shown low potential to inhibit CYP enzymes (IC50 values 
of 3.49 for CYP2C8 and >25 uM for CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6) and 
UDP-glucuronosyltransferase (UGT) (IC50 value of 13.9 for UGT1A1) in vivo. GS-1056756 did 
not inhibit P-gp, BCRP, OCT2, MATE1, MATE2K, and showed low probability to be clinically 
relevant inhibitor of OAT1, OCT1, OATP1B1, OATP1B3 or OATP2B1. No clinical DDI 
liability of GS-1056756 on enzymes and transporters was predicted from in vitro 
characterizations.
GS-1056756 has been identified in nonclinical assays as a substrate of OATP1B1/1B3. In vitro,
GS-1056756 is formed by oxidative metabolism by CYP3A4 and CYP2C8 with additional 
conversion to enantiomers by dehydrogenases (eg, ALDH), and is subsequently metabolized by 
CYP3A and CYP2C8 and UGTs. Together with available clinical data described in
Section 1.3.3, the potential clinical DDI liability of GS-1056756 is low.
The nonclinical toxicity profile of cilofexor has been assessed in mice and cynomolgus monkeys 
administered cilofexor orally for up to 26 and 39 weeks, respectively. Findings attributed to 
cilofexor administration were primarily related to the liver (increases in alkaline phosphatase, 
decreases in serum bile acids, cholesterol and triglycerides, increases in liver weight and 
hepatocellular hypertrophy) and were likely related to the pharmacology of cilofexor. These 
findings were minimal to mild, non-adverse, and reversible after discontinuation of treatment. 
The no observed adverse event levels (NOAELs) after 26 and 39 weeks of dosing in mice and 
monkeys, respectively, were associated with exposures (AUC24h) that were 22- and 32-fold 
higher in mice and monkeys, respectively, than the observed exposure in humans administered 
100 mg cilofexor QD with food.


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1.3.3.
Clinical Trials of Cilofexor
As of 2 August 2018, 4 Phase 1 clinical studies are complete, 2 Phase 1 studies are ongoing 
(GS-US-402-3885 and GS-US-402-4287), 1 Phase 2 study in subjects with NASH is complete 
(GS-US-402-1852) and 4 Phase 2 studies in subjects with NASH (GS-US-384-3914, 
GS-US-454-4378), Primary Biliary Cholangitis (PBC) (GS-US-427-4024), and
PSC (GS-US-428-4025) are ongoing. These Phase 1 and 2 studies are described in the IB. A 
brief summary of relevant PK results supporting this protocol is presented below, including 
preliminary results that are not included in the IB from ongoing study GS-US-402-3885 and 
GS-US-428-4025. Preliminary clinical PK data for the newly identified major circulating 
cilofexor metabolite GS-1056756 (the R-enantiomer of M13) is described in Sections 1.3.4.3. 
Briefly, GS-1056756 exhibits a plasma half-life of approximately 175 h. Preliminary steady-state 
plasma concentrations of GS-1056756 in PSC patients administered 100 mg cilofexor are as 
expected based on the preliminary single dose PK data for GS-1056756 from the ADME study 
(GS-US-402-4287). Additionally, plasma exposures of GS-1056756 are minimally altered in 
subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic 
function. These data, taken together with the adequate safety margins from nonclinical safety 
studies and the nonclinical understanding of the metabolic formation (CYP3A and CYP2C8) and 
clearance (CYP3A, CYP2C8, and UGTs) mechanisms of GS-1056756 support the concomitant 
medication restrictions in Section 5.3.
1.3.4.
A Phase 1, Open-Label, Parallel-Group, Adaptive, Single-Dose Study to 
Evaluate the Pharmacokinetics and Pharmacodynamics of Cilofexor in 
Subjects with Normal and Impaired Hepatic Function 
(Study GS-US-402-3885)
Study GS-US-402-3885 is an ongoing Phase 1, open-label, parallel-group, single dose study 
evaluating the safety, tolerability, PK, and PD of cilofexor in subjects with normal hepatic 
function and mild, moderate, or severe hepatic impairment. Up to 60 subjects are planned for 
enrollment in 1 of 3 hepatic impairment cohorts: Cohort 1 (mild hepatic impairment, CP A), 
Cohort 2 (moderate hepatic impairment, CP B), and Cohort 3 (severe hepatic impairment, CP C). 
Within each cohort, each subject with impaired hepatic function (N 10 per cohort) will be 
matched for age (± 10 years), sex, race, and body mass index (BMI: ± 15%) with a control 
subject with normal hepatic function (N 10 per cohort). Data from healthy subjects may be used 
in >1 cohort if a subject was an appropriate match for a subject with hepatic function in 
>1 cohort. All subjects in Cohorts 1 and 2 will receive a single oral dose of cilofexor 30 mg in 
the fed state on Day 1 with PD collected on Day -1 and Day 1. All subjects in Cohort 3 will 
receive a single oral dose of cilofexor 10 mg in the fed state on Day 1 with PD collected on 
Day -1 and Day 1. 
1.3.4.1.
Subject Disposition
As of 1 November 2017 a total of 37 subjects were enrolled and 36 subjects had completed study 
treatment. One subject prematurely discontinued study treatment due to quality issues at the site 
that justified a suspension in dosing at the site. No subjects prematurely discontinued due to an 
adverse event (AE), withdrew consent, or were lost to follow-up. 


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1.3.4.2.
Preliminary Safety Results 
Overall, 8.8% of subjects had a treatment-emergent adverse event (TEAE) of Grade 1 or 2. There 
was 1 serious adverse event (SAE) of gastrointestinal bleed that was not related to study drug. 
This subject had a history of esophageal variceal bleeding and experienced bleeding requiring 
hospitalization and blood transfusion. There were no pregnancies or deaths. 
In the mild hepatic impairment cohort, there were 2 subjects (20%) that had Grade 3 lab 
abnormalities of elevated gamma glutamyl transferase (GGT) and low platelets. The Grade 3 
GGT was stable from the subject’s baseline. There was 1 healthy matched control subject (10%) 
who had Grade 3 lab abnormalities in total cholesterol and LDL cholesterol (LDL-C), which 
were stable from their baseline. In the moderate hepatic impairment cohort, 2 subjects (20%) had 
Grade 3 lab abnormalities. One subject had low lymphocytes, and the other subject had elevated 
total bilirubin and low platelets. The platelet count was not changed from the subject’s baseline. 
One subject, who had a SAE of gastrointestinal bleeding in the moderate hepatic impairment 
cohort (described above), had a Grade 4 lab abnormality of low hemoglobin. In the severe 
hepatic impairment cohort, 4 subjects (40%) had greater than or equal to Grade 3 lab 
abnormalities at baseline. One subject had low hemoglobin, one subject had elevated total 
bilirubin, one subject had low hemoglobin and low albumin, and one subject had occult blood in 
urine.
1.3.4.3.
Preliminary PK Results
Preliminary PK results are presented below and in Table 1-1:

Cohort 1 (mild hepatic impairment; CP A): cilofexor exposure (AUCinf and Cmax) was higher 
in subjects with mild hepatic impairment (approximately 76% and 57%, respectively) as 
compared to subjects with normal hepatic function. In subjects with mild hepatic impairment, 
exposure (AUCinf and Cmax) of the metabolite GS-716070 was similarly higher 
(approximately 64% and 25%, respectively). Overall exposure for GS-1056756 was modestly 
higher (AUCinf was increased 28% and Cmax increased 7%) in subjects with mild hepatic
impairment compared with subjects with normal hepatic function. cilofexor and GS-716070 
had minor changes in plasma protein binding (unbound fraction [fu] increased ~30%). CILO 
is a hepatic OATP substrate and OATP expression/activity may be altered in patients with 
cirrhosis. Thus, altered OATP expression/activity may contribute to the observed higher 
systemic exposure of cilofexor. At a dose of 100 mg QD in subjects with mild hepatic 
impairment, exposure margins relative to preclinical NOAEL exposures for both parent and 
metabolites are expected to remain adequate.


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
Cohort 2 (moderate hepatic impairment; CP B): CILO exposure (AUCinf and Cmax) was 
higher in subjects with moderate hepatic impairment (approximately 2.3- and 1.6-fold, 
respectively) as compared to subjects with normal hepatic function. Exposure (AUCinf) of the 
metabolite GS-716070 was also higher (approximately 1.6-fold) with minimal change in 
Cmax. GS-1056756 AUCinf was increased 16% and Cmax was 30% lower in subjects with 
moderate hepatic impairment compared with subjects with normal hepatic function. Plasma 
unbound fraction (fu) of cilofexor and GS-716070 was increased ~96% and ~85%, 
respectively, in moderate hepatic impairment, leading to a > 4-fold and > 3-fold increase in 
free drug exposures of parent and metabolites, respectively. 

Cohort 3 (severe hepatic impairment; CP C): cilofexor exposure (AUCinf and Cmax) was 
higher in subjects with severe hepatic impairment (approximately 6.2- and 2.5-fold, 
respectively) as compared to subjects with normal hepatic function. Exposure (AUCinf) of the 
metabolite GS-716070 was also higher (approximately 3-fold) with Cmax reduced by 33%. 
GS-1056756 AUCinf was approximately 2.6-fold higher and Cmax approximately 39% lower 
in subjects with severe hepatic impairment compared with subjects with normal hepatic 
function. 


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Table 1-1.
GS-US-402-3885: Preliminary Cilofexor, GS-716070, and GS-1056756 
PK Parameters Following a Single Dose of Cilofexor 30 mg or 10 mg 
in Subjects with Hepatic Impairment or Normal Hepatic Function
Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched 
Healthy 
Control (N=10)
Hepatic 
Impairment 
(N=10)
%GMR
(90% CI)
1
(Mild HI, 
CILO 30 mg)
Cilofexor
AUCinf (hr.ng/mL)
3030 
(40.5)
5410 
(40.2)
176
(127, 253)
AUClast (hr.ng/mL)
2970 
(41.4)
5380 
(40.4)
178
(128, 247)
Cmax (ng/mL)
604 
(45.6)
994 
(53.7)
157
(108, 229)
GS-716070
AUCinf (hr.ng/mL)
1440 
(49.7)
2330 
(44.8)
164
(104, 259)
AUClast (hr.ng/mL)
1400 
(51.1)
2300 
(44.8)
169
(115, 247)
Cmax (ng/mL)
179 
(42.6)
234 
(50.8)
125
(85.0, 188)
GS-
1056756
AUCinf (hr.ng/mL)
2040 
(57.7)
2850 
(69.5)
128
(80.1, 204)
AUClast (hr.ng/mL)
850 
(45.6)
1030 
(70.0)
109
(73.0, 163)
Cmax (ng/mL)
13.0 
(44.4)
15.5 
(70.1)
107
(70.4-161)
2
(Moderate HI, 
CILO 30 mg)
Cilofexor
AUCinf (hr.ng/mL)
2810 
(30.3)
8280 
(91.4)
230 
(163, 324)
AUClast (hr.ng/mL)
2460 
(30.9)
8220 
(91.1)
249 
(169, 367)
Cmax (ng/mL)
496 
(40.2)
909 
(52.5)
164 
(115, 233)
GS-716070
AUCinf (hr.ng/mL)
1380 
(47.7)
3160 
(81.8)
163 
(95.1, 280)
AUClast (hr.ng/mL)
1340 
(48.8)
3090 
(80.9)
197 
(117, 329)
Cmax (ng/mL)
168 
(51.6)
181 
(61.5)
89.5 
(54.3, 147)
GS-
1056756
AUCinf (hr.ng/mL)
1620 
(41.6)
1900 
(41.2)
116
(83.5-161)
AUClast (hr.ng/mL)
734 
(40.7)
586 
(34)
79.4
(58.3, 108)
Cmax (ng/mL)
11.6 
(39.7)
8.25 
(37.6)
70.0
(50.2, 97.6)


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Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched 
Healthy 
Control (N=10)
Hepatic 
Impairment 
(N=10)
%GMR
(90% CI)
3
(Severe HI, 
CILO 10 mg)
Cilofexor
AUCinf (hr.ng/mL)
989 
(36.4)
6710 
(60.3)
623
(430, 905)
AUClast (hr.ng/mL)
963 
(37.2) 
6535
(58.0) 
631
(437, 913)
Cmax (ng/mL)
182 
(47.5)
427 
(32.0)
254
(177, 365)
GS-716070
AUCinf (hr.ng/mL)
2450 
(77.5)
688 
(50.1)
303
(173, 528)
AUClast (hr.ng/mL)
2070 
(71.2) 
653 
(52.9)
280
(166, 473)
Cmax (ng/mL)
47.9 
(45.6)
77.2 
(55.7)
67.0
(44.3-101)
GS-
1056756
AUCinf (hr.ng/mL)
520 
(38.8)
3360 
(181)
262
(118, 581)
AUClast (hr.ng/mL)
241 
(39.2)
181 
(45.8)
73
(51.0, 104)
Cmax (ng/mL)
3.67 
(37.0)
2.35 
(50.2)
60.7
(41.9, 88.0)
Data reported to 3 significant figures

Preliminary PD results for Cohort 1 are also available for change from baseline (Day -1) in 
plasma FGF19 and serum 7-alpha-hydroxy-4-cholesten-3-one (C4) levels following a single 
30-mg dose of cilofexor. Changes in FGF19 and C4 following a single dose of cilofexor were 
similar in the mild hepatic impairment subjects as compared to the healthy matched controls 
as indicated by the PD parameter ratios (mild hepatic impairment/healthy) for Cmax and 
AUC2 12hr for FGF19 (1.1 and 1.1, respectively) and for Cmin and AUC2 12hr for C4 (0.82 and 
0.87, respectively) that were not significantly different from 1.

Based on the preliminary PK and PD data from this study as well as the overall safety profile 
of cilofexor, dose adjustments are not considered necessary in subjects with mild hepatic 
impairment.

For further information on cilofexor, refer to the current IB.


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1.4.
General Information for Firsocostat
1.4.1.
Firsocostat
Firsocostat is a small molecule allosteric inhibitor that acts at the protein-protein homodimer 
interface of acetyl coenzyme A (acetyl-CoA) carboxylases (ACC) ACC1 and ACC2 to prevent 
dimerization. ACC1 and ACC2 are important regulators of fatty acid metabolism. ACC1 
catalyzes the first step of de novo lipogenesis (DNL) by converting acetyl-CoA to malonyl-CoA 
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. Firsocostat is being developed for the treatment of nonalcoholic steatohepatitis 
(NASH) under IND 124915.
For further information on firsocostat, refer to the current IB.
1.4.2.
Nonclinical Pharmacology
Firsocostat has been characterized in several biochemical and cellular assays to enhance the 
understanding of the mechanism of action and has been well characterized in vivo in several 
mechanistic models to demonstrate target engagement and in animal disease models to 
demonstrate specific activity on endpoints relevant to metabolic disease. Moreover, extensive 
safety pharmacology and receptor screening studies have been conducted.
The results of these pharmacodynamic (PD) studies indicate that firsosostat can reduce the DNL, 
hepatic steatosis, insulin resistance, and fibrosis produced in nonclinical models of metabolic 
disease and fibrosis without affecting food consumption or markers of liver function.
As described in the IB, GS-834356, a liver-targeted ACC inhibitor and analogue of firsocostat, 
reduced steatosis in a murine model of NASH induced by a diet enriched in fat, cholesterol, and 
fructose (Fast food diet, FFD). ACC inhibition by GS-834356 dose-dependently reduced hepatic 
steatosis, liver triglycerides and cholesterol, plasma ALT and AST, and markers of hepatic 
fibrosis, but also dose-dependently increased plasma triglycerides in this model. 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, Hertz 1995, Kim 2017}.
In high fat, high sucrose fed rats, GS-834356-induced increased plasma triglycerides were found 
to be due to increased very-large density lipoprotein (VLDL) secretion and decreased clearance 
of triglyceride-rich VLDL and chylomicrons2. The increase in plasma triglycerides by ACC 
inhibition was accompanied by an increase in plasma ApoC3 protein, which inhibits lipoprotein 
lipase activity and suppresses VLDL and chylomicron clearance. ApoC3 transcription in 
hepatocytes is repressed by the nuclear hormone receptor PPAR. Evaluation of gene 
transcription profiles of FFD-fed mice treated with the ACC inhibitor GS-834356 revealed a 
reduction in PPARtarget gene signatures2.These findings suggest that ACC inhibition in the 
liver leads to a reduction in hepatic PPARactivity and associated increases in VLDL and 
ApoC3 production, and reduced VLDL/chylomicron clearance. Indeed, the combination of ACC 


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inhibition with PPARα agonism using fenofibrate blocked the ACC-induced plasma TG 
increases in the mouse NASH model. Importantly, the combination of the ACC inhibitor and 
fenofibrate caused a similar reduction in hepatic triglycerides compared to ACC inhibitor 
treatment alone. In addition, the combination caused a greater increase in plasma ketone bodies 
(a marker of fatty acid beta-oxidation) and a greater reduction of hepatic cholesterol levels 
relative to ACC inhibition alone2. These findings demonstrate that the addition of fenofibrate 
overcomes triglyceride elevations induced by ACC inhibition and further increases fatty acid 
oxidation and cholesterol metabolism.
In total, these studies confirm the potential for firsocostat to impact important metabolic 
endpoints associated with NASH, and for the addition of PPARagonists to reverse increases in 
plasma triglycerides.
Please refer to the firsocostat IB for additional details.
1.4.3.
Nonclinical Toxicology
The nonclinical toxicologic profile of firsocostat has been well characterized in single- and 
repeat-dose toxicity studies up to 39 weeks in duration and in genetic toxicity, embryo-fetal 
developmental toxicity, and local tolerance studies.
Firsocostat was well tolerated up to 13 weeks in the mouse, 26 weeks in the rat, and 39 weeks in 
the dog. The primary target organ toxicity was the presence of cataracts and/or lens degeneration 
in the mouse and dog after 2 and 13 weeks, respectively. In the 2-week mouse study, while 1 of 
10 female mice at the lowest dose (5 mg/kg/day) had lens degeneration, none of the male mice at 
the same dose, whereas they did at 3 times higher mean firsocostat exposure. In the females, the 
lowest exposure where lens degeneration was observed was 5 times higher than the clinical 
exposure at 20 mg firsocostat.
In contrast, in the 13-week mouse study, there were no eye findings that were attributed to 
firsocostat exposures approximately 8-fold above the clinical exposure at 20 mg. While the 
relevance of the lens degeneration observed in the mouse to humans is currently unknown, the 
lack of eye findings attributable to firsocostat in the 13-week mouse study and the differences in 
the eye anatomy between mouse and human suggest that eye findings at lower exposures in the 
2-week study may not be clinically relevant. In the dog, lens degeneration/cataracts were 
first observed after 13 weeks of firsocostat administration. While lens degeneration/cataracts 
were also observed in the chronic dog study, these findings occurred at exposures > 168 times 
the clinical exposure at 20 mg.
There were no adverse eye findings in the chronic dog study at mean exposures at least 48 times 
the clinical exposure at 20 mg. firsocostat was not genotoxic and there was no embryo-fetal 
developmental toxicity at exposures approximately 50 times the clinical exposure. Firsocostat 
was considered non-corrosive and does not require classification as an eye irritant.


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Based on the systemic concentrations of firsocostat measured in the repeat-dose toxicity studies 
in mice, rat and dog at the projected clinically efficacious AUC (88 ng•h/mL), the margins of 
exposure at the NOAELs are 8, 206 and 48 in the mouse, rat and dog, respectively. Thus, data 
from the nonclinical studies support the continued clinical evaluation of 20 mg firsocostat.
Please refer to the firsocostat IB for additional details.
1.4.4.
Nonclinical Pharmacokinetics
Firsocostat is highly protein bound in plasma, and the volume of distribution of firsocostat across
nonclinical species is greater than total body water (0.7 L/kg), suggesting that firsocostat is well 
distributed. A significant fraction of the absorbed parent compound is extracted by the liver 
indicating that firsocostat is available to the target site (ie, the liver).
The metabolism of firsocostat has been evaluated in in vitro incubations of rat, dog, Cynomolgus 
monkey, and human hepatocytes. No metabolites unique to the human were detected. In vivo 
metabolite identification studies in Sprague-Dawley rat and Beagle dog have demonstrated that 
the primary metabolite of firsocostat is the glucuronide conjugate, NDI-011535, renamed as 
GS-834773.
Neither firsocostat nor GS-834773 inhibits the cytochrome P450 (CYP) enzymes involved in 
drug metabolism. Firsocostat is not an inducer of CYP1A2 or CYP2B6 isozymes and is a mild 
inducer of CYP3A4 in human hepatocytes in vitro.
A single nonclinical study to evaluate elimination of firsocostat and the metabolite GS-834773 
was performed in bile duct cannulated Sprague-Dawley rats to profile concentrations over time 
in plasma, urine, and bile. Overall, the pharmacokinetic (PK) profile in plasma and bile indicate 
that firsocostat is rapidly cleared from the plasma compartment, and the primary route of 
elimination is via the bile.
Please refer to the firsocostat IB for additional details.
1.4.5.
Clinical Trials of Firsocostat
As of 27 November 2017, 12 Phase 1 and 2 Phase 2 clinical studies have been completed or are 
ongoing. 
Information about completed and ongoing clinical studies can be found in the firsocostat IB.


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1.4.5.1.
Study GS-US-426-4074: A Phase 1 Study to Evaluate Transporter and 
Cytochrome (CYP) 450-Mediated Drug-Drug Interactions between Firsocostat
and Probe Drugs
Study GS-US-426-4074 is an ongoing, open-label, multiple-cohort study designed to evaluate 
transporter and CYP-mediated drug-drug interactions (DDIs) between firsocostat (10, 20, or 
50 mg) and various probe drugs in healthy subjects. The effect of an organic anion-transporting 
polypeptide (OATP)1B1/1B3 inhibitor on the PK/PD relationships of firsocostat, as assessed by 
changes in fractional DNL, will also be evaluated.
1.4.5.1.1.
Subject Disposition
As of 1 November 2017, a total of 90 subjects were dosed; 88 subjects had completed study 
treatment. Two subjects discontinued early. One subject withdrew on Study Day 23 due to 
personal reasons, and the second subject withdrew on Study Day 8 following a positive 
pregnancy test.
1.4.5.1.2.
Preliminary Safety Results
Forty-eight out of 90 subjects (53.3%) experienced an AE. Of these subjects, 10 subjects 
experienced AE(s) that were deemed related to the study drug. The most common AE was 
headache (20%). All of these AEs were Grade 1 or 2, and no subject discontinued the study due 
to an AE.
Fourteen subjects (15.6%) experienced a Grade 3 lab abnormality. Thirteen of these subjects had 
asymptomatic hematuria (3+) on their urine dipstick, and all were menstruating females. 
One subject had a Grade 3 asymptomatic elevation of their total and low-density lipoprotein 
(LDL) cholesterol, and one subject had a transient Grade 3 decrease in hemoglobin. There were 
no Grade 4 lab abnormalities.
1.4.5.1.3.
Preliminary PK Results
Preliminary PK results from the following cohorts are presented below and in Table 1-2.
Cohort 1: Impact of OATP/multidrug resistance-associated protein 2 (MRP2)/permeability 
glycoprotein (P-gp) inhibition (single dose cyclosporine [CsA] 600 mg: CsA) or OATP1B1/1B3 
inhibition (single dose rifampin [RIF] 600 mg: RIF) on single dose of firsocostat 20 mg (N 28). 
Single doses of CsA and RIF significantly increased firsocostat exposure (21.2- and 18.4-fold, 
respectively) and resulted in even greater increases in GS-834773 exposures (64.5- and 
55.4-fold, respectively). These data indicate firsocostat is a sensitive substrate of hepatic OATP 
with intestinal P-gp playing a minimal role in firsocostat absorption as seen by a smaller increase 
in firsocostat Cmax by CsA compared to single dose RIF.


