Clinical trial NCT03449446
Conditions: Nonalcoholic Steatohepatitis
Sponsor: Gilead Sciences
Start date: 2018-03-21; Completion date: 2019-11-19
Enrollment: 395 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are:

* To assess the safety and tolerability of selonsertib (SEL), firsocostat (FIR) and cilofexor (CILO), administered alone or in combination, in participants with bridging fibrosis or compensated cirrhosis due to NASH
* To evaluate changes in liver fibrosis, without worsening of NASH

Detailed description:

Arms: arm 1: Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks. arm 2: Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks. arm 3: Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks. arm 4: Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks. arm 5: Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks. arm 6: Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks. arm 7: Participants will receive placebo to match SEL 18 mg + placebo to match FIR 20 mg tablet + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Interventions: intervention 1: SEL intervention 2: FIR intervention 3: CILO intervention 4: Placebo to match FIR intervention 5: Placebo to match CILO intervention 6: Placebo to match SEL
Intervention descriptions: intervention 1: 18 mg tablet administered orally once daily without regard to food intervention 2: 20 mg tablet administered orally once daily without regard to food intervention 3: 30 mg tablet administered orally once daily without regard to food intervention 4: Tablet administered orally once daily without regard to food intervention 5: Tablet administered orally once daily without regard to food intervention 6: Tablet administered orally once daily without regard to food

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Contrnlled Study 
Evaluating the Safety and Efficacy of Selonse1iib, GS-0976, 
GS-9674, and Combinations in Subjects with Bridging (F3) Fibrosis 
or Compensated CnThosis (F4) due to Nonalcoholic Steatohepatitis 
(NASH) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
141683 
Not Applicable 
NCT03449446 
Nonalcoholic Steatohepatitis 
GS-US-454-4378 
Gilead Study Director 
Name: 
PD 
PD 
PD 
PD 
PD 
PD 
PD 
PD 
Telephone: 
Fax: 
Email: 
Gilead Medical 
Name: 
Monitor: 
Telephone: 
Fax: 
Email: 
Protocol Version/Date: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
08 Januaiy 2018 
31 Januaiy 2018 
22 Febrnaiy 2018 
10 May2018 
25 April 2019 
CONFIDENTIALITY STATEMENT 
The info1m ation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational drng 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 necessa1y to obtain infonned consent from those 
persons to whom the drng may be administered. 