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Cohort 2: Impact of pan-UGT inhibition (probenecid [PBC] 500 mg: PBC) and CYP3A4 
inhibition (voriconazole [VORI] 200 mg: VORI) on single dose administration of firsocostat
20 mg (N 14). Co-administration of firsocostat with PBC resulted in a moderate increase in 
firsocostat exposure (61%) indicating UGTs are involved in the metabolism of firsocostat. The 
moderate increase in GS-834773 exposure (74%) with PBC may be due to inhibition of other 
enzymes/transporters involved in the clearance of GS-834773. Co-administration of firsocostat
with VORI increased firsocostat and GS-834773 exposures (37% and 44%, respectively) 
indicating CYP3A4 plays a small role in the elimination of both parent and metabolite.
Cohort 5: Impact of single and multiple doses of firsocostat 50 mg once daily on a sensitive 
CYP3A4 probe substrate (midazolam [MDZ] 2 mg: MDZ; N 12). Neither single dose nor 
multiple doses of firsocostat altered MDZ exposure (90% CIs of the % geometric mean ration 
(GMR) for AUC and Cmax with lack of effect bounds of 70-143%) indicating firsocostat is not an 
inhibitor or inducer of CYP3A4.
Cohort 6: Impact of single and multiple doses of firsocostat 50 mg once daily on a representative 
combined oral contraceptive (drospirenone [DRSP]/EE 3/0.02 mg: DRSP/EE; N 16). There was 
no effect of single dose firsocostat on DRSP or EE exposure (90% CIs of the %GMR for AUC 
and Cmax with lack of effect bounds of 70-143%). Multiple doses of firsocostat slightly increased 
EE exposure (AUCinf increased ~34%) with no effect on DRSP exposure indicating firsocostat
does not induce enzymes/transporters involved in the clearance of DRSP or EE. No loss of 
contraceptive efficacy is expected upon administration of firsocostat with oral contraceptives like 
DRSP/EE. The slight increase in EE exposure is not considered clinically significant and does 
not warrant dose modification.


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Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 
Evaluating DDIs with Firsocostat (20 mg or 50 mg)
Inhibitor/Inducer 
Drug
Firsocostat
%GMR (90% CIs)
GS-834773
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
CsA
2120 
(1810, 2480)
2000 
(1590, 2520)
6450 
(5260, 7900)
7870
(6130, 10100)
RIF
1840 
(1570, 2150)
2710 
(2160, 3400)
5540
(4520, 6790)
10100
(7890, 13000)
PBC
161 
(144, 180)
160 
(132, 195)
174 
(148, 204)
176
(145, 214)
VORI
137 
(123, 152)
145 
(119, 176)
144 
(123, 170)
140
(116, 171)
MDZ + SD Firsocostat
%GMR (90% CIs)
MDZ + MD Firsocostat
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
Firsocostat (50 mg)
111 
(99.8, 123)
102 
(91.6, 115)
102 
(91.4, 113)
106
(94.9, 119)
DRSP + SD Firsocostat
%GMR (90% CIs)
DRSP + MD Firsocostat
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
Firsocostat (50 mg)
96.4 
(86.5, 107)
103 
(91.5, 116)
105 
(94.0, 117)
116
(102, 131)
EE + SD Firsocostat
%GMR (90% CIs)
EE + MD Firsocostat
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
Firsocostat (50 mg)
102 
(87.6, 119)
112 
(104, 122)
134 
(114, 156)
121
(111, 131)
SD  single dose
MD  multiple dose
Data reported to 3 significant figures
1.4.6.
Study GS-US-426-3988: A Phase 1 Open-Label, Parallel-Group, Single-Dose 
Study to Evaluate the Pharmacokinetics of Firsocostat or Fenofibrate in 
Subjects with Normal and Impaired Hepatic Function
Study GS-US-426-3988 is an ongoing Phase 1, open-label, parallel-group, single dose study 
evaluating the safety, tolerability, and PK of firsocostat or fenofibrate in subjects with normal
hepatic function and mild, moderate, or severe hepatic impairment (CP class A, B, or C, 
respectively). Up to 80 subjects are planned for Enrollment in 1 of 4 hepatic impairment cohorts: 
Cohort 1 (mild hepatic impairment), Cohort 2 (moderate hepatic impairment), Cohort 3 
(severe hepatic impairment), and Cohort 4 (mild hepatic impairment). Within each cohort, each 
subject with impaired hepatic function (N 10 per cohort) will be matched for age (± 10 years), 


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sex, race, and body mass index (BMI): ± 15% with a control subject with normal hepatic 
function (N 10 per cohort). Data from healthy subjects may be used in >1 cohort if a subject was 
an appropriate match for a subject with hepatic function in >1 cohort. Subjects in Cohorts 1 and 
2 will receive a single oral dose of firsocostat 20 mg in a fasted state on Day 1. Subjects in 
Cohort 3 will receive a single oral dose of firsocostat5 mg in a fasted state on Day 1. Subjects in 
Cohort 4 will receive a single oral dose of fenofibrate 48 mg in a fasted state on Day 1.
1.4.6.1.
Subject Disposition and Demographics
As of 19 April 2019 a total of 72 subjects were dosed; 67 subjects had completed study 
treatment. No subjects prematurely discontinued study treatment. No subjects withdrew consent, 
and no subjects were lost to follow-up.
1.4.6.2.
Preliminary Safety Results
In the mild hepatic impairment cohort, 1 subject (10%) had a treatment-related AE of facial 
flushing that was Grade 1. One other mild hepatic impairment subject had a Grade 1 headache. 
Two healthy matched controls experienced Grade 1 AEs of headache and herpes simplex virus 
type 2. In the moderate hepatic impairment cohort, 1 subject had a Grade 1 headache that was 
deemed not-related to study drug. There was no Grade 3 or 4 AEs in either cohort. No AEs led to 
dose modification, interruption, or premature discontinuation of study drug. There were no 
SAEs, pregnancies, or deaths.
In the mild hepatic impairment cohort, 4 subjects had Grade 3 lab abnormalities. Elevations in 
GGT (2 subjects) and LDL cholesterol (2 subjects) were the most common, and all Grade 3 lab 
abnormalities of GGT and LDL were present at Screening. In the healthy matched controls, 
2 subjects also had Grade 3 LDL cholesterol lab abnormalities that were present at Day 1. In the 
moderate hepatic impairment cohort, 3 subjects had Grade 3 lab abnormalities 
(decreased lymphocytes, hypomagnesemia, and hyponatremia). There were no Grade 4 lab 
abnormalities.
1.4.6.2.1.
Preliminary PK Results
Preliminary PK results from Cohorts 1 and 2 are presented below and in:

Cohort 1 (Mild Hepatic Impairment; CP A): firsocostat exposure (AUCinf and Cmax) was 
higher in subjects with mild hepatic impairment (approximately 84% and 69%, respectively) 
as compared to subjects with normal hepatic function. In subjects with mild hepatic 
impairment, exposure (AUCinf and Cmax) of the metabolite GS-834773 was also higher 
(approximately 3.9-fold higher for both). Plasma protein binding of both parent and 
metabolite were similar in subjects with mild hepatic impairment as compared to subjects 
with normal hepatic function. firsocostat is a hepatic OATP substrate and OATP 
expression/activity may be reduced in patients with cirrhosis. Thus, altered OATP 
expression/activity may contribute to the observed higher systemic exposure of firsocostat. 
At a dose of 20 mg once daily (QD) in subjects with mild hepatic impairment, exposure 
margins relative to preclinical NOAEL exposures for both parent and metabolite are expected 
to remain adequate.


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
Cohort 2 (Moderate Hepatic Impairment; CP B): firsocostat exposure (AUCinf and Cmax) was 
higher in subjects with moderate hepatic impairment (approximately 8.7- and 9.1-fold higher, 
respectively) as compared to subjects with normal hepatic function. Exposure (AUCinf and 
Cmax) of the metabolite GS-834773 was also higher (approximately 37.5- and 44.7-fold 
higher, respectively). Plasma protein binding of both parent and metabolite were similar in 
subjects with moderate hepatic impairment as compared to subjects with normal hepatic 
function. The increased exposure of firsocostat and GS-834773 in subjects with moderate 
hepatic impairment is likely due to further decreases in OATP expression/activity relative to 
mild hepatic impairment as well as decreases in expression/activity of enzymes involved in 
firsocostat metabolism (ie, UGTs and CYP3A4). At a dose of 20 mg QD, firsocostat plasma 
exposures in subjects with moderate hepatic impairment are ≥ 5-fold and ≥25-fold lower 
than exposures at the NOAEL in the chronic toxicology studies in dogs and rats, respectively.
Table 1-3.
GS-US-426-3988: Preliminary Firsocostat and GS-834773 PK 
Parameters Following a Single Dose of Firsocostat 20 mg in Subjects 
with Mild or Moderate Hepatic Impairment or Normal Hepatic 
Function
Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched Healthy 
Control (N=10)
Moderate Hepatic 
Impairment (N=10)
%GMR
(90% CI)
1
(Mild HI)
Firsocostat
AUCinf (hr.ng/mL)
70.4 
(55.2)
166 
(98.2)
184 
(101, 336)
AUClast (hr.ng/mL)
69.6 
(55.7)
161 
(98.5)
181 
(99.3, 331)
Cmax (ng/mL)
25.4 
(80.6)
50.9 
(90.3)
169 
(87.5, 325)
GS 834773
AUCinf (hr.ng/mL)
8.29 
(69.6)
48.1 
(123)
387 
(177, 846)
AUClast (hr.ng/mL)
7.38 
(79.0)
46.3 
(125)
430 
(187, 990)
Cmax (ng/mL)
2.29 
(91.8)
12.9 
(125)
391 
(164, 935)
2
(Moderate 
HI)
Firsocostat
AUCinf (hr.ng/mL)
65.9 
(52.3)
687 
(72.8)
867
(484, 1550)
AUClast (hr.ng/mL)
64.5 
(51.5)
681 
(72.9)
879
(491, 1580)
Cmax (ng/mL)
20.1 
(60.2)
198 
(60.0)
905
(539, 1520)
GS 834773
AUCinf (hr.ng/mL)
5.9 
(57.5)
399 
(135)
3750
(1640, 8560)
AUClast (hr.ng/mL)
5.1 
(62.9)
396 
(136)
4410
(1900, 10200)
Cmax (ng/mL)
1.4
(81.2)
77.3 
(72.5)
4470
(2190, 9130)
Data presented to 3 significant figures
Based on the preliminary PK data from this study as well as the overall safety profile of 
firsocostat, dose adjustments are not considered necessary in subjects with mild hepatic 
impairment.


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1.4.6.3.
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Safety, Tolerability, and Efficacy of Firsocostat in Subjects with Nonalcoholic 
Steatohepatitis (GS-US-426-3989)
Please refer to the firsocostat IB for additional details.
1.5.
Rationale for This Study
NASH involves a complex interplay between hepatocytes, immune cells, and hepatic stellate 
cells that perpetuates a pathological cycle of hepatocyte injury, inflammation and fibrosis 
{Caligiuri 2016}. Increased synthesis and accumulation of fatty acids in hepatocytes leads to 
lipotoxicity, a state characterized by increased production of toxic lipid metabolites, bile acids, 
ROS, growth factors, and ultimately hepatocyte cell death {Neuschwander-Tetri 2010}. These 
metabolic stress signals directly promote the activation and differentiation of hepatic stellate 
cells into myofibroblasts, the primary source of collagen and extracellular matrix that causes 
fibrosis. In addition, hepatocyte lipotoxicity promotes an immune response by resident 
macrophages, which produce ROS, growth factors and cytokines such as transforming growth 
factor beta (TGF-and platelet-derived growth factor (PDGF), that further increase 
myofibroblast activation, migration, proliferation and survival, and result in fibrosis {Lee 2015}. 
Based on the multiple biological pathways involved in the pathogenesis of NASH, and the 
heterogeneity of the patient population, it is likely that a combination of drugs that have distinct 
mechanisms of action will be required to achieve optimal therapeutic benefit.
Both human and animal studies have shown a beneficial effect of GLP-1 RA on liver lipid 
metabolism, inflammation, and progression of fatty liver to NASH {Gao 2015, Lee 2012, Mells 
2012, Panjwani 2013}. The investigator sponsored study Liraglutide Efficacy and Action in 
NASH (LEAN), enrolled 52 overweight subjects with and without T2D, with biopsy-confirmed 
NASH to receive liraglutide s.c. or placebo once daily. After 48 weeks of treatment, 9 out of 
23 (39%) subjects treated with liraglutide had resolution of NASH with no worsening of fibrosis 
(relative risk 4.3 [1.0 17.7] 95% CI; p 0.019) compared to 2 out of 22 (9%) subjects treated 
with placebo. Furthermore, significantly fewer patients treated with liraglutide had worsening of 
fibrosis compared to placebo {Armstrong 2016}. As semaglutide is structurally similar to 
liraglutide with similar mechanism of action and with potential for more pronounced effect on 
glycemic control and body weight, semaglutide is thought to be a potential candidate for 
treatment of NASH, both alone and in combination with other agents. 
As previously noted, increased rates of hepatic DNL and insufficient fatty acid oxidation lead to 
hepatic steatosis and associated lipotoxicity, which are implicated in the etiology and progression 
of NASH. By inhibiting ACC, firsocostat has been shown to reduce steatosis and fibrosis in 
animal models of NASH and to reduce DNL by >70% at doses of 20 mg daily in humans. In a 
recently-completed Phase 2 study in subjects with NASH (GS-US-426-3989), firsocostat led to 
improvement in hepatic steatosis, liver biochemistry, and markers of fibrosis. 


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FXR agonism has been shown to reduce hepatic lipid and bile acid synthesis due to down 
regulation of sterol regulatory element binding protein-1c (SREBP-1c) and cytochrome 
P450 7A1 (CYP7A1), respectively, as well as reduce insulin resistance and hepatic 
gluconeogenesis {Zhang 2006}. Animal models have demonstrated the ability of cilofexor to 
reduce hepatic fibrosis in a choline-deficient high fat diet/NaNO2 rat model of NASH and to 
reduce hepatic steatosis in obese mice fed a fat and carbohydrate rich diet. In the proof of 
concept study (GS-US-384-3914), cilofexor led to statistically significant reductions in hepatic 
steatosis and GGT, and thus, cilofexor is postulated to have these and other benefits with longer 
duration of dosing. 
Preclinical studies in animal models of NASH have demonstrated that combinations of an FXR 
agonist and ACC inhibitor lead to greater efficacy to reduce hepatic steatosis and measures of 
liver fibrosis compared to the respective monotherapies. Combination toxicology studies have 
revealed no new toxicities of the combination of cilofexor and firsocostat. 
In the proof of concept combination study (GS-US-384-3914), 20 subjects received firsocostat
20 mg and cilofexor 30 mg once daily for 12 weeks. 73.7% of subjects (14 of 19 evaluable 
subjects) had at least a 30% relative reduction in MRI-PDFF. The subjects on this regimen also 
had significant median relative reductions in liver biochemistry (i.e., ALT, GGT) and 
FibroSure®/FibroTest® after 12 weeks of treatment. From a safety perspective, these subjects had 
similar rates of AEs compared to monotherapy treatment with firsocostat or cilofexor treatment 
alone for 12 weeks in this study.  
In previous and ongoing studies with firsocostat and cilofexor (GS-US-426-3989, 
GS-US-402-1852, GS-US-384-3914, and GS-US-454-4378), subjects have been concurrently 
treated with GLP-1 agonists including liraglutide and semaglutide for diabetes. Because these 
were well tolerated previously, there is no indication of an increased safety concern with the 
combinations for this study.
Given the complex pathophysiology of NASH and the belief that combination regimens are 
likely to be the most efficacious, as well as the hypothesis that weight loss is a key driver of
NASH resolution in patients without advanced fibrosis, supported by earlier clinical studies with 
liraglutide, this study aims to evaluate the safety and tolerability of combining semaglutide 
(an agent approved for treatment of type 2 diabetes, and in clinical testing for weight loss 
treatment and NASH) with cilofexor and firsocostat which address separate but complementary 
pathophysiologic pathways in this complex disease.  
1.5.1.
Rationale for Dose Selection of Semaglutide
The proposed target dose of semaglutide 2.4 mg once weekly in the Phase 3 weight management 
study (NN9536) 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
subjects with obesity showed that the semaglutide 0.4 mg once-daily dose was the greatest 
effecton weight loss while displaying an acceptable tolerability profile. Furthermore, data from 
the semaglutide s.c. T2D development program (SUSTAIN trials with once-weekly dosing and 
study NN9535-4191 with once-daily s.c. dosing of up to 0.3 mg/day) did not support the 
hypothesis that once-daily dosing provides better gastrointestinal (GI)tolerability as compared to 


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once-weekly dosing. Hence, the proportion of subjects with GI AEs and the rates of such events 
were generally higher in study NN9535-4191 and in study NN9536-4153 where semaglutide was 
dosed once daily as compared to the Phase 3a trials where semaglutide was dosed once weekly.
Based on population pharmacokinetic modelling, it was estimated that the Cmax at steady-state, 
with a once-weekly maintenance dose of 2.4 mg semaglutide s.c., will not exceed that obtained 
with the once-daily 0.4 mg semaglutide s.c. dose investigated in study NN9536-4153. When 
comparing the simulated human exposure at 2.4 mg/week to the animal exposures at the 
NOAEL, exposure ratios are above 1, indicating that exposure at 2.4 mg is supported by the 
nonclinical studies. Consequently, the proposed semaglutide s.c. target dose for the Phase 3 
weight management development program is 2.4 mg once weekly.
It is well known that to mitigate GI side effects with GLP-1 RA treatment, dose escalation to the
target dose is required. Based on experience from the semaglutide s.c. T2D development
program and study NN9536-4153, 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.
1.5.2.
Rationale for the Dose Selection of Cilofexor
This study will evaluate the safety and tolerability of 30mg and 100mg cilofexor QD in 
combination with semaglutide over 24 weeks in subjects with NASH. These doses were selected 
based on short-term safety, PK and PD results from Study GS-US-402-1851 in healthy subjects.  
In the Phase 1 study GS-US-402-1851, cilofexor was tested at doses ranging from 10 to 300 mg 
once daily for up to 14 days and was well tolerated. Across the range of cilofexor doses 
evaluated, doses ≥ 30 mg provided comparable intestinal FXR agonism as assessed by increases 
in FGF19 exposure. Food, by slowing oral absorption of cilofexor, resulted in prolonged 
elevation of plasma FGF19 concentrations. Exposure-response relationships showed that changes 
in C4 exposure are negatively correlated with changes in exposure of FGF19 and cilofexor. 
In a Phase 2 study GS-US-402-1852, evaluating the safety, tolerability and efficacy of 30 mg and 
100 mg cilofexor in subjects, 140 NASH patients were treated with cilofexor 100 mg, cilofexor 
30 mg or placebo orally once daily for 24 weeks. A decline of at least 30% in hepatic fat 
measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was observed 
in 38.9% of patients treated with cilofexor 100 mg (p 0.011 vs placebo), 14% treated with 
cilofexor 30 mg (p 0.87), and 12.5% with placebo. Improvements in liver biochemistry tests 
(serum GGT) and markers of reduced bile acid synthesis (serum C4 and bile acids) were 
observed in the 30 mg and 100 mg arms of cilofexor -treated patients. Cilofexor was generally 
well tolerated; moderate to severe pruritus, or itching, occurred in 14% of patients in the 
cilofexor 100 mg arm compared to 4% in the cilofexor 30 mg and placebo arms. Changes in lipid 
profile and glycemic parameters did not differ between cilofexor and placebo-treated patients. 
The most common adverse events in patients treated with cilofexor were pruritus, upper 
respiratory tract infection, headache and fatigue. Treatment was discontinued due to adverse 
events in one patient treated with cilofexor 100 mg (2%), five patients treated with cilofexor 
30 mg (9%), and two patients with placebo (7%).


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1.5.3.
Rationale for the Dose Selection of Firsocostat
The dose of firsocostat chosen for evaluation in this study, 20 mg QD, is supported by the safety, 
tolerability and effects of firsocostat on DNL from studies 0976-101, 0976-102, and 0976-103 
described in the IB, the efficacy observed in the Phase 2 NASH study (GS-US-426-3989), and 
the safety of firsocostat in subjects with cirrhosis due to NASH (proof of concept study 
GS-US-384-3914), including those with mild hepatic impairment (GS-US-426-3988). In healthy 
subjects, single doses of firsocostat up to 1000 mg or multiple daily doses (10 days) of 
firsocostat up to 200 mg were administered. In healthy but overweight or obese subjects, a single 
firsocostat dose of 20 mg resulted in a mean inhibition of fractional DNL of 71%. In study 
GS-US-426-3989, firsocostat 5 mg and 20 mg were evaluated for 12 weeks in subjects 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 MRI-PDFF. 
firsocostat 20 mg also had larger reductions in liver biochemistry (i.e., ALT) and serum markers 
of fibrosis (i.e., tissue inhibitor of metalloproteinase 1 (TIMP-1) and procollagen III amino 
terminal peptide (PIIINP)). In study GS-US-426-3989, approximately 40% of subjects were 
presumed to have advanced fibrosis at baseline based on MRE values ≥3.64 kPa and/or ELF™
Test scores ≥ 9.8. These subjects showed similar efficacy and safety profiles as subjects with less 
advanced fibrosis according to these noninvasive markers of fibrosis. Also, subjects with 
cirrhosis due to NASH have been dosed with firsocostat 20 mg for 12 weeks in the proof of 
concept study described above with similar safety as subjects with less advanced fibrosis. 
Additionally, nonclinical toxicology studies up to 26 and 39 weeks in duration have been 
conducted in rats and dogs, respectively, at exposure margins multiple folds above the expected 
clinical exposure. Firsocostat exposures in non-cirrhotic subjects are expected to remain 
> 48-and 206-fold lower than the firsocostat exposures observed at the NOAELs in the 39-week 
dog and 26-week rat toxicity studies, respectively. Based on preliminary data from Study 
GS-US-426-3988, firsocostat exposures in subjects with mild hepatic impairment (CP A) are 
expected to remain ≥ 22 and ≥105-fold lower than the firsocostat exposures observed at the 
NOAELs in the 39-week dog and 26-week rat toxicity studies, respectively. Based on 
preliminary PK data in subjects with mild hepatic impairment and the overall safety profile of 
firsocostat, dose adjustments are not considered necessary for subjects with compensated 
cirrhosis in this study. 
1.5.4.
Rationale for Study Population
The progression from NAFLD to NASH to cirrhosis occurs over decades. The highest levels of 
morbidity and mortality are found in NASH patients with advanced fibrosis and cirrhosis 
{Ekstedt 2014, Yeh 2014}. Thus, evaluating agents in this patient population is anticipated to
have the greatest impact on morbidity and mortality. 