Selonsertib, GS-0976, GS-9674 
Protocol GS-US-454-4378 
Gilead Sciences, Inc. 
Final 
Amendment4 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 16 
1. 
INTRODUCTION .............................................................................................................................................. 22 
1.1. 
Background ............................................................................................................................................ 22 
1.2. 
Selonsertib (SEL) ................................................................................................................................... 23 
1.2.1. 
General Infonnation for SEL ............................................................................................... 23 
1.2.2. 
Nonclinical Phrumacology and Toxicology ......................................................................... 24 
1.2.3. 
Clinical Trials ofSEL ........................................................................................................... 24 
1.3. 
GS-0976 ................................................................................................................................................. 28 
1.3.1. 
General Infonnation for GS-0976 ........................................................................................ 28 
1.3.2. 
Nonclinical Phrumacology and Toxicology ......................................................................... 28 
1.3.3. 
Clinical Trials ofGS-0976 ................................................................................................... 29 
1.4. 
GS-9674 ................................................................................................................................................. 37 
1.4.1. 
General Infonnation for GS-9674 ........................................................................................ 37 
1.4.2. 
Nonclinical Phrumacology and Toxicology ......................................................................... 38 
1.4.3. 
Clinical Trials ofGS-9674 ................................................................................................... 38 
1.5. 
Combination Studies of SEL, GS-0976, and GS-9674 .......................................................................... 44 
1.5.1. 
Nonclinical Pha1macology, Phrumacokinetics, Drng Metabolism, and 
Toxicology ........................................................................................................................... 44 
1.5.2. 
Clinical Trials ....................................................................................................................... 46 
1.6. 
Rationale for This Study ........................................................................................................................ 52 
1.6.1. 
Rationale for Dose Selection of SEL. ................................................................................... 54 
1.6.2. 
Rationale for Dose Selection of GS-0976 ............................................................................ 54 
1.6.3. 
Rationale for Dose Selection of GS-9674 ............................................................................ 55 
1.6.4. 
Rationale for Dose Selection of Combinations .................................................................... 55 
1. 7. 
Risk/Benefit Assessment for the Study .................................................................................................. 56 
1.8. 
Compliance ............................................................................................................................................ 57 
2. 
OBJECTIVES ..................................................................................................................................................... 58 
3. 
STUDY DESIGN ................................................................................................................................................ 59 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
Study Design .......................................................................................................................................... 59 
Study Treatments ................................................................................................................................... 59 
Duration of Study ................................................................................................................................... 60 
End of Study ........................................................................................................................................... 60 
Post Stud Cru·e ...................................................................................................................................... 60 
4. 
SUBJECT POPULATION .................................................................................................................................. 63 
4.1. 
Number of Subjects and Subject Select.ion ............................................................................................ 63 
4.2. 
Inclusion Criteria .................................................................................................................................... 63 
4.3. 
Exclusion Criteria ................................................................................................................................... 64 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 67 
5.1. 
Randomization, Blinding and Treatment Codes .................................................................................... 67 
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5.1.1. 
Procedures for Breaking Treatment Codes ........................................................................... 67 
5.2. 
Description and Handling of SEL, GS-0976, GS-9674 .......................................................................... 68 
5.2.1. 
Foimulation .......................................................................................................................... 68 
5.2.2. 
Packaging and Labeling ....................................................................................................... 69 
5. 2. 3. 
Storage and Handling ........................................................................................................... 69 
5.2.4. 
Dosage and Adininisti·ation .................................................................................................. 69 
5.3. 
Prior and Conconutant Medications ....................................................................................................... 70 
5.4. 
Accountability for SEL, GS-0976, and GS-9674 ................................................................................... 72 
5 .4.1. 
Investigational Medicinal Product Retwn or Disposal ........................................................ 72 
6. 
STUDY PROCEDURES .................................................................................................................................... 73 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
6.6. 
6.7. 
6.8 . .. 
6.11. 
6.12. 
Subject Enrollment and Treatment Assignment ..................................................................................... 73 
Preti·eahnent Assessments ...................................................................................................................... 73 
6.2.1. 
Screening Visit ..................................................................................................................... 73 
Day 1 Assessments ................................................................................................................................. 75 
6.3.1. 
Day 1: Randomization and Assessments .............................................................................. 75 
On-Treahnent Assessments .................................................................................................................... 77 
6.4.1. 
Week 1 Visit (± 3 days) ........................................................................................................ 77 
6.4.2. 
Week 4, Week 12, and Week 36 Visits (±3 days) ................................................................ 78 
6.4.3. 
Week 8, Week 16, Week 20, Week 28, Week 32, Week 40, and Week 44 
6.4.4. 
6.4.5. 
6.4.6. 
Visits (±3 days) .................................................................................................................... 79 
Week 24 and Week 48 (±7 days) ......................................................................................... 80 
Early Te1mination (ET) Visit ............................................................................................... 82 
Unscheduled Visits ............................................................................................................... 84 
Post-ti·eatment Assessments ................................................................................................................... 85 
6.5.1. 
Follow-Up Visit (±5 days) ................................................................................................... 85 
Criteria for Discontinuation of Study Dmg ............................................................................................ 86 
Inte1111ption of Study D1ug ..................................................................................................................... 87 
Assessments for Premature Discontinuation from Stud ....................................................................... 87 
Descnphon o Assess1nents ................................................................................................................... 88 
6.11.1. 
Clinical Laborato1y Analytes ............................................................................................... 88 
6.11.2. 
Physical Examination ........................................................................................................... 89 
6.11.3. 
Vital Signs, Hip and Waist Circumference .......................................................................... 89 
6.11.4. 
Medical Histo1y .................................................................................................................... 90 
6.11.5. 
Clinical Liver Assessments .................................................................................................. 90 
6.11.6. 
6.11.7. 
6.11.14. 
Abdo1ninal Ultrasound ......................................................................................................... 94 
6.11.15. 
Liver Biopsy ......................................................................................................................... 94 
6.11.16. 
Lifes le Modification Counselin ....................................................................................... 94 
.
Storage ....................................................................................................................................... 95 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 96 
7 .1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 96 
7 .1.1. 
Adverse Events ..................................................................................................................... 96 
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Final 
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7.1.2. 
Serious Adverse Events ........................................................................................................ 96 
7.1.3. 
Clinical Laborato1y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 97 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 97 
7.2.1. 
Assessment of Causality for Study Drngs and Procedw-es ................................................... 97 
7.2.2. 
Assess1nent ofSeverity ........................................................................................................ 98 
7.3. 
Investigator Requirements and Instrnctions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 98 
7 .4. 
Gilead Repo1t ing Requirements ........................................................................................................... 100 
7.5. 
Toxicity Management .......................................................................................................................... 100 
7 .5 .1. 
Observation for Drng Induced Liver Injwy (DILi) ............................................................ 100 
7.5.2. 
Close Observation .............................................................................................................. 101 
7.5.3. 
CP Score ............................................................................................................................. 103 
7.5.4. 
Hype111·iglyceridelllia .......................................................................................................... 103 
7.5.5. 
Pruritus Management ......................................................................................................... 104 
7.6. 
Special Situations Repoits .................................................................................................................... 104 
7 .6.1. 
Definitions of Special Situations ........................................................................................ 104 
7.6.2. 
Instiuctions for Reporting Special Situations ..................................................................... 105 
8. 
STATISTICAL CONSIDERATIONS .............................................................................................................. 107 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
.. 
8.11. 
8.12. 
Analysis Objectives and Endpoints ...................................................................................................... 107 
8.1.1. 
Analysis Objectives ............................................................................................................ 107 
8.1.2. 
Endpoints ............................................................................................................................ 108 
Analysis Conventions ........................................................................................................................... 109 
Analysis Sets ........................................................................................................................................ 109 
8.3.1. 
Efficacy .............................................................................................................................. 109 
8.3.2. 
Safety .................................................................................................................................. 109 
Interi1n Analysis ................................................................................................................................... 110 
Data Handling Conventions ................................................................................................................. 110 