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Inclusion criteria for this study were developed in order to enrich this small proof-of-concept 
study with subjects who have definite inflammatory and fibrotic processes that can be measured 
both through a historical biopsy and non-invasive tests. Specifically, all subjects must either have 
histologic evidence of NASH with F2-3 fibrosis, or have a clinical diagnosis of NAFLD with 
evidence of ≥ 10% hepatic steatosis on MRI-PDFF {Bannas 2015}, a Screening FibroTest®
<0.75 (unless historical liver biopsy does not reveal cirrhosis), and a FibroScan® with liver 
stiffness >7 kPa. 
Based on these criteria, subjects enrolled without a historical liver biopsy will have a high 
probability of NASH with fibrosis, a population with a large unmet medical need {Loomba 
2014}.
Ongoing clinical trials are evaluating the efficacy of cilofexor and firsocostat in combination for 
subjects with NASH with bridging fibrosis and compensated cirrhosis. Given the potential 
benefits of semaglutide in the NASH patient population, this study will evaluate the safety and 
tolerability of a GLP-1 receptor agonist as a component of future combination therapy for NASH 
(i.e., in addition to cilofexor or firsocostat alone, or to both). 
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study drug(s) in subjects with NASH. 
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3.
STUDY DESIGN
3.1.
Study Design
This is a proof of concept, open-label study evaluating the safety, tolerability, and efficacy of 
monotherapy and combination regimens in subjects with NASH.
Subjects meeting the study’s entry criteria will be randomly assigned in a 1:1:1:1:1 ratio to 1 of 5 
treatment groups, with approximately 20 subjects in each group, as shown in the figure below:
Figure 3-1.
Overall Study Design
Randomization will be stratified by the presence or absence of type 2 diabetes mellitus, as 
determined by medical history or based on the Screening laboratory values if previously 
undiagnosed (hemoglobin A1c [HbA1c] ≥ 6.5%).
3.2.
Study Treatments
Subjects meeting the study’s entry criteria will be randomly assigned in a 1:1:1:1:1 ratio to 1 of 5 
treatment groups, with approximately 20 subjects in each group, as shown in the Figure 3-1.
3.3.
Duration of Study
Participation in the study can last up to 35 weeks, which includes a 2-week Screening period, a 
2 week Pre-Treatment period, up to a 24-week Treatment period, and a 7-week Follow-Up 
period.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4. 
End of Study 
End of study is considered to be completion of the Telephone Follow-Up visit. 
3.5. 
Post Study Care 
There is no offered post study care. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 100 subjects with a clinical diagnosis of nonalcoholic fatty 
liver disease (NAFLD) with a Screening FibroTest® < 0.75 (unless all historical liver biopsies do 
not reveal cirrhosis), a Screening MRI-PDFF with ≥ 10% steatosis (as assessed by the central 
reader), and a Screening FibroScan® with liver stiffness ≥ 7 kPa, OR subjects with a historical
liver biopsy within 6 months of the date of the Screening Visit consistent with NASH 
(defined as the presence of steatosis, inflammation, and ballooning) with stage 2-3 fibrosis 
according to the NASH Clinical Research Network (CRN) classification (or equivalent).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Males and females between 18-75 years of age inclusive, based on the date of the Screening 
Visit;
2) Willing and able to provide informed consent prior to any study specific procedures being 
performed;
3) Subjects must meet all of the following conditions (a-d) OR (e):
a.
Clinical diagnosis of nonalcoholic fatty liver disease (NAFLD);
b. Screening FibroTest® < 0.75, unless all previous historical liver biopsies do not reveal 
cirrhosis. In subjects with Gilbert’s syndrome or hemolysis, FibroTest® will be calculated 
using direct bilirubin instead of total bilirubin;
c.
Screening MRI-PDFF with ≥ 10% steatosis, as assessed by the central reader. Historical 
MRI-PDFF within 4 weeks of the date of the Screening Visit may be used if deemed 
acceptable by the central reader;
d. Screening FibroScan® with liver stiffness ≥ 7 kPa. Historical FibroScan® within 4 weeks 
of the date of the Screening Visit is acceptable;
OR
e.
An historical liver biopsy within 6 months of the date of the Screening Visit consistent 
with NASH (defined as the presence of steatosis, inflammation, and ballooning) with 
stage 2-3 fibrosis according to the NASH Clinical Research Network (CRN) 
classification (or equivalent). Report will be reviewed by the Medical Monitor;


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4) Subject has the following laboratory parameters at the Screening Visit, as determined by the 
central laboratory:
a.
Alanine aminotransferase (ALT) ≤ 5 x ULN;
b. eGFR ≥ 30 milliliter/minute (mL/min), as calculated by the MDRD study equation;
c.
HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 μmol if HbA1c is unable to be resulted);
d. INR ≤ 1.2, unless due to therapeutic anti-coagulation therapy;
e.
Platelet count ≥ 100,000/μL;
f.
Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert’s syndrome present;
g. Calcitonin ≤ 100 ng/L;
5) Body Mass Index (BMI) > 23 kg/m2 and body weight of > 60 kg;
6) A negative serum pregnancy test is required for female subjects of childbearing potential as 
defined in Appendix 3;
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 3.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Documented weight loss > 5% within 6 months of the date of the Screening Visit; 
2) Any historical liver biopsy consistent with cirrhosis;
3) Pregnant or lactating females;
4) Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30 mL of alcohol is present in 1 12oz/360 mL beer, 1 4oz/120 mL glass of wine, and a 
1oz/30 mL measure of 40% proof alcohol);
5) Positive urine screen for amphetamines, cocaine or opiates (ie, heroin, morphine) at 
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 
6 months prior to the date of Screening Visit may be included in the study. Subjects with a 
positive urine drug screen due to prescription opioid-based or amphetamine-based 
medication are eligible if the prescription and diagnosis are reviewed and approved by the 
investigator;


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6) Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or 
variceal bleeding;
7) Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, 
hepatitis C, autoimmune disorders (eg, primary biliary cholangitis [PBC], primary sclerosing 
cholangitis [PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, 
clinically significant iron overload, or alpha-1-antitryspin deficiency requiring treatment;
8) History of liver transplantation;
9) History of hepatocellular carcinoma;
10) Weight reduction surgery in the past 2 years or planned during the study;
11) Chronic hepatitis B (HBsAg positive);
12) Chronic hepatitis C (HCV RNA positive). Subjects cured of HCV infection less than 2 years 
prior to the date of the Screening Visit are not eligible;
13) HIV Ab positive;
14) Unstable cardiovascular disease as defined by any of the following:
a.
Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary 
angioplasty within 6 months prior to the date of the Screening Visit;
b. Transient ischemic attack or cerebrovascular accident within 6 months prior to the date of 
the Screening Visit;
c.
Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy;
d. Symptomatic congestive heart failure;
e.
Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an 
automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial 
fibrillation is allowed;
f.
An emergency room visit or hospitalization for confirmed cardiovascular disease within 
6 months prior to the date of the Screening Visit;
15) History of a malignancy within 5 years of the date of the Screening Visit with the following 
exceptions:
a.
Adequately treated carcinoma in situ of the cervix;
b. Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer;


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16) Presence of acute pancreatitis within the past 180 days prior to the date of the Screening 
Visit;
17) History or presence of chronic pancreatitis;
18) Presence or history of type 1 diabetes mellitus;
19) For subjects with type 2 diabetes diagnosed prior to the date of the Screening Visit OR on 
Screening Visit labs (defined as HbA1c ≥6.5%), subjects must have no evidence of 
uncontrolled and potentially unstable retinopathy or maculopathy as determined by: 
a.
A fundus exam performed in the 90 days prior to the date of the Screening Visit. If there 
has been worsening of the subject’s visual function since this historical fundus exam in 
the opinion of the investigator, then the fundus exam must be repeated;
OR
b. A fundus exam performed between the date of the Screening Visit and Enrollment 
(Day -14) 
Pharmacological pupil-dilation is a requirement in both of the above cases unless using a 
digital fundus photography camera specified for non-dilated examination;
20) Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma;
21) Treatment with GLP-1 RAs in the period from 90 days prior to the date of the Screening 
Visit;
22) Subjects on Vitamin E regimen ≥800 IU/day must be on a stable dose (defined as no changes 
in prescribed dose, new Vitamin E containing medications, or discontinuation) for at least 
180 days prior to the date of the Screening Visit and in the period between the date of the 
Screening Visit and Enrollment (Day -14);
23) Subjects on antidiabetic medications must be on a stable dose for at least 90 days prior to the 
date of the Screening Visit and in the period between the date of the Screening Visit and 
Enrollment (Day -14); 
24) Use of any prohibited concomitant medications as described in Section 5.6;
25) Any investigational medication or device within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to the date of the Screening Visit throughout 
the study (e.g., obeticholic acid, elafibranor, and cenicriviroc) is prohibited;
26) Known hypersensitivity to the study drug, the metabolites, or formulation excipient.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of type 2 
diabetes mellitus, as determined by medical history or based on the Screening Visit lab values if 
previously undiagnosed (HbA1c ≥ 6.5%).
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS. Study drugs will be dispensed by the study pharmacist, or designee 
to the subjects.
Study drugs will be dispensed in an open-label fashion to the subjects.
5.2.
Description and Handling of Semaglutide 3.0 mg/mL
The drug product formulation for the semaglutide solution for injection has the composition 
shown in Table 5-1. All other ingredients 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.
Table 5-1.
Composition of Semaglutide Solution for Injection
Name of ingredient
Function 
Pharmacopoeia
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
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.


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5.2.1.
PDS290 pen-injector for Semaglutide for use in Clinical Trials
Device Information
The PDS290 pen-injector for semaglutide is a dial-a-dose prefilled device integrated with a 3 mL 
cartridge filled with semaglutide 3.0 mg/mL. 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 semaglutide can be used multiple times until either the in-use time 
has passed or the cartridge is empty. 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 semaglutide are 
included in the directions for use (DFU) provided to trial sites and to be provided directly to 
subjects. Storage instructions are printed on the drug product label and are also provided in the 
Site Operations Manual. Investigators must ensure that these instructions are strictly followed.
Regulatory Status
The PDS290 pen-injector for semaglutide complies with relevant standards and regulations. 
Several other variants of PDS290 pen-injectors have been approved worldwide since 2010 for 
s.c. injection of insulins (under the brand name modifier FlexTouch®), growth hormone
(under the brand name modifier FlexPro®) and GLP-1 products (Saxenda®, Ozempic®).
Existing Clinical Data
The adequate safety and performance of the PDS290 pen-injector for semaglutide (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 post-market safety data for the PDS290 pen-injector family. 
It is concluded that the PDS290 pen-injector for semaglutide (3.0 mg/mL) gives a favorable 
benefit-risk profile for administration of semaglutide in NASH clinical trials.
Thus far, no clinical trials have been completed with the PDS290 pen-injector for semaglutide 
(3.0 mg/mL) in NASH clinical programs.


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5.2.2.
Storage and Handling
Drug products must be stored at 2 8°C. Exposure to light and freezing must be avoided. Under 
these storage conditions, semaglutide products will retain full biological activity until the expiry 
date stated on the label. As for other parenteral preparations, the semaglutide trial products 
should be inspected visually for particulate matter and discoloration prior to administration. The 
products should be discarded if either is present. Only use the semaglutide solution for injection 
if it has colorless or almost colorless appearance free from turbidity and essentially free from 
particulate matter.
5.2.3.
Shelf-life and in-use time for Semaglutide in PDS290 
The shelf life of semaglutide in the PDS290 pen-injector is up to 36 months when stored at 
2-8°C. The product should not be used after the expiry date unless an extension of the expiry 
date has been notified and received in writing from Gilead Sciences, Inc. The in-use time is up to 
8 weeks between 8-30°C. Do not refrigerate. Exposure to excessive heat and light as well as 
freezing must be avoided during use. 
5.3.
Description and Handling of Cilofexor (GS-9674) 
5.3.1.
Formulation
Cilofexor is supplied as 100 mg and 30 mg strength (as free form equivalent) tablets. The tablets 
contain cilofexor-02 (tromethamine salt) and the following inactive ingredients: mannitol, 
microcrystalline cellulose, crospovidone, magnesium stearate and film-coating material 
polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, yellow iron oxide and black iron 
oxide. Cilofexor 100 mg tablets are capsule-shaped, film-coated green tablets debossed with 
“100” on one side and “GSI” on the other side. Cilofexor 30 mg tablets are round, film-coated 
green tablets debossed with “30” on one side and “GSI” on the other side.
5.3.2.
Packaging and Labeling
Cilofexor 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, aluminum-faced liner.
Study drug(s) to be distributed to centers in the US shall be labeled to meet applicable 
requirements of the United States Food and Drug Administration (FDA) and/or other local 
regulations.
5.3.3.
Storage and Handling
Study drug cilofexor should be stored below 30°C (86 °F). Storage conditions are specified on 
the label.


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Until dispensed to the subjects, all bottles of study drugs 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. 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 cilofexor tablets.
5.4.
Description and Handling of Firsocostat (GS-0976) 
5.4.1.
Formulation
Firsocostat tablets are round, plain-faced, film-coated white tablets containing 20 mg firsocostat. 
In addition to the active ingredient, firsocostat tablets contain the following inactive ingredients: 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.
5.4.2.
Packaging and Labeling
Firsocostat tablets are packaged in white HDPE bottles. Each bottle contains 30 tablets 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 centers in the US shall be labeled to meet applicable 
requirements of the United States Food and Drug Administration (FDA) and/or other local 
regulations.
5.4.3.
Storage and Handling
Firsocostat tablets should be stored at controlled room temperature of 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are specified on 
the label. 
Until dispensed to the subjects, all bottles of study drugs 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. 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.


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5.5.
Dosage and Administration 
The administration of study drug will be recorded in the source documentation and in the 
electronic case report form (eCRF).
Firsocostat and cilofexor tablets will be provided by Gilead Sciences, Inc. and semaglutide 
3.0 mg/ml in PDS290 pen-injectors will be provided by Gilead Sciences, Inc. and manufactured 
by Novo Nordisk, Inc. Subjects will take semaglutide subcutaneously with a PDS290 
pen-injector at approximately the same time each week. Subjects should be instructed to inject 
semaglutide once-weekly at the same day of the week throughout the trial. Injections may be 
administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. 
Subjects should be encouraged to inject in the same area throughout the trial, but changing 
between left and right side is allowed. Subjects will take firsocostat and/or cilofexor tablets
(if applicable) at approximately the same time each day, with or without food, swallowed whole 
with water. For firsocostat and cilofexor, a dose will be considered missed if the subject cannot 
take the complete dose within 12 hours of their regular dosing time. If a subject misses a dose, 
the subject should take their next dose at the regular dosing time.
For semaglutide, if a single dose of trial product is missed, it should be administered as soon as 
noticed, provided the time to the next scheduled dose is at least 48 hours. If a dose is missed and 
the next scheduled dose is less than 48 hours away, the subject should not administer a dose until 
the next scheduled dose. A missed dose should not affect the scheduled dosing day of the week. 
If ≥ 2 consecutive doses of trial product are missed, the subject should be encouraged to 
recommence the treatment if considered safe as per the investigator’s discretion and if the subject 
does not meet any of the discontinuation criteria. The trial product should be continued as early 
as the situation allows. The missed doses should not affect the scheduled dosing day of the week. 
The start dose for re-initiation of trial product is at the investigator’s discretion. In case of 
questions related to re-initiation of trial product, the investigator should consult the Medical 
Monitor.
Study drug dosing and administration will occur as follows, based on-treatment group 
randomization:

Treatment Group A: Semaglutide administered subcutaneously with pre-filled pen-injector 
once weekly

Treatment Group B: Semaglutide administered subcutaneously with pre-filled pen-injector 
once weekly, one firsocostat 20 mg tablet, administered orally once daily without regard to 
food

Treatment Group C: Semaglutide administered subcutaneously with pre-filled pen-injector 
once weekly, one cilofexor 30 mg tablet, administered orally once daily without regard to 
food


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
Treatment Group D: Semaglutide administered subcutaneously with pre-filled pen-injector 
once weekly, one cilofexor 100 mg tablet, administered orally once daily without regard to 
food

Treatment Group E: Semaglutide administered subcutaneously with pre-filled pen-injector 
once weekly, one firsocostat 20 mg tablet administered orally once daily and one cilofexor 
30 mg tablet administered orally once daily, both without regard to food
5.5.1.
Management of Semaglutide Dose Escalation
After randomization semaglutide will be initiated with a starting value of 8 (0.24 mg), as shown 
on the dose counter of the pre-filled pen-injector, for the first 4 weeks, and subsequently the 
value will be increased every 4 weeks. All subjects must aim at reaching the recommended target 
dose of semaglutide s.c. 2.4 mg once-weekly.
Table 5-2.
Semaglutide Dose Escalation Schedule
Product
Dose
Volume
Value shown in the 
dose counter
Duration
Semaglutide 
3.0 mg/mL PDS290
0.24 mg
80 μl
8
Day 1* through Week 4
Semaglutide 
3.0 mg/mL PDS290
0.50 mg
170 μl
17
Weeks 5 through 8
Semaglutide 
3.0 mg/mL PDS290
1.0 mg
340 μl
34
Weeks 9 through 12
Semaglutide 
3.0 mg/mL PDS290
1.7 mg
570 μl
57
Weeks 13 through 16
Semaglutide 
3.0 mg/mL PDS290
2.4 mg
800 μl
80
Weeks 17 through 24
*
Subject will take first dose of study drugs on site at Day 1.
If a subject does not tolerate the planned 4-week dose-escalation regimen due to GI AEs or for 
other reasons as judged by the investigator, the subject is allowed to stay longer at the individual 
dose steps. It is recommended that the Investigator aim for maximum 1 extra week on each dose 
level. If the planned dose escalation regimen is not adhered to, the Investigator should evaluate 
weekly if the dose can be escalated to the next planned level.
If a subject does not tolerate the recommended target dose of s.c. 2.4 mg once-weekly, the 
subject may stay at the lower dose level. This is only allowed if the subject would otherwise 
discontinue trial product completely and if considered safe to continue on trial product, as per the 
investigator’s discretion. It is recommended that the subject makes at least one attempt to 
escalate to the recommended target dose of s.c. 2.4 mg once-weekly, as per the investigator’s 
discretion.
It is recommended that the investigator contact the Medical Monitor 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 
concomitant medications taken within 30 days prior to the date of the Screening Visit and any 
taken during the study until the end of the Follow-Up period.
Subjects on Vitamin E regimen ≥ 800 IU/day must be on a stable dose (defined as no changes in 
prescribed dose, new Vitamin E containing medications, or discontinuation) for at least 180 days 
prior to the date of the Screening Visit and in the period between the date of the Screening Visit
and Enrollment (Day -14). If possible, the doses of these medications should remain stable 
through the end of study.
Subjects treated with insulin at the date of the Screening Visit:
Throughout the trial, insulin dose should be titrated at the discretion of the investigator. 
For the individual subject, increasing the insulin dose before two weeks after the end of 
the final dose escalation should be avoided, unless required to control acute 
hyperglycemia and acute diabetic complications.
Subjects treated with insulin and HbA1c ≤ 8.0 % at the date of the Screening Visit: 
Subjects treated with semaglutide 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 trial should be 
considered at the discretion of the investigator.
Subjects treated with sulfonylureas at the date of the Screening Visit:
Subjects treated with semaglutide 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 trial 
should be considered.
Treatment with GLP-1 RAs, other than semaglutide, is prohibited in the period from 90 days 
prior to the date of the Screening Visit and through the end of study. 
Any investigational medication or device within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to Screening up to and through the end of study 
(eg, obeticholic acid, elafibranor, and cenicriviroc) is prohibited. 
The following medications are prohibited for all treatment groups, from 30 days prior to Day 1
and through the end of study:

Any medication or supplement prescribed for weight loss.  


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
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers 
of drug transporters OATP1B1 or 1B3, potent or moderate inducers of CYP2C8, or potent 
inducers of CYP3A4) with study 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 should be used with caution are listed 
below in Table 5-3.
Table 5-3.
List of Representative Disallowed and Use with Caution Medicationsa
Disallowed 30 days prior to Day 1 through the End of Treatment
Chronic systemic corticosteroidsb, tacrolimus, sirolimus, cyclosporine, mycophenolate mofetil, infliximab, and 
methotrexate
H2-Receptor antagonistsc
azithromycin, clarithromycin, erythromycin
phenobarbital, phenytoin, carbamazepine, oxcarbazepine
rifamycins, isoniazid
Bosentan
St. John’s Wort, Echinacea, milk thistle (ie, silymarin), Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Otherd: gemfibrozil, modafinil
Agents to be used with Caution from 30 days prior to Day 1 through End of Treatment
antacidse
cholestyramine, colestipol, colesevelemf
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
H2 Receptor antagonists can be taken up to 3 days prior to Day 1.
d
May result in an increase or decrease in the concentration of study drugs.
e
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.
f
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) oral study drug administration.


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5.7.
Accountability for Deuterated Water and Investigational Medicinal Product 
(IMP) and Devices
The investigator is responsible for ensuring adequate accountability of all used and unused
deuterated water, study drug, kits, and devices. This includes acknowledgement of receipt of 
each shipment of deuterated water, study drug and/or devices (quantity and condition). All used 
and unused deuterated water, study drug and/or devices dispensed to subjects must be returned to 
the site.
IMP and device accountability records will be provided to each study site to:

Record the date received and quantity of deuterated water, study drug and/or devices

Record the date, subject number, deuterated water, study drug lot/kit number and/or devices 
dispensed

Record the date, quantity of used and unused deuterated water, study drug and/or devices
returned, along with the initials of the person recording the information.
5.7.1.
Investigational Medicinal Product and Device Return or Disposal
Study drug return disposal will be performed as outlined in Section 9.1.8.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject screened and/or enrolled in the study are 
presented in tabular form in Appendix 2 and described in the text that follows. Additional 
information is provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to Enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the Screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
Entry into Screening does not guarantee Enrollment into the study. In order to manage the total 
trial Enrollment, Gilead, at its sole discretion, may suspend Screening and/or Enrollment at any 
site or trial-wide at any time.
6.2.
Screening Assessments
6.2.1.
Screening Visit
Subjects will be screened within 2 weeks prior to Day -14 to determine eligibility for 
participation in the study. The Screening period also may be extended under special 
circumstances with the explicit approval of Gilead Sciences, Inc. 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
Screening Visit to ensure an approximate 10-hour fast prior to the fasting blood sample 
collection the next morning.
The following will be performed and documented during the Screening period:

Obtain written informed consent before initiation of any Screening procedures

Review and record whether the subject has met inclusion and exclusion criteria

Obtain Screening number from IWRS

Obtain medical history including, but not limited to, information related to the following: 
type 2 diabetes mellitus, NAFLD, and NASH


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
Review of historical liver biopsy report (if applicable) obtained within the last 6 months of 
the date of the Screening Visit.