Demographic Data and Baseline Characteristics ................................................................................. 110 
Efficacy Analysis ................................................................................................................................. 111 
8. 7 .1. 
Primru Efficac End oints Anal sis ................................................................................ 111 
• 
Ana ys1s ..................................................................................................................................... 111 
8.8.1. 
ExtentofExposw·e ............................................................................................................. 111 
8.8.2. 
Adverse Events ................................................................................................................... 111 
8.8.3. 
Laborato1 Evaluations ...................................................................................................... 112 
Samp e Size .......................................................................................................................................... 112 
Data Monitoring Comlllittee ................................................................................................................ 113 
9. 
RESPONSIBILITIES ........................................................................................................................................ 114 
9.1. 
Investigator Responsibilities ................................................................................................................ 114 
9 .1.1. 
Good Clinical Practice ........................................................................................................ 114 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
9.1.3. 
9.1.4. 
9.1.5. 
9.1.6. 
9.1.7. 
9.1.8. 
9.1.9. 
Ethics Committee (EC) Review and Approval .................................................................. 114 
Info1med Consent ............................................................................................................... 114 
Confidentiality .................................................................................................................... 115 
Study Files and Retention of Records ................................................................................ 115 
Electi·onic Case Repo11 F onns ............................................................................................ 116 
Investigational Medicinal Product Accountability and Retwn ........................................... 117 
Inspections .......................................................................................................................... 117 
Protocol Compliance .......................................................................................................... 118 
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9.2.
Sponsor Responsibilities ......................................................................................................................118
9.2.1.
Protocol Modifications.......................................................................................................118
9.2.2.
Study Report and Publications ...........................................................................................118
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................119
9.3.1.
Payment Reporting.............................................................................................................119
9.3.2.
Access to Information for Monitoring................................................................................119
9.3.3.
Access to Information for Auditing or Inspections ............................................................119
9.3.4.
Study Discontinuation........................................................................................................119
10.
REFERENCES .................................................................................................................................................120
11.
APPENDICES ..................................................................................................................................................123
Appendix 1.
Investigator Signature Page..................................................................................................124
Appendix 2.
Study Procedures Table........................................................................................................125
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................129
Appendix 4.
West Haven Criteria .............................................................................................................133
LIST OF IN-TEXT TABLES
Table 1-1.
Pharmacokinetic Results from Study GS-US-384-4266 Evaluating DDE between 
SEL 18 mg QD and Representative Hormonal Contraceptive, Ethinyl 
Estradiol/Levonorgestrel ........................................................................................................25
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 Evaluating 
DDIs with GS-0976 (20 mg or 50 mg)...................................................................................31
Table 1-3.
GS-US-426-3988: Preliminary GS-0976 and GS-834773 PK Parameters Following 
a Single Dose of GS-0976 20 mg in Subjects with Mild or Moderate Hepatic 
Impairment or Normal Hepatic Function ...............................................................................34
Table 1-4.
GS-US-454-4315: Summary of Changes in Primary PK Parameters for GS-9674 
and GS-716070 Following Administration of GS-9674 Single Agent Tablets with a 
Light Meal or High-Fat Meal as Compared to Fasted State ...................................................41
Table 1-5.
GS-US-402-3885: Preliminary GS-9674 and GS-716070 PK Parameters Following 
a Single Dose of GS-9674 30 mg in Subjects with Hepatic Impairment or Normal 
Hepatic Function ....................................................................................................................43
Table 1-6.
GS-US-402-2101: Changes in primary PK parameters for SEL, GS-9674, and GS-
0976 and their respective metabolites (GS-607509, GS-716070, and GS-834773) 
following once daily administration of SEL, GS-9674, and/or GS-0976 in 
combination for 7 days compared with the single agent for 7 days........................................48
Table 1-7.
GS-US-384-3914: Safety Summary .......................................................................................51
Table 1-8.
GS-US-384-3914: Treatment-Emergent Grade 3 and 4 Lab Abnormality Summary ............52
Table 5-1.
List of Representative Disallowed and Use with Caution Medicationsa ................................71
LIST OF IN-TEXT FIGURES
Figure 1-1.
ASK1 Signaling in NASH......................................................................................................23
Figure 3-1.
Overall Study Design .............................................................................................................59
Figure 7-1.
On-Treatment ALT/AST Monitoring Requiring Close Observation....................................101
Figure 7-2.
On-Treatment Monitoring Requiring Withholding of Study Drugs .....................................102
Figure 7-3.
Algorithm for Monitoring and Treatment of Hypertriglyceridemia .....................................104
CCI
CCI