Complete physical examination including vital signs, body weight, and height

Perform fundus exam with pharmacological pupil-dilation or digital fundus photography 
specified for non-dilated examination (For subjects with type 2 diabetes diagnosed prior to 
the date of the Screening Visit OR on Screening Visit labs (defined as HbA1c ≥6.5% only). 
If a fundus exam matching this description has been performed within 90 days prior to the 
date of the Screening Visit, the procedure does not need to be repeated, unless there has been 
worsening of visual function since the historical fundus exam in the opinion of the 
investigator.)

Conduct standard 12-lead ECG

Perform MRI-PDFF (Historical MRI-PDFF within 4 weeks of the date of the Screening Visit 
acceptable)

Perform MRE (Historical MRE within 4 weeks of the date of the Screening Visit acceptable)

Perform FibroScan® (Historical FibroScan® within 4 weeks of the date of the Screening Visit 
acceptable)

Collect blood samples for:
Chemistry and hematology
Coagulation Panel
Insulin and Lipids
Hemoglobin A1c
eGFR
HIV-1, HBV & HCV Serology
Calcitonin 
ELF™ Test 
FibroTest® 
Serum pregnancy test (only for female subjects of childbearing potential)
CCI


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
Collect urine samples for:
Drug screen 

Record any serious adverse events (SAEs) and all adverse events (AEs) related to protocol 
mandated procedures occurring after signing of the informed consent form.

Record all concomitant medications that the subject has taken within 30 days prior to the date 
of the Screening Visit.
From the time of obtaining informed consent through the first administration of study drug(s), 
record all SAEs, as well as any adverse events related to protocol-mandated procedures on the 
adverse events case report form eCRF. All other untoward medical occurrences observed during 
the Screening period, including exacerbation or changes in medical history are to be captured on 
the medical history eCRF. See Section 7 Adverse Events and Toxicity Management for 
additional details.
After review of the inclusion and exclusion criteria to confirm eligibility, subjects will return to 
the site for Enrollment and the initiation of Kinetic Biomarkers Cycle 1 on Day -14.
6.3.
Pretreatment Assessments
6.3.1.
Day -14 Visit 
After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will be 
enrolled via IWRS.
Subjects returning to the clinic for Enrollment on Day -14 should be instructed to fast (no food or 
drink, except water) on the evening prior to the visit to ensure an approximate 10-hour fast prior 
to the fasted blood sample collection the next morning. The following assessments will be 
performed and documented at the visit:

Review and record whether the subject has met eligibility criteria 

Update medical history if a change has occurred during the Screening period

Symptom driven physical examination 

Record vital signs and body weight

Collect blood samples (prior to deuterated water administration):
Chemistry and Hematology 
Coagulation panel 
CCI


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eGFR
Kinetic Biomarkers

Collect urine samples (prior to deuterated water administration):
Kinetic Biomarkers

Dispense deuterated water. Subjects will drink approximately 45 mL of deuterated water 
three times per day starting on Day -14 through Day -8. The first dose of deuterated water 
will be administered under the supervision of investigative site personnel and monitored for 
at least 30 minutes after for any side effects.  

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the previous visit.

Record all concomitant medications that the subject has taken since the previous visit.
Refer to the laboratory manual for additional information on the Kinetic biomarkers assessments.
6.3.2.
Day -11 and Day -7 Visits (± 1 day) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at each visit:

Collect blood samples:
Kinetic Biomarkers

Collect urine samples:
Kinetic Biomarkers

Subjects will continue to drink deuterated water three times per day through Day 8. 

Review deuterated water compliance (Day -7 only)

Record any serious adverse events and all adverse events related to protocol mandated 
procedures since the previous visit.

Record all concomitant medications that the subject has taken since the previous visit.
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.


Protocol GS-US-454-5533 
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6.4. 
6.4.1. 
Treatment Assessments 
Day 1 Visit 
Subjects will be randomized to study drug assigmnent via IWRS. 
Final 
Amendment2 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. The following assessments will be perfonn ed and docmn ented at the Day 1 Visit prior 
to dosing: 
• 
Symptom driven physical examination 
• 
Record vital signs and body weight 
• 
QoL questio1maires (CLDQ-NAFLD, EQ-5D) 
Note: It is recommended that the questionnaires be completed prior to any study procedures 
being perfonned and prior to the subject seeing a health care provider. 
• 
Subjects with type 2 diabetes must be instructed to measure their blood glucose in c01mection 
with symptoms of hypoglycemia from the Day 1 Visit through the Telephone Follow-Up 
Visit. Plasma glucose values ~70 mg/dL (~3.9 mmol/L) should be reported to the site as a 
hypoglycemic episode. Hypoglycemic episodes must be reported as an AE in the AE 
fonn. If the hypoglycemic episode fulfills the serious criteria, the event must be reported in 
the eCRF database and to Gilead PYE as an SAE. 
• 
Calculate CP Score once central laboratory results are available 
• 
Collect blood samples for: 
I 
Chemistry and Hematology 
Coagulation panel 
Insulin and Lipids 
eGFR 
Kinetic Biomarkers 
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
Collect urine samples:
Urine pregnancy test (only for female subjects of childbearing potential)
Kinetic Biomarkers

Dispense study drugs, and provide subject with dosing instruction on appropriate dosing and 
administration; subject will take the Day 1 dose of study drugs on-site

Record any SAEs and all AEs related to protocol mandated procedures occurring since the 
previous visit

Record all concomitant medications that the subject has taken since the previous visit
6.4.2.
Day 7 (Week 1) Visit (± 3 days)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. Subjects should also be instructed to hold their dose of study drug on the morning of 
the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at this visit:

Symptom driven physical examination

Record vital signs and body weight

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
eGFR
Single PK sampling anytime during the visit

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
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6.4.3.
Day 28 (Week 4) Visit (± 3 days) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
Insulin and Lipids
eGFR
Single PK sampling anytime during the visit

Collect urine samples for: 
Urine pregnancy test (only for female subjects of childbearing potential)

Review study drug dosing compliance

Dispense study drugs 

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.4.
Day 56 (Week 8) Visit (± 3 days) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.


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The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
Insulin and Lipids
eGFR
Single PK sampling anytime during the visit

Collect urine samples for:
Urine pregnancy test (only for female subjects of childbearing potential)

Review study drug dosing compliance

Dispense study drugs 

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.5.
Day 84 (Week 12) Visit (± 3 days) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Perform MRI-PDFF


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
Perform MRE

Perform FibroScan® 

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
Insulin and Lipids
Hemoglobin A1c
eGFR
FibroTest®
ELF™ Test
Single PK sampling anytime during the visit

Collect urine samples for:
Urine pregnancy test (only for female subjects of childbearing potential)
 

QoL questionnaires (CLDQ-NAFLD, EQ-5D)
Note: It is recommended that the questionnaires be completed prior to any study 
procedures being performed and prior to the subject seeing a health care provider.

Review study drug dosing compliance

Dispense study drugs 

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
CCI
CCI


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6.4.6.
Day 112 (Week 16) Visit (± 3 days)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
eGFR

Collect urine samples for: 
Urine pregnancy test (only for female subjects of childbearing potential)

Review study drug dosing compliance

Dispense study drugs 

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.7.
Day 140 (Week 20) Visit (± 3 days)  
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.


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The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
eGFR

Collect urine samples for: 
Urine pregnancy test (only for female subjects of childbearing potential)

Review study drug dosing compliance

Dispense study drugs 

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.8.
Day 154 (Week 22) Visit (± 1 day) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
Subjects will complete one additional cycle of Kinetic Biomarkers from Day 154 through 
Day 160 (Cycle 2).
The following assessments will be performed and documented at the visit:

Collect blood samples for (prior to dose of deuterated water administration):
Kinetic Biomarkers 

Collect urine samples (prior to dose of deuterated water administration):
Kinetic Biomarkers


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
Dispense deuterated water. Subjects will drink approximately 45 mL of deuterated water 
three times per day starting on Day 154 through Day 160. The first dose of deuterated water 
in Cycle 2 will be administered under the supervision of investigative site personnel and 
monitored for at least 30 minutes after for any side effects.

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.9.
Day 157 (Week 22 Day 2) and Day 161 (Week 23) Visit (± 1 day)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Collect blood samples for:
Kinetic Biomarkers 

Collect urine samples:
Kinetic Biomarkers

Subjects will continue to drink deuterated water three times per day through Day 160.

Review deuterated water compliance (Day 161 (Week 23) only)

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.10.
Day 168 (Week 24) / End of Treatment Visit (± 3 days)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination


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
Record vital signs and body weight 

Conduct standard 12-lead ECG

Perform MRI-PDFF

Perform MRE

Perform FibroScan®

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
Insulin and Lipids
Hemoglobin A1c
eGFR
FibroTest®
ELF™ Test
Kinetic Biomarkers

Collect urine samples for: 
Urine pregnancy test (only for female subjects of childbearing potential)
Kinetic Biomarkers

QoL questionnaires (CLDQ-NAFLD, EQ-5D)
Note: It is recommended that the questionnaires be completed prior to any study 
procedures being performed and prior to the subject seeing a health care provider.

Dispense urine pregnancy testing kit and provide instructions for home testing at the 
Telephone Follow-Up visit (only for female subjects of childbearing potential). 
CCI
CCI


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
Review study drug dosing compliance.

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.11.
Early Termination (ET) Visit
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of 
last dose of study drugs or pretreatment deuterated water. 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs and body weight 

Conduct standard 12-lead ECG

Perform MRI-PDFF (at the discretion of the investigator)

Perform MRE (at the discretion of the investigator)

Perform FibroScan® (at the discretion of the investigator)

Calculate CP Score once central laboratory results are available

Collect blood samples for:
Chemistry and Hematology
Coagulation panel
eGFR
Insulin and Lipids (at the discretion of the investigator)
Hemoglobin A1c (at the discretion of the investigator)
FibroTest® (at the discretion of the investigator)
ELF™ Test (at the discretion of the investigator)
CCI


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
Collect urine samples for: 
Urine pregnancy test (only for female subjects of childbearing potential)

Dispense urine pregnancy testing kit and provide instructions for home testing at the 
Telephone Follow-Up visit (only for female subjects of childbearing potential). 

Review study drug dosing compliance

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit
6.4.12.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator. At a 
minimum, the following will be performed and documented.

Symptom driven PE

Record vital signs, and body weight

Collect blood samples for:
Chemistry and Hematology
Coagulation panel 

Record all concomitant mediations that the subject has taken since the previous visit

Record any SAEs / AEs since the previous visit

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.
Posttreatment Assessments
6.5.1.
Telephone Follow-Up Visit (± 3 days) 
Subjects that received at least one dose of study drug will be contacted for a Telephone 
Follow-Up Visit 7 weeks after the date of the last dose of study drugs. 
The following assessments during the Telephone Follow-Up visit:

Record all concomitant medications that the subject has taken since previous study visit
CCI


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
Record any SAEs / AEs since the previous visit

Record subject reported results of the urine pregnancy test (only for female subjects of 
childbearing potential).
At the discretion of the investigator, an unscheduled visit may be completed if the subject reports 
abnormal or concerning symptoms.
Table 6-1.
Visit Windows
Study Visit
Window
Screening Visit
≤ 2 weeks prior to Day -14, window begins with the signing of the 
informed consent*
Day -14 
Day of enrollment and first dose of deuterated water
Day -11 & Day -7 
± 1 day 
Day 1 
Day of randomization and first dose of study drugs. All 
on-treatment study visits are calculated based on the Day 1 date
Day 7 (Week 1), Day 28 (Week 4), 
Day 56 (Week 8), Day 84 (Week 12), 
Day 112 (Week 16) & Day 140 (Week 20)
± 3 days
Day 154 (Week 22), 
Day 157 (Week 22 Day 2) & 
Day 161 (Week 23)
± 1 day
Day 168 (Week 24/EOT)
± 3 days
ET Visit
Within 30 days of last dose of study drug or pre-treatment 
deuterated water
Telephone Follow-Up Visit 
± 3 days
* The Screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences, Inc.
6.6.
Criteria for Discontinuation of Study Treatment
Study drug may be discontinued in the following instances:

Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product

Diagnosis of acute pancreatitis

Diagnosis of medullary thyroid carcinoma

Surgical treatment for obesity

Treatment with other GLP-1 receptor agonists other than semaglutide 


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
Subject progression to decompensated cirrhosis, as defined by any of the following:
Clinically apparent ascites requiring treatment
HE of Grade 2 or above (according to the West Haven criteria in Appendix 5) requiring 
treatment.
Portal hypertension-related upper gastrointestinal bleeding identified by endoscopy and 
requiring hospitalization, including events of bleeding from esophageal varices, gastric 
varices, and portal hypertensive gastropathy.

CP score ≥ 7 on two consecutive occasions at least two weeks apart unless due to an alternate 
etiology (e.g., therapeutic anticoagulation); refer to Section 7.6.3.

Liver transplantation 

Subject develops an SAE consisting of a serious hypersensitivity reaction to study drug

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 subject 
may resume study dosing at the discretion of the Investigator, in consultation with the 
Medical Monitor.

Unacceptable toxicity or toxicity that, in the judgment of the Investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest.

Subject or Investigator request to discontinue for any reason.

Significant subject noncompliance.

Significant protocol violation that impacts subject safety.

Pregnancy during the study; refer to Appendix 3

Discontinuation of the study at the request of Gilead, a regulatory agency, or an IRB.
6.7.
Assessments for Premature Discontinuation from Study
It is recommended that subjects who discontinue study drugs be encouraged to stay on study and 
complete the scheduled assessments. Subjects prematurely discontinuing from the study 
(eg, due to subject withdrawing consent, investigator decision, or sponsor decision) should 
complete an ET visit within 30 days of last dose of study drugs or pretreatment deuterated water. 
Subjects that received at least one dose of study drug will be contacted for a Telephone 
Follow-up Visit 7 weeks after the date of the last dose (refer to Section 6.4.10). Discussion with 
the Medical Monitor prior to discontinuation of study drug or study is recommended
If a subject is lost to follow-up, survival data may be gathered from public records such as 
government census or death records (if permitted by local regulations) prior to the completion of 
the study.


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6.8.
Interruption of Study Drug
If dosing is interrupted (i.e., as a result of an AE), the subject must stop dosing of all study drugs. 
Every attempt should be made to keep the subject in the study and continue to perform the 
required study-related procedures. Discussion with the Medical Monitor is recommended. If this 
is not possible or acceptable to the subject or Investigator, the subject may be withdrawn from 
the study. 
6.9.
End of Study
End of study is considered to be completion of the Telephone Follow-Up visit.
6.10.
Description of Assessments
6.10.1.
Clinical Laboratory Analytes
Fasting is required prior to all study visits.
Chemistry:
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline 
phosphatase (ALP), bicarbonate, blood urea nitrogen (BUN),) creatine kinase (CPK), calcium, 
chloride, creatinine, glucose, magnesium, phosphorus, potassium, sodium, total and direct 
bilirubin, total protein, uric acid, and gamma-glutamyl transferase (GGT). 
Hematology:
Hematocrit (Hct), hemoglobin (Hb), platelet count, red blood cell count (RBC), white blood cell 
count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV).
Coagulation Panel:
INR, prothrombin time (PT), partial thromboplastin time (PTT).
Insulin and lipids:
Insulin homeostasis model assessment of Insulin resistance (HOMA-IR, based on fasting glucose 
and insulin), C-peptide and lipid panel.
Pregnancy Tests:
Serum β-hCG or urine β-hCG (if positive, requires immediate confirmation with serum β-hCG).


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Additional Tests: 
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HIV-1 (reflex to HIV-1 RNA), HBV (HBsAg), HCV (reflex to HCV RNA) serology, urine drug 
screen (for amphetamines, cocaine, methadone, opiates), eGFR as calculated by MDRD, HbAlc, 
calcitonin, genomic sample collection, ELfTM Test, and FibroTest®. 
Phannacokinetic (PK) Assessments: 
Single PK samples may also be used to measure protein-binding of study drug(s) and/or its 
metabolites, as applicable. 
Biomarker Tests: 
Kinetic Biomarker Assessments 
6.10.2. 
Creatinine Clearance/eGFR 
eGFR is estimated by creatinine clearance calculated by as calculated by the Modification of 
Diet in Renal Disease (MDRD) Study equation: 
eGFR (mL/min/1.73 m2) 
175 x Serum Creainine-1.154 x (Age)--0-203 x (1.212 if 
African American) x (0. 742 if female) 
Serum creatinine in umol/L should be rom1ded to zero decimal places and converted to mg/dL by 
multiplying by 0.01131 prior to applying the fonnula. Creatinine in mg/dL is rom1ded to 
2 decimal places prior to applying fonnula. 
6.10.3. 
Child-Pugh (CP) Score 
Child Pugh score is used to assess the prognosis of chronic liver disease, primarily cirrhosis. 
CP scores will be calculated by the site from the central laboratory values at each applicable 
visit. 
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Table 6-2. 
Child-Pugh Classification of the Severity of Cirrhosis 
I 
2 
Hepatic 
Medication-Controlled 
Encephalopathy 
No encephalopathy and 
Subject is lethargic, may 
(HE) 
not on any treatment for 
have moderate confusion 
hepatic encephalopathy 
Subject is receiving medical 
Ascites 
No ascites and not on 
treatment for ascites 
Bilirubin (mg/dL) 
< 2 
Albumin (g/dL) 
> 3.5 
INR 
< 1.7 
CP 
is obtained by adding the score for each parameter. 
CP class: 
A 
5 6 points 
B 
7 9 points 
C 
IO 15 po ints 
therapy for HE 
Mild/Moderate 
Cross sectional imaging 
showing ascites 
Abdominal distension 
Medication for ascites 
2-3 
2.8-3.5 
1.7-2.3 
3 
Medication-Refractorl'. 
Marked confusion/incoherent, 
rousable but sleeping or 
comatose 
Severe 
(diuretic-refractor:i} 
Visible clinically 
> 3 
< 2.8 
> 2.3 
Records of concomitant medications for ascites and HE will be collected in the eCRF. 
6.10.4. 
MRE and MRI-PDFF 
The sites will perfonn liver stiffness assessments by MRE (shear wave 60 Hz) and MRI-PDFF at 
the Screening Visit, Day 84 (Week 12) and Day 168 (Week 24). For ET visits, the assessments 
are perfonned at the discretion of the investigator. The assessments can occur sequentially. 
At least 4 hours fasting is reco1mnended prior to all MR assessments. The MRE and MRI-PDFF 
sc 
· 
ET visits 
Please refer to the MR Procedures Manual for instructions on MRE and MRI-PDFF 
measurements. 
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6.10.5.
FibroScan®
FibroScan® examinations will be performed at the Screening Visit, Day 84 (Week 12) and 
Day 168 (Week 24) and median liver stiffness in kilopascals (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 interquartile range of CAP values will be recorded 
from FibroScan® examinations. For ET visits, the assessments are performed at the discretion of 
the investigator.
For individual subjects, the same device must 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 XL probe should be used at all exams if available. If an XL 
probe is not available and/or a valid result cannot be obtained, an examination with the M probe 
must be performed and the result recorded. At least 2-3 hours fasting is recommended prior to all 
elastography assessments.
6.10.6.
Electrocardiogram
Standard 12-lead electrocardiogram (ECG) assessments will be performed at Screening,
Day 168 (Week 24) and the Early Termination (ET) visits. The Investigator will review the 
ECGs for any clinically significant abnormalities to ensure subject 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.
6.10.7.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
the Screening period.
6.10.8.
Physical Examination
A complete physical examination must 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. Height, vital signs, and body weight will also be collected.
The focus of a symptom driven PE will be determined by the investigator based on subject
complaints. For example, if a subject complains of a cough, a lung exam should be performed. If
consistent with pneumonia (rales/crackles on exam) then an AE would be documented.
Height and body weight will be collected at specified time points.


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6.10.9.
Fundus Examination
For subjects with type 2 diabetes (from medical history or from Screening Hemoglobin A1c 
≥6.5%), a fundus exam will be performed at Screening. Fundus examinations require 
pharmacological dilation of both pupils or the use of a digital fundus photography camera 
specified for non-dilated examination. Results of the fundus exam will be evaluated by the
investigator and the investigator evaluation must be documented either on the fundus 
examination result report or in the subject’s medical record. 
The investigator or medically qualified delegate must sign, date and interpret the fundus 
examination by using the following categories:

Normal

Abnormal
Was the result clinically significant? (Yes/No)
If a fundus examination matching this description has been performed within 90 days prior to the 
date of the Screening Visit, 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 Enrollment (Day -14). 
If the dilated fundus examination is performed before the subject has signed the informed 
consent form, it must be documented in the medical records that the reason for performing the 
procedure was not related to this trial.
6.10.10.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, and 
temperature.
Blood pressure will be measured using the following standardized process:

Subject 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 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.10.11.
Pregnancy Testing
All females of childbearing potential will have a serum pregnancy test at Screening. Urine
pregnancy testing will occur at Day 1 (prior to dosing), Week 4, Week 8, Week 12, Week 16, 
Week 20 and Week 24 (EOT) or ET visits. All females of childbearing potential that received at 
least one dose of study drug will be dispensed a urine pregnancy testing kit at the
Week 24 (EOT) or ET visit for home testing at the Telephone Follow-Up visit. At the Telephone 


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Follow-Up visit, subjects will be requested to report the result of the urine pregnancy tests. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drug 
iimnediately (if applicable) and return to the clinic as soon as possible for a serum pregnancy 
test. 
6.10.12. 
Health Related Quality of Life (HRQoL) Measures 
It is recommended that these questio1maires be completed prior to the clinical and laboratory 
assessments. The subject should read the questio1maires by hiinself/herself and record the 
answers by himself/herself. 
6.10.12.1. 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease 
(CLDQ-NAFLD) 
The CLDQ-NAFLD asks questions related to liver disease and specifically NAFLD, to measure 
health related quality of life in subjects with chronic liver disease. 
6.10.12.2. 
EuroQol Five Dimensions (EQ-5D) 
The EQ-5D questio1maire is a standard measure of health status developed by the EuroQol 
Group to provide a simple, generic measure of health for clinical and economical appraisal {The 
EuroQol Group 1990}. The EQ-5D is not disease specific and has been validated in nmnerous 
health states. The tool consists of the EQ-5D descriptive system and the EQ Visual Analog Scale 
(VAS). The descriptive part comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each of these 5 dimensions has 5 levels (no problem, 
slight problems, moderate problems, severe problems and unable to). Results for each of the 
5 diinensions are combined into a 5-digit nmnber to describe the subject's health state. The VAS 
records the subject's health on a 0-100 1mn VAS scale, with 0 indicating "the worst health you 
can imagine" and 100 indicating "the best health you can imagine". 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, 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 medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or posttreatment complications that occur as a 
result of protocol specified procedures or special situations (Section 7.7). Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the clinical 
study will also be considered AEs.
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 adverse event and must be reported.