Selonsertib, GS-0976, GS-9674
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404 USA
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety and Efficacy of Selonsertib, GS-0976, GS-9674, 
and Combinations in Subjects with Bridging (F3) Fibrosis or 
Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis 
(NASH)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
141683
Not Applicable
NCT03449446
Study Centers 
Planned:
Approximately 135 centers in the United States, Canada, Australia, 
New Zealand, and Hong Kong
Objectives:
The primary objectives of this study are: 

To assess the safety and tolerability of selonsertib (SEL), GS-0976, 
and GS-9674, administered alone or in combination, in subjects 
with bridging fibrosis or compensated cirrhosis due to NASH 

To evaluate changes in liver fibrosis, as measured by the NASH 
Clinical Research Network (CRN) classification, without 
worsening of NASH (defined as any increase in hepatocellular 
ballooning or lobular inflammation) 
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled study 
evaluating the safety and efficacy of SEL, GS-0976, GS-9674, and 
combinations in subjects with bridging fibrosis or compensated 
cirrhosis due to NASH.
Subjects meeting the study’s entry criteria will be randomly assigned in 
a 2:2:1:1:1:1:2 ratio to 1 of 7 treatment groups, with approximately 
70 subjects in each combination treatment group and approximately 
35 subjects in each single agent or placebo group, as shown in the 
figure below:


Selonsertib, GS-0976, GS-9674 
Protocol GS-US-454-4378 
Gilead Sciences, Inc. 
Final 
Amendment4 
8Weeks 
C 
.,. 
0 
C 
i 
'f -
-~ 
0 
.... 
-a 
Ill 
C 
ra 
a:: 
48Weeks 
_,. I 
A: SEL18mg + GS-0976 20 mg+ PTM GS-967430 mg {N ~ 70) 
_,. I 
B: SEL18mg + PTM GS-097620 mg+ GS-967430 mg {N ~ 70) 
_,. I C: SEl 18 mg + PTMGS-097620 mg+ PTMGS-967430mg (N ~ 35) 
-1 
D: PTM SEL 18 mg• GS-097620 mg+ PTM GS·967430mg (N ~ 35) 
-I 
E: PTM SEL18 mg + PTM GS-097620 mg +GS-967430mg (N-35) 
14 Weeks I 
-I 
I 
I .. 
C ., 
E 
1i 
I~ 
w 
-I 
F: PTM SEL 18 mg + PTM GS-097620 mg + PTM GS-9674 30 mg (N • 35) I 
-+I G: PTM SEl 18 mg+ GS-097620mg + GS-967430 mg {N ~ 70) 
I -
Randomized Study Phase 
Randomization will be stratified by the presence or absence of diabetes 
mellitus, as detennined by medical histo1y or based on the Screening 
laborato1y values if previously undiagnosed (hemoglobin A 1 c [HbA 1 c] 
:::: 6.5% or fasting plasma glucose :::: 126 mg/dL), and by the presence or 
absence of ciIThosis (F4) as detennined by the central biopsy reader at 
Screening. Study dmgs will be administered for a total of 48 weeks. 
Subjects who develop evidence of hepatic decompensation, including a 
Child-Pugh (CP) score :::: 7 on at least two consecutive occasions at 
least two weeks apart, or undergo liver transplantation, must 
discontinue study dmgs. 
Number of 
Approxnnately 350 subjects 
Subjects Planned: 
Target Population: 
Males and non-pregnant, non-lactating females between 18 - 80 years 
of age with bridging fibrosis or compensated ciIThosis due to NASH. 
Duration of Study: 
Paiiicipation can last up to 60 weeks, which includes an 8-week 
Screening period, a 48-week On-Treatment period, and a 4-week 
Follow-Up period. 
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Diagnosis and 
Main Eligibility 
Criteria:
Key Inclusion Criteria
1)
Males and non-pregnant, non-lactating females between 
18 - 80 years of age inclusive, based on the date of the Screening 
visit;
2)
Bridging fibrosis or cirrhosis due to NASH as defined by one of 
the following; all subjects must not have documented weight loss 
> 5% between the date of the biopsy and Screening:
a) NASH (defined as the presence of a steatosis grade ≥1, 
hepatocellular ballooning grade ≥ 1, and lobular inflammation 
grade ≥ 1, according to the nonalcoholic fatty liver disease
[NAFLD] Activity Score [NAS]) and bridging fibrosis (F3) 
within 6 months of Screening, in the opinion of the central 
reader;
b) Compensated cirrhosis (F4) due to NASH (defined as the 
presence of a steatosis grade ≥ 1, hepatocellular ballooning 
grade ≥ 1, and lobular inflammation grade ≥ 1, according to the 
NAS) within 12 months of Screening, in the opinion of the 
central reader;
c) Compensated cirrhosis (F4) due to NASH with < 5% steatosis 
(defined as a steatosis grade of 0, hepatocellular ballooning 
grade ≥ 1, and lobular inflammation grade ≥ 1, according to the 
NAS) within 12 months of Screening, in the opinion of the 
central reader; and at least two of the following criteria for 
metabolic syndrome, modified from the National Cholesterol 
Education Program Adult Treatment Plan III {Grundy 2005}
Guidelines at Screening:
i.
Fasting glucose ≥100 mg/dL or receiving drug 
treatment for elevated glucose;
ii.
Fasting HDL cholesterol < 40 mg/dL in men and 
< 50 mg/dL in women or receiving drug treatment for 
low HDL cholesterol;
iii.
Fasting triglycerides ≥ 150 mg/dL or receiving drug 
treatment for elevated triglycerides;
iv.
Waist circumference ≥102 cm for men or ≥88 cm for 
women or BMI ≥ 30 kg/m2;
v.
Systolic blood pressure ≥130 mmHg or diastolic blood 
pressure ≥ 85 mmHg or receiving drug treatment for 
hypertension;


Selonsertib, GS-0976, GS-9674
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d) In subjects who have never had a liver biopsy, liver stiffness by 
FibroScan® XL probe ≥ 14.0 kPa, Enhanced Liver Fibrosis 
(ELF™) Test score ≥9.8, and at least two of the criteria for 
metabolic syndrome modified from the NCEP ATP III 
Guidelines, at Screening. In subjects eligible based on this 
criterion, a liver biopsy must be performed during Screening 
and must be deemed evaluable for fibrosis stage and NAS by 
the central reader; however, the reported stage of fibrosis will 
not determine eligibility for the study;
3)
Screening laboratory parameters, as determined by the central 
laboratory:
a) Estimated glomerular filtration rate (eGFR) ≥60 mL/min, as 
calculated by the Cockcroft-Gault equation;
b) HbA1c ≤ 9.5% (or serum fructosamine ≤381 µmol if HbA1c is 
unable to be resulted);
c) Hemoglobin ≥ 10.6 g/dL; 
d) International normalized ratio (INR) ≤ 1.4, unless due to 
therapeutic anticoagulation;
e) Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due 
to an alternate etiology such as Gilbert’s syndrome or 
hemolytic anemia;
f)
Platelet count ≥ 125,000/µL;
g) Serum triglyceride level ≤ 250 mg/dL;
h) Alanine aminotransferase (ALT) < 5 x ULN.
Key Exclusion Criteria
1)
Prior history of decompensated liver disease including ascites, 
hepatic encephalopathy (HE), or variceal bleeding;
2)
CP score > 6 at Screening, unless due to an alternative etiology 
such as Gilbert’s syndrome or therapeutic anticoagulation;
3)
Model for End-Stage Liver Disease (MELD) score > 12 at 
Screening, unless due to an alternate etiology such as therapeutic 
anticoagulation;
4)
Chronic hepatitis B virus (HBV) infection (hepatitis B surface 
antigen [HBsAg] positive);
5)
Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] 
and HCV ribonucleic acid [RNA] positive). Subjects cured of 
HCV infection less than 2 years prior to the Screening visit are not 
eligible;