Pre-existing 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 (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject 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 was more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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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 subject 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;  
Development of drug dependency or drug abuse. 

A hypoglycemic episode is considered an SAE if it meets a criteria above or it requires the 
assistance of another person to correct (e.g., to administer carbohydrate).
For the avoidance of doubt, infections resulting from contaminated medicinal product will be 
considered a medically important event and reported as a SAE.
7.1.2.1.
Events of Special Interest 
Hypoglycemic episodes must be reported as an AE in the AE form. For subjects without T2D, 
episodes must be reported in accordance with Section 7. Subjects with T2D 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 and other 
relevant clinical data must be reported on a hypoglycemic episode form in the eCRF. If the 
hypoglycemic episode fulfills the serious criteria, the event must be reported in the eCRF 
database and to Gilead PVE as an SAE.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to 
study drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship of an AE or SAE to study procedures (eg, invasive procedures such as 
venipuncture or biopsy) or study devices (eg, PDS290 pen-injector) should be assessed using
clinical judgement describing the event as either unrelated (No) or related (Yes) consistent with 
the following definitions:

No: Evidence exists that the adverse event has an etiology other than the study procedure or 
device.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture) or 
device.
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4, or 5 according to the Common 
Terminology Criteria for Adverse Events (CTCAE), which can be found in the Site Operations 
Manual and Appendix 4.
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.
The distinction between the seriousness and the severity of an adverse event should be noted.
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For
example, a headache may be severe in intensity, but would not be classified as serious unless it
met one of the criteria for serious events listed above.


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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form eCRF: all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
through 7 weeks after last administration of study drug, must be reported to the eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences, Inc may request that certain AEs are followed beyond the protocol defined
follow up period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment Follow-Up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the posttreatment Follow-Up visit but within 7 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 study participation has 
concluded and the event is deemed relevant to the use of study drug or device, he/she should 
promptly document and report the event to Gilead Pharmacovigilance and Epidemiology (PVE).
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

At the time of study start, SAEs may be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. 


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• 
Site perso1mel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PYE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be fom1d in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
fonn and submit within 24 hours to: 
Gilead Sciences PYE: 
Fax: 
PPD 
Email: PPU 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper fonn because the eCRF database has been locked, no 
further action is necessary. 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a docmnent to the subject identifiers. 
• 
Additional infonnation 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 subject's eCRF and the event description section of the SAE fonn. 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, Gilead may be required to expedite to worldwide regulatory agencies 
reports of SAEs, serious adverse drug reactions (SADRs), or suspected unexpected serious 
adverse reactions (SUSARs). 
Assessment of expectedness for SAEs will be detennined by Gilead using reference safety 
infonnation specified in the investigator's brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB of SU SAR 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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7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and 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, electrocardiogram, 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).
For specific information on handling of clinical laboratory abnormalities in this study, 
please refer to Sections 7.1 and 7.6.
Severity should be recorded and graded according to the CTCAE Toxicity Grading Scale 
(Appendix 4). For AEs associated with laboratory abnormalities, the event should be graded on 
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.
7.6.
Toxicity Management 
7.6.1.
Observation for Drug Induced Liver Injury (DILI)
At baseline, some subjects may have liver biochemistry levels above the upper limit of the 
normal range (ULN). Baseline values for liver tests (ALT, AST, and total bilirubin) will be 
determined by averaging the values obtained between and including Screening and Enrollment 
(Day -14). Please refer to the Covance Laboratory Manual or individual subject Covance 
laboratory report for gender and age specific reference ranges.
Unless the clinical context points towards an apparent etiology, on-treatment elevations of ALT 
and/or AST should be confirmed with repeat testing within 72 hours of results. If the results are 
confirmed, and if no other cause of the laboratory abnormalities is immediately apparent, notify 
the Medical Monitor. 
Subjects with repeat ALT or AST elevations as per Figure 7-1 subjects must be placed into close 
observation (as described below).


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Figure 7-1.
On-Treatment ALT/AST Monitoring Requiring Close Observation
7.6.2.
Close Observation
Close observation includes:

Repeating liver biochemistries (ALT, AST, ALP, GGT, total bilirubin, INR) and obtaining a 
CPK level within 72 hours of results

Obtaining a more detailed history of symptoms and prior or concurrent disease

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets

Obtaining a history of exposure to environmental chemical agents

Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the Investigator)

Continue to monitor liver biochemistries at least twice weekly. Frequency can decrease to 
once a week or less if abnormalities stabilize or study drugs have been discontinued and the 
subject is asymptomatic
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 


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During a period of close observation for DILI, study drugs can be continued, if desired, at the 
discretion of both the Medical Monitor and Investigator.
If on-treatment elevations of ALT and/or AST exceed the values shown in Figure 7-2, are 
confirmed on repeat testing within 72 hours of results, and no alternative cause is immediately 
apparent, the subject must be placed into close observation and all three study drugs must be 
withheld. 
Figure 7-2.
On-Treatment Monitoring Requiring Withholding of Study Drugs
If study drugs are withheld, they may be reintroduced with approval from the Gilead Medical 
Monitor.
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Medical Monitor. Whether or not considered treatment-related, all subjects experiencing AEs 
must be monitored periodically until symptoms subside, any abnormal laboratory values have 
resolved or returned to baseline levels or they are considered irreversible, or until there is a 
satisfactory explanation for the changes observed. 
Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laboratory abnormalities should be confirmed by repeat testing as soon as practical to do so, and 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
  
 
   
 
 
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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preferably within 3 calendar days of receipt of the original test results. 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. 
Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.3.
CP Score
If a subject has an increase in their CP score to ≥ 7, this should be confirmed with repeat testing 
within 72 hours of receipt of results. If confirmed, the Medical Monitor should be notified and 
the subject should be placed in close observation described above, unless an alternate etiology 
(eg, therapeutic anticoagulation) is identified. If the CP remains ≥ 7 for 2 consecutive weeks, and 
an alternate etiology has not been identified, study drugs must be discontinued.
7.6.4.
Hypertriglyceridemia
Although some randomized subjects will have baseline dyslipidemia, some subjects may 
experience further elevations in their triglycerides. Figure 7-3 describes the recommended 
monitoring and intervention strategy for subjects that meet the criteria for on-treatment 
hypertriglyceridemia of Grade 3 or 4 (≥ 500 mg/dL).
Figure 7-3.
Algorithm for Monitoring and Treatment of Hypertriglyceridemia
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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7.6.5.
Pruritus Management
The development or worsening of pruritus during the study is a consideration for patients 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 the study drug dosing, as described in Table 5-3. Administration of study 
drugs with a light-fat meal may be beneficial. If interruption of study drugs is deemed necessary, 
all study drugs must be held (see Section 6.9). There is no option for dose reduction. 
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, and 
pregnancy reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product 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 medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.


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7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the post study drug Follow-Up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. Reports should be sent directly to Gilead PVE at 
fax number
or email 
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. 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 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email:
and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the pregnant partner 
should continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after 
the study has been completed, the outcome should be reported directly to 
Gilead PVE, fax number 
 or email 
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
PPD
PPD
PPD
PPD
PPD
PPD


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Special situations involving non-Gilead concomitant medications does not need to be reported on
the special situations report 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.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/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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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study drug(s) in subjects with NASH 
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Primary Endpoint 
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The primary endpoint is the safety and tolerability of study drug(s) in subjects with NASH. 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
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The primary analysis set for efficacy analyses will be the Full Analysis Set (FAS) which includes 
all subjects who were randomized and received at least one dose of study drug. 
Subjects who receive study drugs other than that to which they were assigned will be analyzed 
according to the treatment group to which they were randomized. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses will include all subjects who received at least one 
dose of study drug. Treatment-emergent data will be analyzed and defined as data collected from 
the first dose of study drug through the date of last dose of study drug plus 30 days. Subjects who 
received study drug other than that to which they were assigned will be analyzed according to the 
study drug received. 
8.2.1.2.1. 
Phannacokinetics 
The PK analysis set will include all randomized subjects who took at least one dose of study 
drug and have at least 1 nomnissing postdose concentration value for the corresponding analyte 
in plasma. - -
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8.2.2. 
Interim Analysis 
Final 
Amendment2 
Administrative interim analyses may be perfonned during the study to support publications or 
interactions with regulatory agencies. 
8.3. 
Data Handling Conventions 
Missing data can have an impact on the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study drug, the subject will be included in 
a smmnary of adverse events according to the treatment received; otherwise, if the subject is not 
dosed, then they will be excluded from the smmnary. If safety laboratory results for a subject are 
missing for any reason at a time point, the subject will be excluded from the calculation of 
smmnary statistics for that time point. If the subject is missing a pre-dose value, then the subject 
will be excluded from the calculation of smmnary statistics for the pre-dose value and the change 
from pre-dose values. 
Values for missing safety laboratory data and vital signs will not be imputed; however, a missing 
baseline result will be replaced with a Screening result, if available. If no pre-treatment 
laboratory value is available, the baseline value will be assumed to be nonnal (ie, no grade 
[Grade OJ) for the smmnary of graded laboratory abnonnalities. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be smmnarized using standard descriptive 
methods by treatment group and overall. Demographic smmnaries will include sex, race, 
ethnicity, and age. 
Baseline characteristics smmnary will include body weight, height, body mass index, presence or 
absence of type 2 diabetes, and other disease characteristics as necessary. 
8.5. 
Efficacy Analysis 
The biological activity of study drug(s) will be evaluated using radiologic endpoints and 
biomarker variables. Because efficacy endpoints will be evaluated for exploratory purpose, 
fonnal statistical comparisons will not be made for these endpoints. Instead, descriptive statistics 
(n, mean, SD, median, Ql, Q3, minimum, and maximum) will be provided by treatment group. 
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8.6.
Safety Analysis
Safety will be assessed by clinical laboratory tests and vital signs measurements at various time 
points during the study, and through the documentation of AEs.
All safety data collected on or after the first dose of study drug administration (up to and 
including 30 days after the last dose of study drug) will be summarized by treatment group 
according to the study drug received.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration eCRF page. Exposure data will be summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. Adverse event severity will be graded using CTCAE.
Events will be summarized on the basis of the date of onset for the event. Treatment-emergent 
adverse events (TEAEs) are 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 30 days
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC (HLT,) and PT will be 
provided by treatment group. Treatment-emergent AEs will also be summarized by relationship 
to study drug and severity. In addition, TEAEs leading to premature discontinuation of study 
drug will be summarized.
All AEs reported during the study will be presented in data listings with TEAE indicated
(yes/no).
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, 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.


Protocol GS-US-454-5533 
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Amendment2 
The incidence of treatment-emergent laboratory abnonnalities, defined as values that increase at 
least one toxicity grade from baseline at any time post-baseline up to and including the date of 
last dose of study drug plus 30 days, will be smmnarized by treatment group. If baseline data are 
missing, then any graded abnonnality (ie, at least a Grade 1) will be considered treatment 
emergent. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentrations of study drug(s) and relevant metabolites, as applicable, will be listed. 
8.7.1. 
Other Safety Evaluations 
Vital sign measurements and 12-lead ECG data will be smmnarized by treatment group and 
listed by subject. 
8.8. 
Biomarker Analysis 
The kinetic biomarkers will be analyzed to evaluate the PD effects of study drug(s). The 
assessment will involve the analysis of DNL values; specifically, the change (absolute and 
relative) from baseline between the post-dose and pre-dose deuterated water loading periods. 
8.9. 
Sample Size 
Due to the exploratory nature of this study, the sample size was not detennined by any fonnal 
power calculation. The number of subjects in each treatment group was decided based on clinical 
experience with other similar proof of concept studies. 
8.10. 
Data Monitoring Committee 
An internal Gilead data monitoring c01mnittee (DMC) will review the progress of the study and 
perfonn interim reviews of safety data. The DMC will be notified of any case of suspected DILi 
by the Medical Monitor. The DMC will provide reco1mnendations whether the nature, 
frequency, and severity of adverse effects associated with study treatment warrant the early 
tennination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications. The DMC's specific 
activities will be defined by a mutually agreed upon charter, which will define the DMC's 
membership, conduct, and meeting schedule. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, International Conference on Harmonization (ICH) guidelines, or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The Investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The Investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under 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 Gilead 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 subject completes the protocol-defined activities.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under 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 Gilead 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 subject completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board (IRB) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB. The investigator will not begin any study subject activities until 
approval from the IRB has been documented and provided as a letter to the investigator.


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Before implementation, the investigator will submit to and receive documented approval from 
the IRB any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IRB approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
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 and before undertaking any study-related procedures. The 
investigator must use the most current approved consent form for documenting written informed 
consent. Each informed consent will be appropriately signed and dated by the subject or the 
subject’s legally authorized representative, the person conducting the consent discussion, and an 
impartial witness (if required by local requirements). The consent form will inform subjects 
about pharmacogenomic testing and sample retention, and their right to receive clinically 
relevant pharmacogenomic analysis results.
9.1.5.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the Sponsor, IRB or laboratory. Laboratory specimens must be 
labeled in such a way as to protect subject identity while allowing the results to be recorded to
the proper subject. Refer to specific laboratory instructions. NOTE: The investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. Subject data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRFs, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (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 further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise 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 two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.


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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject 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 adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including 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 until 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, United States, 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, until 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 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.


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9.1.7.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any 
interim time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents. The eCRF capture the data required 
per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator 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 (e.g. data entry error). At the conclusion of the trial, Gilead will provide the 
site with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.6
9.1.8.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. If the site has an appropriate standard 
operating procedure (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 central files. If study drug
is destroyed on 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 eventual destruction. The study 
monitor will provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs, or to regulatory authority or health authority 
inspectors.


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9.1.10.
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 subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB in 
accordance with local requirements and receive documented IRB approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared. 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. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.5).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.


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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, e.g. attendance at Investigator's 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 trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
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 subject records needed to 
verify the entries on 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 of 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 Gilead medical monitor 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 Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs. In terminating the study, Gilead and the investigator will assure 
that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
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Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
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Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes 
Hypertriglyceridemia in Rodents [Accepted Article]. Hepatology 2018.


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Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of Action of Peroxisome Proliferators as 
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Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
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in chronic liver disease: 2014 Practice Guideline by the American Association for 
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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. 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE)
Appendix 5.
West Haven Criteria


Protocol GS-US-454-5533 
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Amendment 2 
Appendix 1. 
Investigator Signature Page 
Gilead Sciences, Inc. 
333 Lakeside Dr. 
Foster City, CA 94404 USA 
STUDY ACKNO\VLEDGEMENT 
A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of 
Monotherapy and Combination Regimens in Subjects with Nonalcoholic Steatohepatitis (NASH) 
GS-US-454-5533, Amendment 2, 22 October 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
[P[PD 
PPD 
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 
CONFTDE1'-.T'fIAL 
Page 115 
22 October 2019 


Protocol GS-US-454-5533 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 2. 
Study Procedures Table 
Pretreatment Period 
Treatment Period 
Kinetic Biomarkers 
Kinetic Biomarkers 
(Cycle 1) 
(Cycle 2) 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 7 
28 
56 
84 
112 
140 
154 
157 
161 
Day 168 
Day 
Day 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 22 
(WK 
(WK 
T elephon 
Day 
- 11 
- 7 
Day 
1) 
4) 
8) 
12) 
16) 
20) 
22) 
Day 2) 
23) 
24/EOT) 
e Follow-
Screening 
- 14 
(±Id) 
(±Id) 
1 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±Id) 
(±Id) 
(±Id) 
(±3d)" 
ET 
Up• (±3d) 
Clinical Assessments 
Written 
lnfom1ed 
X 
Consent 
Confim1 
X 
X 
Eligibility 
Medical History 
X 
X 
PE, V ital Signs 
including 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight< 
Fundus 
X 
Exam inat iond 
Height 
X 
12 lead ECG 
X 
X 
X 
Quality of Life 
X 
X 
X 
Questionnaires 
Calculate CP 
X 
X 
X 
X 
X 
X 
X 
X 
Score 
D ispense 
Deuterated 
X 
X 
Water 
CONFIDENTIAL 
Page I 16 
22 October 2019 


Protocol GS-US-454-5533 
Gilead Sciences, Inc. 
Dispense study 
drugs 
Review of 
Deuterated 
Water 
Compliance 
Review of 
Study Drug 
Dosing 
Comp liance 
Concomitant 
Medications 
Adverse Events 
FibroScan* 
MRI POFF, 
MRE 
Subject Fasting 
Chemistry, 
Hematology, 
Coagulation 
Screening 
X 
xr 
xs 
xs 
X 
X 
CONFIDENTIAL 
Pretreatment Period 
Treatment Period 
Kinetic Bioma rkers 
Kinetic Bioma rkers 
(Cycle 1) 
(Cycle 2) 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 7 
28 
56 
84 
112 
140 
154 
157 
161 
Day 
Day 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 22 
(WK 
Day 
- 11 
- 7 
Day 
1) 
4) 
8) 
12) 
16) 
20) 
22) 
Day 2) 
23) 
- 14 
(±Id) 
(±Id) 
1 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±Id) 
(±Id) 
(±Id) 
x• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging Assessments 
11 I 11 I I 1: 1 I I 
I 
I 
I 
Labor atory Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 117 
Day 168 
(WK 
24/EOT) 
(±3d)" 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 2 
T elephon 
e Follow-
ET 
Up• (±3d) 
X 
X 
X 
X 
X 
X 
X 
22 October 2019 


Protocol GS-US-454-5533 
Final 
Gilead Sciences, Inc. 
Amendment2 
Pretreatment Period 
Treatment Period 
Kinetic Biomarkers 
Kinetic Bioma rkers 
(Cycle 1) 
(Cycle 2) 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 7 
28 
56 
84 
112 
140 
154 
157 
161 
Day 168 
Day 
Day 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 
(WK 22 
(WK 
(WK 
T elephon 
Day 
- 11 
- 7 
Day 
1) 
4) 
8) 
12) 
16) 
20) 
22) 
Day 2) 
23) 
24/EOT) 
e Follow-
Screening 
- 14 
(±Id) 
(±Id) 
1 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±Id) 
(±Id) 
(±Id) 
(±3d)" 
ET 
Up• (±3d) 
Insulin and 
X 
X 
X 
X 
X 
X 
x• 
Lipids 
Hemoglobin 
X 
X 
X 
x• 
Alc(HbAlc) 
eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV I, HBV, 
X 
HCV Serology 
Calcitonin 
X 
FibroTest* 
xs 
X 
X 
x• 
ELF"' Test; 
X 
X 
X 
x• 
Blood 
Collection 
X 
X 
X 
X 
X 
X 
X 
X 
(Kinetic 
Biomarkers) 
PK Sampling 
Xi 
Xi 
Xi 
x; 
Pregnancy 
Testing' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug 
X 
Screen 
CONFIDENTIAL 
Page I 18 
22 October 2019 


Protocol GS-US-454-5533 
Gilead Sciences, Inc. 
Screening 
Pretreatment Period 
Day 
- 14 
Kinetic Biomarkers 
(Cycle 1) 
Day 
- 11 
(±Id) 
Day 
-7 
(±Id) 
Day 7 
(WK 
Day 
1) 
1 
(±3d) 
Day 
28 
(WK 
4) 
(±3d) 
Day 
56 
(WK 
8) 
(±3d) 
Day 
84 
(WK 
12) 
(±3d) 
Treatment Period 
Day 
112 
(WK 
16) 
(±3d) 
Day 
140 
(WK 
20) 
(±3d) 
Kinetic Bioma rkers 
(Cycle 2) 
Day 
Day 
Day 
154 
157 
161 
Day 168 
(WK 
(WK 22 
(WK 
(WK 
22) 
Day 2) 
23) 
24/EOT) 
(±Id) 
(±Id) 
(±Id) 
(±3d)" 
a 
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of last dose of study dmgs or pretreatment deuterated water. 
b 
Subjects that received at least one dose of study dmg will be contacted for a Telephone Follow up Visit 7 weeks after the date of the last dose 
Final 
Amendment2 
T elephon 
e Follow-
ET 
Up• (±3d) 
c 
Complete physical examination to be perfom1ed at Screening. Symptom driven physical examination to be perfom1ed at Day 14, Day I, Day 7 (Week I), Week 4, Week 8, 
Week 12, Week 16, Week 20 and Week 24 (EOT) or ET visits 
d 
For subjects with type 2 diabetes (from medical history or from Screening Hemoglobin A I c 2;:6.5%), a fundus exam will be perfom1ed at Screening. Fundus examinations 
re.quire pham1acological dilation of both pupils or the use of a digital fundus photography camera specified for non dilated examination. If a fundus examination matching this 
description has been perfom1ed within 90 days prior to the date of the Screening Visit, 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 Enrollment (Day 14) 
e 
Subject will take first dose of study dmgs on site at Day I. 
f 
AE reporting during Screening is limited to SAEs and AEs related to study procedures 
g 
Required for all subjects. Will not be used to assess eligibility for subjects that meet inclusion criteria based on historical liver biopsy. If a FibroScan® and/or MRE has been 
perfom1ed within 4 weeks prior to the date of the Screening Visit, the procedure does not need to be repeated. Similarly, if an MRI POFF has been perfom1ed within 4 weeks 
prior to the date of the Screening Visit and is deemed acceptable by the central reader, the procedure does not need to be repeated 
h 
At the discretion of the Investigator 
ELF"' Test score will not be provided to the sites 
j 
Single PK sample anytime during visit 
k 
All females of childbearing potential will have a semm pregnancy test at Screening. Urine pregnancy testing will occur at Day I (prior to dosing), Week 4, Week 8, Week 12, 
Week 16, Week 20 and Week 24 (EOT) or ET visits. All females of childbearing potential that received at least one dose of study dmg will be dispensed a urine pregnancy 
testing kit at the Week 24 (EOT) or ET visit for home testing at the Telephone Follow Up visit. At the Telephone Follow Up visit, subjects will be re.quested to report the 
result of the urine pregnancy test 
CONFIDENTIAL 
Page I 19 
22 October 2019 


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 120
22 October 2019
Appendix 3.
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 subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with 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 of any 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 subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Cilofexor has not yet been studied in pregnant women. In the initial dose range-finding studies in
pregnant mice and rabbits, there were no effects on embryofetal development other than a
decrease in fetal body weights in pregnant rabbits administered 1000 mg/kg/day. The decrease in
fetal body weights are likely secondary to maternal toxicity rather than a direct effect of
cilofexor. The NOAEL for embryofetal development is 300 mg/kg/day in mice and 
200 mg/kg/day in rabbits. These doses were associated with exposures that are > 50-fold higher 
than the anticipated human exposure at the maximum proposed human dose of 100 mg once 
daily. DDI data do not suggest a potential for interaction with hormones used for contraception.
No formal studies have been conducted to evaluate the reproductive toxicity of firsocostat;
therefore, the reproductive toxicity of firsocostat in humans is unknown. However, mutant mice
lacking ACC1, one of the targets of firsocostat, are embryonically lethal. Therefore, firsocostat is
contraindicated in pregnancy. Preclinical data in human hepatocytes indicate that firsocostat is a
mild inducer of CYP3A4 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 firsocostat with hormonal contraceptives.