Selonsertib, GS-0976, GS-9674 
Protocol GS-US-454-4378 
Gilead Sciences, Inc. 
Final 
Amendment4 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
6) Other causes of liver disease based on medical histo1y and/or 
centralized review of liver histology, including but not limited to: 
alcoholic liver disease, hepatitis B, hepatitis C, autoimmune 
disorders (eg, primaiy biliaiy cholangitis [PBC], primaiy 
sclerosing cholangitis [PSC], autoimmune hepatitis), mug-induced 
hepatotoxicity, Wilson disease, clinically significant iron overload, 
or alpha-1-antitiyspin deficiency requiring treatment; 
7) Histo1y of liver ti·ansplantation; 
8) CmTent or prior histo1y of hepatocellular cai·cinoma (HCC); 
9) Any weight reduction surge1y within 2 yeai·s prior to Screening or 
malabsorptive weight loss surge1y (eg, Roux-en-Y or distal gasti·ic 
bypass) at any time prior to Screening. Weight reduction surge1y is 
disallowed during the study; 
10) Intestinal resection that could result in malabso1ption of study 
diug; 
11) Weight loss > 10% within 6 months of Screening; 
12) Human immunodeficiency vims (HIV) infection; 
13) Unstable cardiovascular disease. 
Screening assessments will include complete medical histo1y, complete 
physical examination (PE) includin assessment of ascites and HE, 
vital signs including weight, height, 
laborato1y assessments includin a 
of childbeai·in 
otential 
Eligible subjects will be randomized to one of seven treatment groups, 
with approximately 70 subjects in each combination ti·eatment group 
and approximately 35 subjects in each single agent or placebo group: 
Group A: SEL 18 mg, GS-0976 20 mg, and placebo to match 
(PTM) GS-9674 30 mg 
Group B: SEL 18 mg, PTM GS-0976 20 mg, and 
GS-9674 30 mg 
Group C: SEL 18 mg, PTM GS-0976 20 mg, and 
PTM GS-9674 30 mg 
Group D: PTM SEL 18 mg, GS-0976 20 mg, and 
PTM GS-9674 30 mg 
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Gilead Sciences, Inc. 
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Amendment 4 
CONFIDENTIAL 
Group E: PTM SEL 18 mg, PTM GS-0976 20 mg, and 
GS-9674 30 mg 
Group F: PTM SEL 18 mg, PTM GS-0976 20 mg, and 
PTM GS-9674 30 mg 
Group G: PTM SEL 18 mg, GS-0976 20 mg, and 
GS-9674 30 mg 
Prior to initial dosing, the following Day 1 assessments will be 
peifonned: symptom driven PE includin assessment of ascites and 
HE, vital signs, body weight, 
, laborato1y 
assessments including a urine 
a es of 
childbearin 
otential 
After the randomization visit at Day 1, study visits will occur on 
Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. 
While on study, subjects will undergo the following procedures and 
laborato1y assessments: 
• 
Symptom driven PE at Weeks 1, 4, 8, 12, 16, 20, 28, 32, 36, 40, 44 
• 
Complete PE at Weeks 24 and 48 
• 
Vital signs including body weight at each visit 
I 
• 
12-lead ECG at Week 48 
• 
Chemistry, hematology, and coagulation at each visit 
• 
HbAlc at Weeks 4, 12, 24, 36, and 48 
• 
Insulin and lipids at Weeks 4, 12, 24, 36, and 48 
I 
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Test Product and 
Dose 
Reference Therapy 
and Dose 
CONFIDENTIAL 
I 
• 
Urine pregnancy test (for females of childbearing potential) at 
I 
I 
I 
I 
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 
• 
Lifestyle questionnaire at each visit 
I 
I 
I 
• 
Liver biopsy at Week 48 
I 
I 
All subjects will complete a Follow-Up visit 4 weeks after the date of 
last dose of study diugs. At this visit sub· ects will have a symptom 
di·iven PE, vital signs, weight, 
12-lead 
ECG review of concomitant me 1cat10ns an AEs, 
_
, and laborato1y assessments mc u mg a urine 
~
es of childbearing potential). 
SEL 18 mg, GS-0976 20 mg, and GS-9674 30 mg oral tablets 
once daily, alone or in combination 
PTM SEL 18 mg, PTM GS-0976 20 mg, and PTM GS-9674 30 mg 
oral tablets once daily 
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Treatment Groups 
and Mode of 
Administration:

Treatment Group A: one SEL 18 mg tablet, one GS-0976 20 mg 
tablet, and one PTM GS-9674 30 mg tablet administered orally 
once daily with or without food