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 121
22 October 2019
Semaglutide adversely affected embryo foetal 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 foetal 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. There are 
limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not
be used during pregnancy. Oral contraceptives are considered effective as no clinically relevant 
decrease in the overall exposure of ethinylestradiol and levonorgestrel was observed when 
co-administered with semaglutide s.c.
Please refer to the latest version of the corresponding Investigator’s Brochure of each compound
for additional information.
3) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to Enrollment unless permanently 
sterile or postmenopausal as defined in Appendix 3. Urine pregnancy tests will be performed at 
monthly intervals thereafter until week 24. A urine pregnancy testing kit will be dispensed at the 
Week 24 (EOT) or ET visit for home testing at the Telephone Follow-Up visit. Female subjects 
must agree to one of the following from Screening until 7 weeks following the last dose of study
drug.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure® micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 122
22 October 2019
Should female subjects wish to use a hormonally based method, use of a male condom by the 
female subject's male partner is required. Subjects who utilize a hormonal contraceptive as one 
of their birth control methods must have used the same method for at least three months prior to 
study dosing. Hormonally-based contraceptives permitted for use in this protocol are as follows:
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Implants of levonorgestrel
Transdermal contraceptive patch
Contraceptive vaginal ring
Not all of these methods may be approved in each of the countries where the study is being 
conducted: please refer to local product information. Additional local regulatory requirements 
may apply.
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 7 weeks after the last dose of study drug.
4) Contraception Requirements for Male Subjects

It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with 
female partners of childbearing potential must use condoms during treatment until 7 weeks
after the last dose of study drug. Female partners of male study subjects are asked to select 
one of the above methods.

Male subjects must also refrain from sperm donation during treatment and until at least 
7 weeks after the last dose of study drug.
5) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 123
22 October 2019
6) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 7 weeks of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is within 7 weeks of last study drug dose must report the 
information to the investigator. Instructions for reporting pregnancy, partner pregnancy, and 
pregnancy outcome are outlined in Section 7.7.2.1.


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 124
22 October 2019
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) 
Refer to the Site Operations Manual for additional CTCAE information. 


Protocol GS-US-454-5533
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 125
22 October 2019
Appendix 5.
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 three of the 
followings 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 three 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}

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Monotherapy and Combination 
Regimens in Subjects with Nonalcoholic Steatohepatitis 
(NASH)
Name of Test Drugs:
Semaglutide® (SEMA)
Firsocostat (FIR; GS-0976)
Cilofexor (CILO; GS-9674)
Study Number:
GS-US-454-5533
Protocol Version (Date):
Original:
17 May 2019
Amendment 1:
16 August 2019
Amendment 2:
22 October 2019
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
06 August 2020
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


SEMA, FIR, ClLO 
GS-US-454-5533 
Statistical Analysis Plan 
Version 1.0 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXTTABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIG URE ......................................................................................................................................... 4 
LIST OF ABBREVIA TIONS ........................................................................................................................................ 5 
I. 
INTRODUCTION ................................................................................................................................................ 7 
1.1. 
Study Objectives ...................................................................................................................................... 7 
1.2. 
Study Design ............................................................................................................................................ 7 
1.3. 
Sample Size and Power ............................................................................................................................ 8 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 9 
2.1. 
Data Monitoring Committee Analyses ..................................................................................................... 9 
2.2. 
Interim Analyses ...................................................................................................................................... 9 
2.3. 
Final Analysis .......................................................................................................................................... 9 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 10 
3.1. 
Analysis Sets .......................................................................................................................................... I 0 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 10 
3 .1.2. 
Full Analysis Set .................................................................................................................. I 0 
3.1.3. 
Safety Analysis Set ............................................................................................................... 10 
3 .1.4. 
Pharmacokinetic Analysis Set .............................................................................................. I 0 
3.2. 
Subject Grouping ................................................................................................................................... 11 
3.3. 
Strata and Covariates .............................................................................................................................. 11 
3 .4. 
Examination of Subject Subgroups ........................................................................................................ 11 
3.5. 
Multiple Comparisons ............................................................................................................................ 11 
3.6. 
Missing Data and Outliers ...................................................................................................................... 11 
3 .6.1. 
Missing Data ........................................................................................................................ 11 
3 .6.2. 
Outliers ................................................................................................................................. 12 
3.7. 
Data Handling Conventions and Transformations ................................................................................. 12 
3.8. 
Analysis Visit Windows ......................................................................................................................... 13 
3 .8.1. 
Definition of Study Day ....................................................................................................... 13 
3 .8.2. 
Analysis Visit Windows ....................................................................................................... 13 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 15 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 17 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 17 
4.2. 
Extent of Study Dtug Exposure and Adherence ..................................................................................... I 8 
4.2.1. 
Duration of Exposure to Study Dtug .................................................................................... 18 
4.2.2. 
Adherence to Study Drug ..................................................................................................... 19 
4.3. 
Protocol Deviations ................................................................................................................................ 20 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 2 1 
5.1. 
Demographics ........................................................................................................................................ 2 1 
5.2. 
Other Baseline Characteristics ............................................................................................................... 2 1 
5.3. 
Medical History ...................................................................................................................................... 23 
6. 
EFFICACY ANALYSES ................................................................................................................................... 24 
I 
CONFIDENTIAL 
Page 2 
06 August 2020 


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 3
06 August 2020
7.
SAFETY ANALYSES........................................................................................................................................28
7.1.
Adverse Events and Deaths....................................................................................................................28
7.1.1.
Adverse Event Dictionary ....................................................................................................28
7.1.2.
Adverse Event Severity........................................................................................................28
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................28
7.1.4.
Relationship of Adverse Events to Pen-Injector...................................................................28
7.1.5.
Serious Adverse Events........................................................................................................28
7.1.6.
Treatment-Emergent Adverse Events...................................................................................29
7.1.6.1.
Definition of Treatment-Emergent Adverse Events .......................................29
7.1.6.2.
Incomplete Dates ............................................................................................29
7.1.7.
Summaries of Adverse Events and Deaths...........................................................................29
7.1.8.
Additional Analysis of Adverse Events ...............................................................................31
7.2.
Laboratory Evaluations ..........................................................................................................................32
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................32
7.2.2.
Graded Laboratory Values ...................................................................................................33
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................33
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities ...............................33
7.2.2.3.
Summaries of Laboratory Abnormalities........................................................33
7.2.3.
Liver-related Laboratory Evaluations...................................................................................34
7.2.3.1.
Criteria for Close Observation........................................................................34
7.2.3.2.
Criteria for Withholding Study Drug..............................................................35
7.2.3.3.
Summary of Liver-Related Laboratory Abnormalities...................................35
7.3.
Body Weight and Vital Signs.................................................................................................................36
7.4.
Prior and Concomitant Medications.......................................................................................................36
7.4.1.
Prior Medications .................................................................................................................36
7.4.2.
Concomitant Medications.....................................................................................................37
7.5.
Electrocardiogram Results .....................................................................................................................37
7.5.1.
Investigator Electrocardiogram Assessment ........................................................................37
7.6.
Changes From Protocol-Specified Safety Analyses...............................................................................38
8.
PHARMACOKINETIC ANALYSES ................................................................................................................39
8.1.
PK Sample Collection............................................................................................................................39
8.2.
PK Analyses Related to Sparse PK Sampling........................................................................................39
9.
REFERENCES ...................................................................................................................................................40
10.
SOFTWARE.......................................................................................................................................................41
11.
SAP REVISION..................................................................................................................................................42
12.
APPENDICES ....................................................................................................................................................43
Appendix 1.
Schedule of Assessments........................................................................................................44
Appendix 2.
CTCTAE Grade for Laboratory Parameters...........................................................................48
Appendix 3.
Liver Function Prognostic Scores...........................................................................................52
Appendix 4.
Noninvasive Markers for Fibrosis ..........................................................................................53
Appendix 5.
Health Related QoL Score......................................................................................................55
Appendix 6.
Determining Missing and Virtual Visits Due To COVID-19.................................................56


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 4
06 August 2020
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Imaging, HbA1c, FibroTest (and Components), and 
ELF Test Score (and Components) ........................................................................................14
Table 3-2.
Analysis Visit Windows for Plasma Glucose, Insulin, HOMA-IR, and Lipids......................14
Table 3-3.
Analysis Visit Windows for Vital Signs, Weight, and Laboratory Data ................................14
Table 3-4.
Analysis Visit Windows for CP Score....................................................................................15
Table 3-5.
Analysis Visit Windows for 12-lead ECG..............................................................................15
LIST OF IN-TEXT FIGURE
Figure 1-1.
Overall Study Design ...............................................................................................................8


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 5
06 August 2020
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ApoA1
apolipoprotein A1
APRI
aspartate transaminase to platelet ratio index
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CAP
controlled attenuation parameter
CCG
case report form completion guidelines
CLDQ
chronic liver disease questionnaire
CLDQ-NAFLD
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease
CI
confidence interval
CILO
Cilofexor
CK-18
cytokeratin 18
COVID-19
corona virus disease 2019
CP
Child-Pugh
CRF
case report form
CRP
C-reactive protein
CSR
clinical study report
CTCAE
common toxicity criteria for adverse events
DILI
Drug Induced Liver Injury
DNL
de novo lipogenesis
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELFTM
Enhanced Liver Fibrosis
ET
early termination
EQ-5D
EuroQoL five dimensions
FAS
full analysis set
FGF19
fibroblast growth factor 19
FIR
Firsocostat
FU
follow-up
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
HA
hyaluronic acid
HbA1c
hemoglobin A1c
HBV
hepatitis B virus


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HCV
hepatitis C virus
HDL
high-density lipoprotein
HE
hepatic encephalopathy
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HOMA-IR
homeostasis model assessment of insulin resistance
HRQoL
Health-related quality of life
IDMC
internal data monitoring committee
INR
International normalized ratio
LDL
low-density lipoprotein
LLT
lower-level term
LOQ
limit of quantitation
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
NASH
nonalcoholic steatohepatitis
NFS
nonalcoholic fatty liver disease fibrosis score
NLP
natural language processing
PIIINP
procollagen type III amino-terminal propeptide
PK
Pharmacokinetic
PT
preferred term
Q1
first quartile
Q3
third quartile
SAE
serious adverse event
SAP
SD
statistical analysis plan
standard deviation
SEMA
Semaglutide®
SOC
System Organ Class
TE
treatment-emergent
TEAE
treatment-emergent adverse event
TIMP1
tissue inhibitor of metalloprotease 1
ULN
upper limit of the normal range 
VAS
Visual Analog Scale
VLDL
very low-density lipoprotein
WBC
white blood cell
WHO
World Health Organization


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Statistical Analysis Plan 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings in the clinical study report (CSR) for 
Study GS-US-454-5533. This SAP is based on the study protocol amendment 2 dated 
22 October 2019 and the electronic case report fonn ( eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented 
in the CSR. 
1.1. 
Study Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study drug(s) in subjects with NASH. 
I 
I 
I 
I 
I 
I 
1.2. 
Study Design 
This is a proof of concept, open-label study evaluating the safety, tolerability, and efficacy of 
monotherapy and combination regimens in subjects with NASH. 
Males or females between 18 and 75 years of age with noncirrhotic NASH may be eligible for 
entry (refer to the protocol for complete inclusion and exclusion criteria). 
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A total of approximately 100 Subjects meeting the study’s entry criteria will be randomly 
assigned in a 1:1:1:1:1 ratio to 1 of 5 treatment groups, with approximately 20 subjects in each 
group, as shown in Figure 1-1.
Figure 1-1.
Overall Study Design
Centralized randomization will be used. Randomization will be stratified by the presence or 
absence of type 2 diabetes mellitus, as determined by medical history or based on the screening 
laboratory values if previously undiagnosed (hemoglobin A1c [HbA1c] ≥ 6.5%).
Adverse events (AEs) and concomitant medications will be documented at each visit throughout 
the entire study. Imaging assessments (FibroScan including CAP, MRI-PDFF and MRE) and 
laboratory assessments of FibroTest, ELF test score and HbA1c will be performed at Screening
and at Weeks 12 and 24. Other laboratory assessments will include serum chemistry, 
hematology, coagulation panel and estimated glomerular filtration rate (eGFR) at Screening, Day 
-14, Day 1 and at Weeks 1, 4, 8, 12, 16, 20 and 24; and insulin and lipids at Screening, Day 1 
and at Weeks 4, 8, 12 and 24. Pregnancy testing will occur at Screening, Day 1, every 4 weeks 
thereafter through Week 24 and at 7 weeks posttreatment. The complete schedule of assessments 
is included in Appendix 1.
1.3.
Sample Size and Power
Due to the exploratory nature of this study, the sample size was not determined by any formal
power calculation. The number of subjects in each treatment group was decided based on clinical
experience with other similar proof-of-concept studies.
2 Weeks 
2 Weeks 
24 Weeks 
7 Weeks 
-
-
Group A 
• 
Semaglutide 0.24 - 2.4 mg once weekly -
(n=20) 
..... 
Group B 
C 
• 
Semaglutide 0.24 - 2.4 mg once weekly -
(1J 
Cl. 
E 
+ Firsocostat 20mg once daily (n=20) 
..... 
::::, 
..... 
C 
C 
ro 
0 
(1J 
tlO 
·.;::; 
E 
.2 
C 
..... 
ro 
Group C 
..... 
0 
N 
ro 
C 
f---+ 
.E .. 
(1J 
u.. 
(1J 
a.. 
-
Semaglutide 0.24 - 2.4 mg once weekly -... 
i= .-. 
(1J 
----
0 
C 
..... 
+ Cilofexor 30mg once daily (n=20) 
-
u 
C 
-0 
0 
<.I) 
(1J 
C 
0 
r. 
E 
ro 
-0 
Cl. 
0::: 
C 
(1J 
Group D 
w 
Q) 
.. 
I-
C 
Semaglutide 0.24 - 2.4 mg once weekly -
w 
+ Cilofexor 100mg once daily (n=20) 
Group E 
• 
Semaglutide 0.24 - 2.4 mg once weekly+ -
Firsocostat 20mg once daily+ Cilofexor 30mg once 
-
-
dailv (n=20) 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
An internal Data Monitoring Committee (IDMC) within Gilead Sciences, Inc. (GSI) will review 
the progress of the study and perform interim reviews of safety data in order to protect subject 
welfare and preserve study integrity. The IDMC will be notified of any case of suspected Drug 
Induced Liver Injury (DILI) by the Medical Monitor. To ensure the best interests of the 
participants, the IDMC will recommend to the study team whether the nature, frequency, and 
severity of adverse effects associated with the study treatment warrant the early termination of 
the study, the continuation of the study, or the continuation of the study with modifications.
The initial review will be conducted after the first 25 randomized subjects either have completed
the Week 12 visit assessments or have prematurely discontinued study treatment. Subsequent 
IDMC meetings will be held on an ad hoc basis. The frequency of meetings can be adjusted if 
deemed necessary by the IDMC. Documentation of such change may be done in the meeting 
minutes or a note to file without an amendment to the charter.
The IDMC’s role and responsibilities and the scope of analysis to be provided to the IDMC are 
provided in a mutually agreed upon charter, which defines the IDMC membership, meeting 
logistics, and meeting frequency.
2.2.
Interim Analyses
No administrative interim analyses will be performed during the study to support publications or 
interactions with regulatory agencies.
2.3.
Final Analysis
After all subjects have completed or prematurely discontinued the study, outstanding data 
queries have been resolved or adjudicated as unresolvable, and the data have been cleaned and 
finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable). Data collected on log forms, 
such as AEs, will be presented in chronological order for each subject. Age, sex at birth, race, 
and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion will be 
summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized in the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who took at least 1 dose of any 
study drug. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all randomized subjects who took at least 1 
dose of any study drug and have at least 1 nonmissing concentration value reported by the PK 
laboratory. The PK Analysis Set will be used for the listing of concentration data.


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3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were randomized. For analyses based on the Safety Analysis Set, subjects will be grouped 
according to actual treatment received. The actual treatment received will differ from the
randomized treatment only when the actual treatment differs from randomized treatment for the 
entire treatment duration. 
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive mobile/web response 
system (IXRS) using a stratified randomization schedule. Randomization will be stratified by the 
presence or absence of type 2 diabetes mellitus, as determined by medical history or based on the 
screening laboratory values if previously undiagnosed (hemoglobin A1c [HbA1c] ≥ 6.5%).
If there are discrepancies in stratification factor values between the IXRS and the clinical 
database, the values recorded in the clinical database will be used for analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for efficacy analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.
For missing last dose date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for
prior and concomitant medications in Section 7.4.


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3.6.2.
Outliers
Outliers will be identified during the data management and data analysis processes, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth.

If only year of birth is collected, then “01 July” will be imputed as the day and month of 
birth.

If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a subject, then age derived based on date of birth and the Day 1 
visit date will be used instead. If a randomized subject was not dosed with any study drug, the 
randomization date will be used instead of the Day 1 visit date. For subjects who were enrolled 
but not randomized, enrollment date will be used instead of the Day 1 visit date. For screening
failures, the date the first informed consent was signed will be used for the age derivation. Age 
required for longitudinal and temporal calculations and analyses (eg, estimates of creatinine 
clearance, age at date of AE) will be based on age derived from date of birth and the date of the 
measurement or event, unless otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).


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If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log-transformed data) or nonparametric 
analysis methods may be used, as appropriate.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
When any ELF component (hyaluronic acid, procollagen III N-terminal propeptide [PIIINP], and
tissue inhibitor of metalloproteinase 1 [TIMP1]) is below the lower LOQ or above the upper
LOQ, the ELF test score will be calculated based on the imputed value of the component(s) as
defined in Appendix 4.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
The first dose date of individual study drug will be calculated separately for each study drug 
(ie, SEMA, FIR and CILO) within a treatment group. Study Day 1 is defined as the first dose 
date of any study drug, which is the minimum of the first dose dates of individual study drugs 
within a treatment group. Therefore, Study Day 1 is the day of first dose of any study drug.
Study day will be calculated from the first dose date of any study drug and derived as follows:

For postdose study days: Assessment Date First Dose Date of Any Study Drug + 1

For days prior to the first dose: Assessment Date First Dose Date of Any Study Drug
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of any study drug. For Health-Related Quality of Life (HRQoL) questionnaire data, nominal 
baseline values will be used.
On-treatment visit windows will be calculated from Study Day 1 for selected efficacy measures, 
vital signs, electrocardiogram (ECG) and safety laboratory data.
Efficacy (except for imaging) and safety data, collected up to and including the last dose date + 
30 days, will be mapped according to the following analysis windows.
All patient-reported HRQoL questionnaire data will not be windowed, but rather analyzed 
according to their nominal visits. Also, missing baseline values will not be imputed.
The analysis windows for imaging (liver stiffness as measured by transient elastography
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lipid profile (total cholesterol, high-density lipoprotein [HDL] cholesterol, fasting triglycerides, 
fasting low-density lipoprotein [LDL] cholesterol, fasting non-HDL cholesterol, fasting very 
low-density lipoprotein [VLDL] cholesterol), HbA1c, FibroTest (and components), and ELF test 
score (and components) are provided in Table 3-1 and Table 3-2.
Table 3-1.
Analysis Visit Windows for Imaging, HbA1c, FibroTest
(and Components), and ELF Test Score (and Components)
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
126
Week 24
169
127
≥ 169
Table 3-2.
Analysis Visit Windows for Plasma Glucose, Insulin, HOMA-IR, and 
Lipids
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
42
Week 8
57
43
70
Week 12
85
71
126
Week 24
169
127
≥ 169
The analysis windows for vital signs (eg, systolic and diastolic blood pressure), weight, and 
laboratory data including chemistry (eg, ALT, AST, bilirubin, GGT, and ALP), hematology, and 
coagulation panel are provided in Table 3-3.
Table 3-3.
Analysis Visit Windows for Vital Signs, Weight, and Laboratory Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
8
2
18
Week 4
29
19
42
Week 8
57
43
70
Week 12
85
71
98
Week 16
113
99
126
Week 20
141
127
154
Week 24
169
155
≥ 169


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The analysis windows for calculated Child-Pugh (CP) score are provided in Table 3-4.
Table 3-4.
Analysis Visit Windows for CP Score
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
42
Week 8
57
43
70
Week 12
85
71
98
Week 16
113
99
126
Week 20
141
127
154
Week 24
169
155
≥ 169
The analysis windows for 12-lead ECG are provided in Table 3-5.
Table 3-5.
Analysis Visit Windows for 12-lead ECG
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 24
169
2
≥ 169
Data relating to unscheduled visits or ET visits may be assigned to a particular visit or time point 
based on the visit windows. The following conventions will be used: 

An unscheduled visit prior to the first dose of any study drug may be included in the 
calculation of the baseline value, if applicable.

Unscheduled visits after the first dose of any study drug will be included in determining the 
maximum postbaseline toxicity grade.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.


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If multiple, valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the first dose date of any study drug
will be selected unless specified differently. If there are multiple records with the same time 
or no time recorded on the same day, the baseline value will be the average of the 
measurements for continuous data, or the measurement with the lowest severity (eg, normal 
will be selected over abnormal for safety ECG findings) for categorical data.

Baseline values for liver tests (ALT, AST, total bilirubin, and direct bilirubin) will be 
determined by averaging the values obtained between and including screening and Day 1.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worse severity will be taken for categorical data unless otherwise 
specified.

For serum creatinine, if both enzymatic and regular creatinine are collected from the same 
blood sample and are analyzable, regular creatinine will be chosen for analysis.
If multiple, valid, nonmissing measurements from transient elastography for liver stiffness exist 
in an analysis visit window, records will be chosen based on the following rules if a single value 
is needed:

For baseline, measurements by XL probe, if available, will be selected for analysis; 
otherwise, measurements by M probe will be selected.

For postbaseline visits, measurements by the same probe type (XL or M) as baseline will be 
selected. If no measurement by the same probe type as baseline is available, the analysis 
value for the corresponding postbaseline visit will be considered as missing. If there are 
multiple records by the same probe type at baseline, the rules to choose postbaseline 
continuous measurements described above will apply.

Controlled attenuation parameter (CAP) data will be analyzed if the liver stiffness data are
available from the same record of transient elastography.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for All Randomized Analysis Set by
treatment group and overall for each investigator within a country or region. The summary will 
present the number and percentage of subjects randomized. For each column, the denominator 
for the percentage calculation will be the total number of subjects analyzed for that column.
A similar enrollment table will be provided for the All Randomized Analysis Set by 
randomization stratum. The denominator for the percentage of subjects in the stratum will be the 
total number of randomized subjects. If there are discrepancies in the value used for stratification 
assignment between the IXRS and the clinical database, the value collected in the clinical 
database will be used for the summary. A listing of subjects with discrepancies in the value used 
for stratification assignment between the IXRS and the clinical database at the time of data 
finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR. 
A summary of subject disposition will be provided by treatment group and overall. This 
summary will present the number of subjects screened, the number of subjects enrolled, the 
number of subjects enrolled but not randomized, the number of subjects randomized, the number 
of subjects randomized but never treated, and the number of subjects in each of the categories 
listed below:

Safety Analysis Set

FAS

PK Analysis Set

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study

Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition
at the final analysis.


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The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and/or bottle ID
A summary of subjects affected by the corona virus disease 2019 (COVID-19) pandemic will be 
provided for each scheduled study visit by treatment group and overall. For each visit the 
summary will present the number and percentage of subjects who missed the visit due to 
COVID-19 and those who had a virtual visit due to COVID-19. For each column, the 
denominator for the percentage calculation will be the total number of subjects in the safety 
population for that column.
The determination of missing or virtual visits due to COVID-19 was done using Natural 
Language Processing (NLP) to search the CRF comment fields. A detailed explanation of the 
algorithm is given in Appendix 6. 
A by-subject listings will be provided by subject ID number in ascending order to support the 
above summary table.
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
The last dose date of individual study drug will be calculated separately for each study drug in a 
treatment group, and will be the end date on the study drug administration case report form 
(CRF) for the record where the “study drug was permanently withdrawn” flag is ‘Yes’.
Total duration of exposure to individual study drug that is administered daily (ie, FIR and CILO)
will be defined as last dose date of individual study drug minus first dose date of individual study 
drug plus 1. Total duration of exposure to individual study drug that is administered weekly (ie, 
SEMA) will be defined as last dose date of individual study drug minus first dose date of 
individual study drug plus 7. Total duration of exposure to treatment regimen will be defined as 
the maximum of [(last dose date of SEMA plus 6) and last dose date(s) of daily administered
individual study drug(s)] minus first dose date of any study drug plus 1. Total duration of 
exposure will be calculated regardless of any temporary interruptions in study drug 
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Total duration of exposure to treatment regimen (weeks)  [maximum of (last dose date of 
SEMA + 6, last dose date[s] of daily administered individual study drug[s]) first dose date of 
any study drug + 1] / 7
Total duration of exposure to daily administered individual study drug (weeks)  (last dose date 
of individual study drug first dose date of individual study drug + 1) /7
Total duration of exposure to weekly administered individual study drug (weeks)  (last dose 
date of individual study drug first dose date of individual study drug + 7) /7
If the last study drug dose date is missing, the latest date among the study drug end date, clinical 
visit date, laboratory sample collection date, and vital signs assessment date that occurred during 
the on-treatment period will be used for subjects included in the final analysis. At the time of any
interim analysis (eg, DMC), the missing last dosing date will be imputed by the data snapshot 
date for subjects who are still on treatment.
The total duration of exposure to treatment regimen and the total duration of exposure to each 
individual study drug will be summarized using descriptive statistics. In addition, the total 
duration of exposure to treatment regimen will be summarized by the number (ie, cumulative 
counts) and percentage of subjects exposed through the following time periods: 1 day, 1 week, 4
weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and 24 weeks. Summaries will be provided by 
treatment group for the Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
For the individual study drugs that are orally administered once daily in tablet forms (ie, FIR 
20 mg, CILO 30 mg, CILO 100 mg), the presumed total amount of study drug administered to a 
subject will be determined by the data collected on the drug accountability CRF using the 
following formula:
Total Amount of Study Drug Administered 
(∑No. of Tablets Dispensed) −(∑No. of Tablets Returned)
For SEMA, the presumed total amount of study drug administered to a subject will be 
determined by the data collected on the study drug administration CRF using the following 
formula:
Total Amount of Study Drug Administered  ∑Actual Dose (mg)
The total amount of study drug administered will be summarized using descriptive statistics for 
each individual study drug by treatment group for the Safety Analysis Set.
Prescribed adherence will be calculated. The level of prescribed adherence to the individual 
study drug will be determined by the total amount of study drug administered relative to the total 


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amount of study drug specified by the protocol for a subject who completes 24 weeks of 
treatment.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Prescribed Adherence (%) = #
Total Amount of Study Drug Administered
Total Amount of Study Drug Specified by Protocol& × 100%
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
The total amount of individual study drugs that are administered orally once daily (ie, FIR 
20 mg, CILO 30 mg, CILO 100 mg) for 24 weeks will be 168 tablets. According to the 
SEMA dose escalation schedule, the total amount of SEMA administered for 24 weeks will 
be 32.96 mg.
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (< 75%, ≥ 75 to < 90%, ≥ 90%) will be provided for 
each individual study drug by treatment group for the Safety Analysis Set. The number and 
percentage of subjects with ≥ 75% level of prescribed adherence to all individual study drugs in a 
treatment group will also be provided by treatment group.
The summary of prescribed adherence will be provided. No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided by 
subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but were randomized in the 
study will be summarized regardless of whether they were exempted by the sponsor or not. The 
summary will present the number and percentage of subjects who did not meet at least 1 
eligibility criterion and the number of subjects who did not meet specific criteria by treatment 
group based on the All Randomized Analysis Set. A by-subject listing will be provided for those 
subjects who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will 
present the eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and 
related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the All Randomized Analysis Set. A by-subject 
listing will be provided for those subjects with important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2] as a continuous variable 
and as categories [< 30 kg/m2, and 30 kg/m2]) will be summarized by treatment group and 
overall using descriptive statistics for continuous variables and using number and percentage of 
subjects for categorical variables. The summary of demographic data will be provided for the 
Safety Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

Type 2 diabetes mellitus (presence or absence; as determined by medical history or based on 
the screening laboratory values if previously undiagnosed [HbA1c] ≥6.5%)

ALT (U/L)

AST (U/L)

Total bilirubin (mg/dL)

Direct bilirubin (mg/dL)

ALP (U/L)

GGT (U/L)

Albumin (g/dL)

International normalized ratio (INR)

Platelets (× 103/uL)

Steatosis by MRI-PDFF (%)

Steatosis by CAP from transient elastography

Steatosis by CAP from transient elastography (XL probe)


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
Liver stiffness by MRE (kPa)

Liver stiffness by transient elastography

Liver stiffness by transient elastography category (< 9.9 kPa, ≥ 9.9 to < 14.0 kPa, 14.0 kPa)

ELF test score and its components (hyaluronic acid, procollagen type III amino-terminal 
propeptide [PIIINP], and tissue inhibitor of metalloprotease 1 [TIMP1])

ELF test score category (< 9.8, ≥ 9.8)

FibroSure/FibroTest and selected components (α2-macroglobulin, haptoglobin, 
apolipoprotein A1 nephelometry)

AST to platelet ratio index (APRI)

Fibrosis-4 (FIB-4) Index

FIB-4 category (< 1.30, 1.30 to < 2.67, 2.67)

Non-alcoholic fatty liver disease fibrosis score (NFS)

NFS category (< -1.455, -1.455 to < 0.676, 0.676)

Model for End-Stage Liver Disease (MELD) score

Calculated CP score

Fasting insulin (uIU/mL)

Fasting plasma glucose (mg/dL)

HOMA-IR

HbA1c (%)

Total cholesterol (mg/dL)

HDL cholesterol (mg/dL)

Fasting non-HDL cholesterol (mg/dL) (ie, total cholesterol minus HDL cholesterol)

Fasting triglycerides (mg/dL)

Fasting VLDL cholesterol (mg/dL)


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
Fasting LDL cholesterol (mg/dL)

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

eGFR (mL/min/1.73m2) calculated by the Modification Diet in Renal Disease (MDRD)
equation (protocol Section 6.10.2)
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. No formal statistical testing is planned.
By-subject listings of baseline characteristics will be provided by subject ID number in 
ascending order.
Methods for derivation of ELF, FIB-4, FibroSure/FibroTest, APRI, NFS, CP score and MELD 
score are described in Appendix 3 and Appendix 4.
5.3.
Medical History
General medical history will be collected at screening and Day -14 for general conditions 
(ie, conditions not specific to the disease being studied).
General medical history data will not be coded but will be listed only.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. System organ 
class, high-level group term (HLGT), high-level term (HLT), preferred term (PT) and lower-
level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Appendix 2). The severity grade 
of events for which the investigator did not record severity will be categorized as “missing” for 
tabular summaries and data listings. The missing category will be listed last in summary 
presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Relationship of Adverse Events to Pen-Injector
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Pen-Injector.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to pen-injector will be considered related for summary purposes. However, 
by-subject data listings will show the relationship as missing.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE that are specified in the study protocol. Serious AEs captured and stored in the clinical 
database will be reconciled with the SAE database from the GSI Pharmacovigilance and 
Epidemiology Department before data finalization.


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7.1.6.
Treatment-Emergent Adverse Events
7.1.6.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are 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 30 days 
after permanent discontinuation of any study drug

Any AEs leading to premature discontinuation of any study drug
7.1.6.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dose date of 
any study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment-emergent (TE). The event is considered TE if both of the 
following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dose date of any
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date
corresponding to 30 days after the date of the last dose of any study drug
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of any study drug, will be considered to be TE. In addition, an 
AE with the onset date missing and incomplete stop date with the same or later month and year 
(or year alone if month is not recorded) as the first dose date of any study drug will be 
considered TE.
7.1.7.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and
summarized by SOC, HLT, PT, and treatment group as follows:

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For the AE categories described below, summaries will be provided by SOC, PT, and treatment 
group:

TEAEs by maximum severity

TEAEs of Grade 2 or higher by maximum severity

TEAEs of Grade 3 or higher by maximum severity

TE treatment-related AEs

TE Treatment-related AEs of Grade 2 or higher by maximum severity

TE Treatment-related AEs of Grade 3 or higher by maximum severity

TE pen-injector related AEs

TE SAEs

TE treatment-related SAEs

TEAEs leading to premature discontinuation of any study drug

TEAEs leading to permanent discontinuation of study

TEAEs leading to death (ie, outcome of death)

TEAEs leading to dose modification or temporary interruption of any study drug
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetical order of SOC (and HLT within each SOC if 
applicable), and then by PT in descending order of total frequency within each SOC. For 
summaries by severity grade, the most severe grade will be used for those AEs that occurred 
more than once in an individual subject during the study.
In addition to the above summary tables, TEAEs, TEAEs of Grade 2 or higher, TEAEs of Grade 
3 or higher, TE SAEs, TE treatment-related AEs, TE treatment-related AEs of Grade 2 or higher, 
TE treatment-related AEs of Grade 3 or higher, TE treatment-related SAEs, TEAEs leading to 
premature discontinuation of any study drug, and TEAEs leading to dose modification or 
temporary interruption of any study drug will be summarized by PT only, in descending order of 
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For AEs that occurred > 30 days after the last dose date of any study drug, a brief, high-level
summary of the number and percentage of subjects who experienced at least 1 such AE in the 
categories described below will be provided by treatment group. The following tables will also 
be provided with the AE categories summarized by PT only, in descending order of total
frequency.

AEs that occurred > 30 days posttreatment

Treatment-related AEs that occurred > 30 days posttreatment

SAEs that occurred > 30 days posttreatment
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is TE

All AEs with severity of Grade 3 or higher

All SAEs

All Deaths

AEs leading to premature discontinuation of any study drug

AEs leading to permanent discontinuation of study

AEs leading to dose modification or temporary interruption of any study drug

AEs occurring greater than 30 days posttreatment
7.1.8.
Additional Analysis of Adverse Events
The incidence of pruritus AEs will be examined between treatment groups. The following PTs 
will be used to identify pruritus AEs:

pruritus

pruritus generalized
The number and percentage of subjects who experienced any of the above events postbaseline
during the study, either treatment-emergent or > 30 days posttreatment, will be summarized by 
PT, severity, and treatment group.


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7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of any study drug plus 
30 days for subjects who have permanently discontinued study drug, or all available data at the 
time of the database snapshot for subjects who were ongoing at the time of an interim analysis
(eg, DMC). The analysis will be based on values reported in conventional units. When values are 
below the LOQ, they will be listed as such, and the closest imputed value will be used for the 
purpose of calculating summary statistics as specified in Section 3.7. Hemolized test results will 
not be included in the analysis, but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and coagulation separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
CTCAE severity grade will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Summaries of ALT, AST, total bilirubin, direct bilirubin, GGT, ALP, platelets, eGFR using the 
MDRD equation, and creatinine are included in the efficacy analysis and thus they are not 
repeated in the safety analysis.
Descriptive statistics will be provided by treatment group for white blood cell (WBC), 
neutrophils, lymphocytes, and hemoglobin as follows:

Baseline values

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
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7.2.2.
Graded Laboratory Values
The CTCAE version 5.0 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately.
For baseline ALT, AST, total bilirubin, and direct bilirubin, the CTCAE version 5.0 will be used 
to assign toxicity grades to the derived average baseline values.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or the 
last available date in the database snapshot for subjects who were still on treatment at the time of 
an interim analysis (eg, DMC). If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered TE.
Treatment-emergent laboratory abnormalities are defined as values within the reference range at 
baseline, but which become lower or higher than the reference range at postbaseline, or values 
had a directional change in abnormality from baseline (eg, the value low at baseline became high 
at postbaseline visit) at any postbaseline time point, up to and including the date of last dose of 
study drug plus 30 days for subjects who permanently discontinued study drug or the last
available date in the database snapshot for subjects who were still on treatment at the time of an 
interim analysis (eg, DMC). If the relevant baseline laboratory value is missing, any postbaseline 
laboratory value that is lower or higher than the reference range will be considered TE.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date 
of the last dose of study drug plus 30 days for subjects who permanently discontinued study drug 
or the last available date in the database snapshot for subjects who were still on treatment at the 
time of an interim analysis (eg, DMC). If the relevant baseline laboratory value is missing, any 
Grade 3 or 4 values observed within the timeframe specified above will be considered TE
marked abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.


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The following summaries (number and percentage of subjects) for TE laboratory abnormalities 
will be provided by lab test and treatment group; subjects will be categorized according to the 
most severe postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose date of any study drug.
A by-subject listing of TE Grade 3 or 4 laboratory abnormalities will be provided by subject ID 
number and visit in chronological order. This listing will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades
abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who meet the criteria for close observation or for 
withholding study drug separately. Subjects will be grouped according to their baseline ALT or
AST level into 2 subgroups: normal (ie, ≤upper limit of the normal range [ULN]) or elevated 
(ie, > ULN). Laboratory tests, ALT and AST, are evaluated independently.
7.2.3.1.
Criteria for Close Observation
Subjects meet the criteria for close observation if they were reported to have any of the following 
laboratory test values for postbaseline measurements:

For subjects with normal baseline ALT or AST:
ALT or AST > 3 ULN

For subjects with elevated baseline ALT or AST:
ALT or AST > 3 baseline
ALT or AST > 300 U/L


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7.2.3.2.
Criteria for Withholding Study Drug
Subjects meet the criteria for withholding of study drug if they were reported to have any of the 
following laboratory test values for postbaseline measurements:

For subjects with normal baseline ALT or AST:
ALT or AST > 8 ULN
ALT or AST > 5 ULN for 2 weeks
ALT or AST > 3 ULN and total bilirubin > 2 ULN (or direct bilirubin > 2 baseline
in subjects with Gilbert’s syndrome)
ALT or AST > 3 ULN and INR > 1.5 (if not on therapeutic anticoagulation)

For subjects with elevated baseline ALT or AST:
ALT or AST > 500 U/L
ALT or AST > 3 baseline or > 300 U/L and total bilirubin > 2 ULN (or direct
bilirubin > 2 baseline in subjects with Gilbert’s syndrome)
ALT or AST > 3 baseline or > 300 U/L and INR > 1.5 (if not on therapeutic 
anticoagulation)
7.2.3.3.
Summary of Liver-Related Laboratory Abnormalities
The summary will include data from all postbaseline visits up to 30 days after the last dose date 
of any study drug. The number and percentage of subjects who meet each criterion will be 
summarized by treatment group. For individual laboratory tests, subjects will be counted once 
based on the most severe postbaseline values. For the composite criteria that evaluate more than 
1 lab test, subjects will be counted once when the criteria are met at the same postbaseline visit 
date. The denominator is the number of subjects in the Safety Analysis Set who have at least 1 
nonmissing postbaseline on-treatment value of all relevant tests at the same postbaseline visit 
date.
A listing of subjects who met at least 1 of the above criteria will be provided.


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7.3.
Body Weight and Vital Signs
Summaries of body weight, BMI, and systolic and diastolic blood pressure are included in the 
efficacy analysis and thus they are not repeated in the safety analysis. For vital signs including 
pulse rate [beats/min] and temperature [°C], descriptive statistics will be provided by treatment 
group for as follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of any study drug. Change from baseline to a postbaseline visit will be defined as 
the postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order. Body weight, height and BMI will be included in a separate by-subject 
listing.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dose date of any 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior medication unless the 
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after the first dosing date. Medications with a completely missing start date will be included in 
the prior medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in descending 
overall frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dose date of
any study drug and continued to be taken after the first dose date, or started after the first dose
date but prior to or on the last dose date of any study drug will be considered concomitant 
medication. Medications started and stopped on the same day as the first dose date of any study 
drug or the last dose date of any study drug will also be considered concomitant. Medications 
with a stop date prior to the date of first dose date of any study drug or a start date after the last 
dose date of any study drug will be excluded from the concomitant medication summary. If a 
partial stop date is entered, any medication with the month and year (if day is missing) or year (if 
day and month are missing) prior to the date of first study drug administration will be excluded 
from the concomitant medication summary. If a partial start date is entered, any medication with 
the month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will be excluded from the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. Summaries will be based on the Safety Analysis Set. No formal 
statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at Week 24 compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. No formal statistical testing is planned.


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A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.6.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Sample Collection
A single PK blood sample will be collected anytime at Week 1, Week 4, Week 8, and Week 12 
for all subjects. The plasma concentrations of study drug(s) and relevant metabolite(s) may be 
evaluated, as applicable. PK samples may also be used to measure protein-binding of study 
drug(s) and/or its metabolites.
8.2.
PK Analyses Related to Sparse PK Sampling
A population PK model may be developed to characterize the PK of study drug(s) and relevant 
metabolite(s). Sparse PK sampling data from this study may be combined with data from other 
studies in a meta-population analysis using mixed-effect modeling techniques. Details of the 
population PK analysis will be provided in a separate population PK analysis plan.
The following listing will be provided for all PK samples collected in this study:

PK sampling details by subject including actual dosing time and actual draw time, calculated 
time postdose of sample collection, differences in scheduled and actual draw times, sample 
age, and sample concentration by analyte.


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9.
REFERENCES
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the
Binomial. Biometrika 1934;26 (4):404-13.


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 41
06 August 2020
10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 42
06 August 2020
11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 43
06 August 2020
12.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
CTCTAE Grade for Laboratory Parameters
Appendix 3.
Liver Function Prognostic Scores
Appendix 4.
Noninvasive Markers for Fibrosis
Appendix 5.
Health Related QoL Score
Appendix 6.
Determining Missing and Virtual Visits Due To COVID-19


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 44
06 August 2020
Appendix 1.
Schedule of Assessments
Pretreatment Per·iod 
Tn·atmrnt Period 
Kinetic Biomarkcrs 
Kinetic Biomarkers 
(Cycle I) 
(Cycle 2) 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 7 
211 
56 
114 
112 
140 
154 
157 
161 
Day 1611 
Day 
Day 
(WK 
(WK 
(WK 
(' K 
(WK 
(WK 
(WK 
(WK 22 
(WK 
(WK 
Tl'lephon 
Day 
- II 
- 7 
Day 
I) 
4) 
8) 
12) 
16) 
20) 
22) 
Day 2) 
23) 
24/IWT) 
e l'oUow-
Screening 
- 14 
(±Id) 
(± Id) 
I 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
(±Id) 
(±Id) 
(± Id) 
(±3d)' 
ET 
Up" (±3d) 
Clinil"lll Assessments 
Written 
lnfonned 
X 
Consent 
onfirm 
X 
X 
Eligibility 
Medical Hi story 
X 
X 
PE, Vital Signs 
including 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight• 
Fundus 
X 
Examinationd 
Height 
X 
12-lead ECG 
X 
X 
X 
Quality of Life 
X 
X 
X 
Questionnaires 
Calculate CP 
X 
X 
X 
X 
X 
X 
X 
X 
Score 
Dispense 
Deuterated 
X 
X 
Water 


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 45
06 August 2020
Dispense study 
drugs 
Review of 
Deuterated 
Water 
Compliance 
Review of 
Study Drug 
Dosing 
Compliance 
Concomitant 
Medication~ 
Adverse Events 
FibroScan"' 
MR I-POFF, 
MR 
Subject Fasting 
Chemistry, 
Hematology. 
Coagulation 
Screening 
X 
xr 
X 
X 
Prrtn·atmcnt Pt•r·iod 
Treatment Period 
Kinetic Biomarkers 
Kinetic Biomarkers 
(Cycle I) 
(Cycle 2) 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 7 
28 
56 
84 
112 
140 
154 
157 
161 
Day 1<,8 
Da • 
Day 
(W K 
(WK 
(WK 
(WK 
(\ K 
(WK 
(WK 
(WK 22 
(WK 
(\ K 
Trkphon 
Day 
- II 
- 7 
Day 
1) 
4) 
8) 
12) 
16) 
20) 
22) 
Day 2) 
23) 
24/EOT) 
r follow-
- 14 
(±Jd ) 
(± Id) 
I 
(±3d) 
(±3d ) 
(±Jd) 
(±Jd) 
(±3d) 
(±3d) 
(± Id ) 
(±Id) 
(±ld) 
(±3d)' 
ET 
Upb (±3d) 
x• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hnaging Asscss111rnts 
I 
I 
I 
I 
I 
I 
I 
I : I 
I 
I 
I 
I 
I 
X 
X 
Laboratory Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


SEMA, FIR, ClLO 
GS-US-454-5533 
Statistical Analysis Plan 
Scrl'enin~ 
Insulin and 
X 
Lipids 
I lcmoglobin 
X 
Alc(HbAlc) 
cGFR 
X 
II IV-1. IIUV, 
X 
HCV Serology 
Cakitonin 
X 
FibroTcg~ 
x• 
ELF"'Test1 
X 
Blood 
Collection 
(Kmct1c 
Biomarkers) 
PK Sampling 
Pregnancy 
Testin!( 
X 
Unne Drug 
X 
Scrocn 
CONFIDENTIAL 
Pretreatment Period 
Kinetic Biomarkers 
(C ycle I) 
Day 
Day 
Day 
11 
7 
- 1-1 
(±Id) 
(±Id) 
X 
X 
X 
X 
Oa)' 
0:1)' 
O:t)' 
Day 7 
28 
56 
(\\ K 
(WK 
(WK 
(WK 
Day 
I) 
4) 
8) 
12) 
I 
(±3d) 
(±3d) 
(±3d) 
(±3d) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
X' 
xJ 
X' 
X 
X 
X 
X 
Page 46 
Version 1.0 
Treatment Period 
Kinetic Biomarkcrs 
(Cycle 2) 
0 11)' 
Day 
Day 
D:ir 
Day 
112 
140 
15-1 
157 
161 
Dar 1611 
(\\,K 
(WK 
(WK 
(WK22 
(WK 
(WK 
Telcphon 
16) 
20) 
22) 
Da:,, 2) 
23) 
24/EO'I) 
e Follow-
(±3d) 
(±3d) 
(± Id ) 
(±l d) 
(± I d) 
(±3d}' 
ET 
u p• (±3d) 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
06 August 2020 


SEMA, FIR, ClLO 
GS-US-454-5533 
Statistical Analysis Plan 
Screening 
Pretreatment Period 
Kinetic Biomar-kers 
(Cycle I) 
Day 
Day 
Day 
- II 
- 7 
- 14 
(±Id) 
(± Id) 
Day 7 
(WK 
Day 
I) 
I 
(±3<1) 
Day 
Day 
Dar 
28 
56 
84 
(WK 
(WK 
(WI,; 
4) 
8) 
12) 
(±3d) 
(±3d) 
(±3d) 
Version 1.0 
Treatmcut Period 
Kinetic Biomarkers 
(Cycle 2) 
D:ty 
Day 
Day 
Day 
Day 
112 
140 
154 
157 
16 1 
Day 168 
(WK 
(WK 
(W K 
(WK 22 
(WK 
(WK 
Tclcphon 
16) 
20) 
22) 
Day 2) 
23) 
24/EOT) 
e Follow-
(±3d) 
(±3d) 
(±Id) 
(±Id) 
(± Id) 
(±3d)" 
ET 
Upb (±3d) 
-----------------------------------------------------------
Urine 
Collection 
(Kmet1c 
Biomarkcrs) 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Subjects premature I) discontinu ing from the study should complete an ET visit within 30 days of last dose of study drugs or pretreatment deuterated water. 
b 
Subject~ that received ai least one do,c of study drug will be contacted for a rclephone Follow-up Vi,it 7 weeks after the elate of the la I dose 
c 
Complete ph),ical examination to be performed at Screening. Symptom dri1 en phy,ical examination 10 be pcrfonned at Day-1-t Da) 1, Da) 7 (Weck I), Weck 4. Weck 8. 
Weck 12. Weck 16. Weck ::!O and Weck 24 (LO r) or ET visits 
d 
For subject~ 11 ith type 2 diabetes (from medical history or from Screening I lcmoglobin 1\ le >6.5~o). a fundus exam will be perfom1ed at Screening. rundus examinations 
require pharmacological dilation of both pupils or the use of a digital fundus photography camera specified for non-dilated examination. If a fundus exam ination matching d1is 
description has bern performed within 90 da) s prior to the date of the Screening Visit. the procedure docs not need to be repeated unless there has been worsening of I isual 
fw1ction ,incc the la.,t examination in the opinion of the i111 c,tigator. Ilic rc,ult, mu,t be a\ai lable prior 10 Enrollment (Da) - 14) 
c 
Subject 11i ll take lir,1 d0:,c of stud) drug, 01H>itc at Da) 1. 
f 
i\L reporting during Screening is limited to Si\Es and J\ Es related to sn.1cl) procedures 
g 
Required for a ll subjects. Will not be used to assess el igibility for subjects that meet inclusion criteria based on historic-al li\·er biopsy. lfa FibroScan~ and/or MRE has been 
perfonncd ,~ id1 in 4 weeks prior to die date of the Screening Visit. the procedure docs not need to be repeated. Sim ilarly. if an MRI-PDfF has been performed II ithin 4 weeks 
prior 10 the date of the Screening Visit and i,, deemed acceptable by the central reader. the procedure doc, not need 10 be repeated 
h 
i\1 the di,crction of the lme,tigator 
ELr"' Test score will 1101 be pro\ idcd to the sites 
j 
Single PK sample anytime during\ isit 
k 
/\II females of chi ldbearing potential will hme a scrtun pregnancy test at Screening. U1inc pregnancy testing will occur at Day I (prior to dosing). Weck 4. Weck 8. Weck 12. 
Weck 16. Weck 20 and Weck 24 (LO r) or Er I i~ib. /\II females of chi ldbearing potential that received at least one do,c of study dmg will be dc.pcnscd a urine pregnancy 
tc,ting kit at the Weck 24 (1.:0 r) or ET visit for home testing at the l'elephone Follow-Up 1isit. i\t the l'dcphonc Follo11-Up \ i,it. subject, \1i ll be requested to report the 
result of the urine pregnancy test 
CONFIDENTIAL 
Page 47 
06 August 2020 


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 48
06 August 2020
Appendix 2.
CTCTAE Grade for Laboratory Parameters
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1   
Grade 2   
Grade 3   
Grade 4
Grade 5   
Anemia
Hemoglobin (Hgb) <LLN 10.0 
g/dL; <LLN 6.2 mmol/L; 
<LLN 100 g/L
Hgb <10.0 8.0 g/dL; <6.2 
4.9 mmol/L; <100 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L; 
<80 g/L; transfusion indicated
Life threatening 
consequences; urgent 
intervention indicated
Death
Activated partial 
thromboplastin time 
prolonged
>ULN 1.5 x ULN
>1.5 2.5 x ULN
>2.5 x ULN; bleeding
Alanine 
aminotransferase 
increased
>ULN 3.0 x ULN if baseline 
was normal; 1.5 3.0 x baseline 
if baseline was abnormal
>3.0 5.0 x ULN if baseline 
was normal; >3.0 5.0 x 
baseline if baseline was 
abnormal
>5.0 20.0 x ULN if baseline 
was normal; >5.0 20.0 x 
baseline if baseline was
abnormal
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal
Alkaline phosphatase 
increased
>ULN 2.5 x ULN if baseline 
was normal; 2.0 2.5 x baseline 
if baseline was abnormal
>2.5 5.0 x ULN if baseline 
was normal; >2.5 5.0 x 
baseline if baseline was 
abnormal
>5.0 20.0 x ULN if baseline 
was normal; >5.0 20.0 x 
baseline if baseline was 
abnormal
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal
Aspartate 
aminotransferase 
increased
>ULN 3.0 x ULN if baseline 
was normal; 1.5 3.0 x baseline 
if baseline was abnormal
>3.0 5.0 x ULN if baseline 
was normal; >3.0 5.0 x 
baseline if baseline was 
abnormal
>5.0 20.0 x ULN if baseline 
was normal; >5.0 20.0 x 
baseline if baseline was 
abnormal
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal
Blood bicarbonate 
decreased
<LLN and no intervention 
initiated
Blood bilirubin increased
>ULN 1.5 x ULN if baseline 
was normal; > 1.0 1.5 x 
baseline if baseline was 
abnormal
>1.5 3.0 x ULN if baseline 
was normal; >1.5 3.0 x 
baseline if baseline was 
abnormal
>3.0 10.0 x ULN if baseline 
was normal; >3.0 10.0 x 
baseline if baseline was 
abnormal
>10.0 x ULN if baseline 
was normal; >10.0 x 
baseline if baseline was 
abnormal


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 49
06 August 2020
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1   
Grade 2   
Grade 3   
Grade 4
Grade 5   
Cholesterol high
>ULN 300 mg/dL; >ULN 
7.75 mmol/L
>300 400 mg/dL; 
>7.75 10.34 mmol/L
>400 500 mg/dL; >10.34 
12.92 mmol/L
>500 mg/dL; 
>12.92 mmol/L
CPK increased
>ULN 2.5 x ULN
>2.5 x ULN 5 x ULN
>5 x ULN 10 x ULN
>10 x ULN
Creatinine increased
>ULN 1.5 x ULN
>1.5 3.0 x baseline; 
>1.5 3.0 x ULN
>3.0 x baseline; 
>3.0 6.0 x ULN
>6.0 x ULN
GGT increased
>ULN 2.5 x ULN if baseline 
was normal; 2.0 2.5 x baseline 
if baseline was abnormal
>2.5 5.0 x ULN if baseline 
was normal; >2.5 5.0 x 
baseline if baseline was 
abnormal
>5.0 20.0 x ULN if 
baseline was normal; 
>5.0 20.0 x baseline if baseline 
was abnormal
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal
Haptoglobin decreased
<LLN
Hemoglobin increased
Increase in >0 2 g/dL
Increase in >2 4 g/dL
Increase in >4 g/dL
INR increased
>1.2 1.5; >1 1.5 x baseline if 
on anticoagulation; monitoring 
only indicated
>1.5 2.5; >1.5 2.5 x
baseline if on 
anticoagulation; dose 
adjustment indicated
>2.5; >2.5 x baseline if on 
anticoagulation; bleeding
Lipase increased
>ULN 1.5 x ULN
>1.5 2.0 x ULN; 
>2.0 5.0 x ULN and 
asymptomatic
>2.0 5.0 x ULN with 
signs or symptoms; 
>5.0 x ULN and asymptomatic
>5.0 x ULN and with signs 
or symptoms
Lymphocyte count 
decreased
<LLN 800/mm3; 
<LLN 0.8 x 10e9/L
<800 500/mm3; 
<0.8 0.5 x 10e9 /L
<500 200/mm3; 
<0.5 0.2 x 10e9 /L
<200/mm3; <0.2 x 10e9 /L
Lymphocyte count 
increased
>4000/mm3 20,000/mm3
>20,000/mm3
Neutrophil count 
decreased
<LLN 1500/mm3; 
<LLN 1.5 x 10e9 /L
<1500 1000/mm3; 
<1.5 1.0 x 10e9 /L
<1000 500/mm3;
<1.0 0.5 x 10e9 /L
<500/mm3; <0.5 x 10e9 /L


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
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Page 50
06 August 2020
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1   
Grade 2   
Grade 3   
Grade 4
Grade 5   
Platelet count decreased
<LLN 75,000/mm3; 
<LLN 75.0 x 10e9 /L
<75,000 50,000/mm3; 
<75.0 50.0 x 10e9 /L
<50,000 25,000/mm3; 
<50.0 25.0 x 10e9 /L
<25,000/mm3; 
<25.0 x 10e9 /L
Serum amylase increased
>ULN 1.5 x ULN
>1.5 2.0 x ULN; 
>2.0 5.0 x ULN and 
asymptomatic
>2.0 5.0 x ULN with 
signs or symptoms; 
>5.0 x ULN and asymptomatic
>5.0 x ULN and with signs 
or symptoms
White blood cell 
decreased
<LLN 3000/mm3; 
<LLN 3.0 x 10e9 /L
<3000 2000/mm3; 
<3.0 2.0 x 10e9 /L
<2000 1000/mm3; 
<2.0 1.0 x 10e9 /L
<1000/mm3; <1.0 x 10e9 /L
Hypercalcemia
Corrected serum calcium of 
>ULN 11.5 mg/dL; 
>ULN 2.9 mmol/L; Ionized 
calcium >ULN 1.5 mmol/L
Corrected serum calcium of 
>11.5 12.5 mg/dL; 
>2.9 3.1 mmol/L; 
Ionized calcium >1.5 1.6 
mmol/L; symptomatic
Corrected serum calcium of 
>12.5 13.5 mg/dL; 
>3.1 3.4 mmol/L; Ionized 
calcium >1.6 1.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; life
threatening consequences
Death
Hyperkalemia
>ULN 5.5 mmol/L
>5.5 6.0 mmol/L; 
intervention initiated
>6.0 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; 
life threatening 
consequences
Death
Hypermagnesemia
>ULN 3.0 mg/dL; 
>ULN 1.23 mmol/L
>3.0 8.0 mg/dL; >1.23 3.30 
mmol/L
>8.0 mg/dL; >3.30 mmol/L; 
life threatening 
consequences
Death
Hypernatremia
>ULN 150 mmol/L
>150 155 mmol/L; 
intervention initiated
>155 160 mmol/L; 
hospitalization indicated
>160 mmol/L; 
life threatening 
consequences
Death
Hypertriglyceridemia
150 mg/dL 300 mg/dL;
1.71 mmol/L 3.42 mmol/L
>300 mg/dL 500 mg/dL; 
>3.42 mmol/L 5.7 mmol/L
>500 mg/dL 1000 mg/dL; 
>5.7 mmol/L 11.4 mmol/L
>1000 mg/dL; 
>11.4 mmol/L; 
life threatening 
consequences
Death
Hyperuricemia
>ULN without physiologic 
consequences
>ULN with physiologic 
consequences
Life threatening 
consequences
Death


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 51
06 August 2020
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1   
Grade 2   
Grade 3   
Grade 4
Grade 5   
Hypoalbuminemia
<LLN 3 g/dL; <LLN 30 g/L
<3 2 g/dL; <30 20 g/L
<2 g/dL; <20 g/L
Life threatening 
consequences; urgent 
intervention indicated
Death
Hypocalcemia
Corrected serum calcium of 
<LLN 8.0 mg/dL; 
<LLN 2.0 mmol/L; Ionized 
calcium <LLN 1.0 mmol/L
Corrected serum calcium of 
<8.0 7.0 mg/dL; <2.0 
1.75 mmol/L; Ionized 
calcium <1.0 0.9 mmol/L; 
symptomatic
Corrected serum calcium of 
<7.0 6.0 mg/dL; <1.75 1.5 
mmol/L; Ionized calcium <0.9 
0.8 mmol/L; hospitalization 
indicated
Corrected serum calcium of 
<6.0 mg/dL; 
<1.5 mmol/L; Ionized 
calcium <0.8 mmol/L; 
life threatening 
consequences
Death
Hypoglycemia
<LLN 55 mg/dL; 
<LLN
3.0 mmol/L
<55 40 mg/dL; 
<3.0 2.2 mmol/L
<40 30 mg/dL; 
<2.2 1.7 mmol/L
<30 mg/dL; <1.7 mmol/L; 
life threatening 
consequences; seizures
Death
Hypokalemia
<LLN 3.0 mmol/L
Symptomatic with 
<LLN 3.0 mmol/L; 
intervention indicated
<3.0 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; 
life threatening 
consequences
Death
Hypomagnesemia
<LLN 1.2 mg/dL; 
<LLN 0.5 mmol/L
<1.2 0.9 mg/dL; 
<0.5 0.4 mmol/L
<0.9 0.7 mg/dL; 
<0.4 0.3 mmol/L
<0.7 mg/dL; 
<0.3 mmol/L; 
life threatening 
consequences
Death
Hyponatremia
<LLN 130 mmol/L
125 129 mmol/L and 
asymptomatic
125 129 mmol/L symptomatic; 
120 124 mmol/L regardless of 
symptoms
<120 mmol/L; 
life threatening 
consequences
Death
*
Since anticoagulation medication is NOT captured in lab data, the condition for anticoagulation medication is ignored in the grade derivation. 
a
Note: Refer to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, which can be found at https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 5.0


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 52
06 August 2020
Appendix 3.
Liver Function Prognostic Scores

Child-Pugh Score
1
2
3
Hepatic 
Encephalopathy
(HE)
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject 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
Cross sectional imaging 
showing ascites
   
Abdominal distension 
  
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Total Bilirubin 
(mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3
There are 5 components for CP score as seen in the first column. Each will be assigned a
subscore ranging between 1 and 3 based on the matching condition as described in the
corresponding row and the value in the header row of the corresponding column. For example, 
when total bilirubin value is 2.5 mg/dL, the total bilirubin subscore will be 2. 
CP score is obtained by adding the subscore for each parameter, ranging between 5 and 15.
For Day 1 and postbaseline visits, HE and ascites will be from the same day as laboratory data 
collected. If baseline CP score is missing due to unevaluable laboratory data or discrepancy in 
the collection dates between HE and ascites and laboratory data, baseline CP score will be 
calculated using the last laboratory values collected prior to Day 1 and the last assessment results 
of HE and ascites prior to Day 1.

MELD Score
MELD score 
3.78 [ln total bilirubin (mg/dL)] + 11.2 [ln INR] + 9.57 [ln serum creatinine 
(mg/dL)] + 6.43.  If the serum creatinine, the total bilirubin or the INR value is < 1.00 mg/dL, 
the calculation will use 1.00 as the test value. If the serum creatinine is > 4.00 mg/dL or subjects 
on dialysis, the calculation will use 4.00 as the serum creatinine value.


SEMA, FIR, CILO
GS-US-454-5533
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 53
06 August 2020
Appendix 4.
Noninvasive Markers for Fibrosis

Enhanced Liver Fibrosis (ELF)
ELF test score  2.278 + 0.851× ln (hyaluronic acid) + 0.751× ln (PIIINP) + 0.394 × ln (TIMP1);
Note: All ELF test score components (hyaluronic acid, PIIINP and TIMP1) need to be measured 
from the same blood draw. ELF test score will only be calculated when ELF test score is missing 
and components are less than the LOQ or above the upper LOQ. Individual components are to be 
imputed per data handling conventions in Section 3.7, and ELF test score will be calculated 
based on the imputed values of components.

FibroSURE/FibroTest
Step-1 formula
f5  4.467 Log[α2-macroglobulin(g/L)] 1.357 Log[Haptoglobin 
(g/L)] + 1.017 Log[GGT(U/L)] + 0.0281 [Age (year)] + 1.737 Log 
[Total Bilirubin (umol/L)] 1.184 [ApoA1 (g/L)] + 0.301 Sex 
(female
 0, male  1) 5.540
Step-2 formula
FibroSURE/FibroTest® Score
 1/(1+exp^(-f5))
Note

In the formula, SI value and units should be applied.

The Log function in the formula is with base 10.

FibroSURE/FibroTest  score should be calculated from the parameters 
from the same blood draw

Age is when the blood draw was taken 
Note: For subject with Gilbert’s syndrome or hemolysis according to the medical history page at 
screening, the FibroSURE/FibroTest score will be calculated using direct bilirubin instead of
total bilirubin in above formula throughout the study.

Fibrosis-4 (FIB-4) Index
FIB-4 Index
 round ((age × AST ) / (platelet × sqrt (ALT)), 0.01);

AST to Platelet Ratio Index (APRI)
APRI  round (AST/ASTULN × 100 / platelet, 0.1);
Note: for FIB-4 index and APRI calculation, the laboratory parameters need to be measured from 
the same blood draw. Age should be the actual age at the date when laboratory values are taken.


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
NAFLD fibrosis score (NFS)
NFS  -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG (impaired fasting 
glucose) / pre-diabetes or diabetes (yes
 1, no  0) + 0.99 × AST / ALT ratio - 0.013 × platelet 
(×109/L) - 0.66 × albumin (g/dL).  Keep 3 decimal places.
The laboratory parameters need to be measured from the same blood draw. The last non-missing 
BMI on or prior to laboratory date should be used. Age should be the actual age at the date when 
laboratory values are taken. Status of pre-diabetes/diabetes should also be decided on the 
laboratory date. If a subject had pre-diabetes/diabetes at baseline, the pre-diabetic/diabetic status 
will be yes for all the postbaseline visits. If the subject does not have pre-diabetic/diabetes at 
baseline, the diabetic status will be determined based on the start date AEs of pre-diabetes and 
diabetes, and the collection date when fasting glucose is greater than 100 (IFG).  If the AE start 
date or the fasting glucose collection date is on or prior to the laboratory date of a specific visit, 
then the pre-diabetic/diabetic status will be yes for that visit and later visits. If the day of the AE 
start date is missing, it will be imputed using the 1st day of the month.


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Appendix 5.
Health Related QoL Score

CLDQ-NAFLD
CLDQ-NAFLD scores are calculated using subject responses to 36 questions in the 
questionnaire. If Ri is the score for the patient’s response to the item i, for i 1, 2, …., 36 then the 
6 domain scores are calculated as follows:
Abdominal  Mean of {R1, R5, R17}
Fatigue  Mean of {R2, R4, R8, R11, R13, R35}
Systemic  Mean of {R3, R6, R21, R23, R27, R36}
Activity  Mean of {R7, R9, R14, R30, R31}
Emotion  Mean of {R10, R12, R15, R16, R19, R20, R24, R26, R34}
Worry  Mean of {R18, R22, R25, R28, R29, R32, R33}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is calculated 
only if at least half of corresponding items are not missing. Otherwise, the score will be missing.
Overall CLDQ score is calculated by taking the mean of 6 domain scores {abdominal, fatigue, 
systemic, activity, emotion, worry}.  Overall CLDQ score will be summarized.

EQ-5D
Scoring of EQ-5D will be performed as described in EQ-5D-5L user guide. Summary will be 
done for 5 dimensions in descriptive system (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression) and the EQ Visual Analogue Scale.


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Appendix 6.
Determining Missing and Virtual Visits Due To COVID-19
This appendix describes the site collection of COVID-19 data as pertains to missed/virtual visits 
and the data processing algorithm used to determine which visits were missing and which visits 
were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites should enter 
“Visit missed due to COVID-19.”  If a visit which was to be conducted in-person was conducted 
virtually, sites should enter “Virtual visit due to COVID-19.”  
Determination of Missed and Virtual visits
Natural Language Processing (NLP) was used to search the CRF comment fields to identify 
instances of “COVID-19” (or synonyms, see Table X1) and “Virtual” (or synonyms, see 
Table X1).  The search terms are maintained in a global lookup and can be modified and/or 
corrected to tune the NLP model. For each comment field the following algorithm was applied:
STEP 1: Eliminate extraneous text from each comment field, e.g. “and”, “or”, “for”, etc. This is 
done using the list of extraneous terms given in Table X2.
STEP 2: Check each of the remaining comment text strings against the “COVID-19” terms and 
“Virtual” terms with the Levenshtein distance, using SAS function COMPGED (Computes a 
generalized edit distance using the Levenshtein operations to compute/summarize the degree of 
difference between two text strings): 
i.
If Levenshtein distance < 149 for any of the “COVID-19” terms then 
COVIDFL
 1, else COVIDFL  0
ii.
If Levenshtein distance < 149 for any of the “Virtual” terms then VIRTFL  1, 
else VIRTFL  0
STEP 3: For any comments with COVIDFL  1, assign “Missed visit” or “Virtual visit as 
follows:
i.
IF COVIDFL 1 and the visit date is missing then result is ‘Missed Visit’
ii.
IF COVIDFL 1 and VIRTFL  1 then result is  ‘Virtual Visit’
iii.
Otherwise result is missing


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Table X1: Examples of search terms for “COVID-19” and “Virtual” used to identify missed and 
virtual visits.
Search terms for “COVID-19”
Search terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE
Table X2: Examples of extraneous text terms to eliminate from the comment fields.
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of
then
where's


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been
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