Treatment Group B: one SEL 18 mg tablet, one PTM GS-0976 
20 mg tablet, one GS-9674 30 mg tablet administered orally 
once daily with or without food

Treatment Group C: one SEL 18 mg tablet, one PTM GS-0976 
20 mg tablet, and one PTM GS-9674 30 mg tablet administered 
orally once daily with or without food

Treatment Group D: one PTM SEL 18 mg tablet, one GS-0976 
20 mg tablet, and one PTM GS-9674 30 mg tablet administered 
orally once daily with or without food

Treatment Group E: one PTM SEL 18 mg tablet, one PTM 
GS-0976 20 mg tablet, and one GS-9674 30 mg tablet 
administered orally once daily with or without food

Treatment Group F: one PTM SEL 18 mg tablet, one PTM 
GS-0976 20 mg tablet, and one PTM GS-9674 30 mg tablet 
administered orally once daily with or without food

Treatment Group G: PTM SEL 18 mg, GS-0976 20 mg, and 
GS-9674 30 mg administered orally once daily with or without 
food
Criteria for 
Evaluation:
Safety:
The safety of SEL, GS-0976, and GS-9674, alone or in combination, in 
subjects with bridging fibrosis or compensated cirrhosis due to NASH 
will be assessed during the study through the reporting of AEs, clinical 
laboratory tests, vital sign assessments, pruritus questionnaires, and 
concomitant medication usage.
An external Data Monitoring Committee (DMC) that consists of 
two hepatologists and a statistician will review the progress of the 
study. The DMC will convene after 35 subjects (approximately 5 per 
treatment group) have completed the Week 4 assessments and 
approximately every 6 months thereafter to monitor for safety events.


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Primary Endpoint: 
The primaiy endpoints ai·e the safety and anti-fibrotic effects of SEL, 
GS-0976, and GS-9674, administered alone or in combination, in 
subjects with bridging fibrosis or compensated cinhosis due to NASH. 
Statistical Methods 
Anti-fibrotic response will be evaluated by the propo1i ion of subjects at 
Week 48 who achieve a ::::: I -stage improvement in fibrosis 
(according to the NASH CRN classification) without worsening of 
NASH ( defined as a::::: I-point increase in hepatocellular ballooning or 
lobular inflammation). 
I 
I 
Safety Analysis: 
Safety analyses include summaries of extent of exposme, AEs, 
laborato1y evaluations, and vital sign assessments. 
Efficacy Analysis: 
Primary Efficacy Endpoints Analysis: 
CONFIDENTIAL 
The point estimates and 95% confidence intervals for the propo1i ion of 
subjects who achieve a ::::: I-stage improvement in fibrosis without 
worsening of NASH at Week 48 will be calculated by treatment group. 
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Sample Size:
Due to the exploratory nature of this study, no formal power 
calculations were used to determine sample size. The number of 
subjects was chosen based on clinical experience with other similar 
proof of concept studies; however, with a sample size of approximately 
70 subjects in each active combination treatment arm and 
approximately 35 in the placebo arm, the study has over 80% power to 
detect a difference in the proportion of subjects with a ≥1-stage 
improvement in fibrosis without worsening of NASH of 25% or more 
at Week 48 at a significance level of 0.05 (two-sided), assuming the 
proportion of subjects that meet the endpoint in the placebo arm is 
7.2%.
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
-SMA 
alpha smooth muscle actin
g
Microgram
ACC
acetyl-CoA carboxylase
AE
adverse event
AH
alcoholic hepatitis
AICD
automatic implantable cardioverter defibrillator
aPTT 
activated partial thromboplastin time
ASK1
apoptosis signal-regulating kinase 1
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
AUCtau
area under the plasma/serum concentration versus time curve from time zero to the last 
quantifiable concentration
BAP
Biomarker Analysis Plan
BID
twice daily
BL
Baseline
BMI
body mass index
BUN
blood urea nitrogen
CAP
controlled attenuation parameter
CCR
Chemokine Receptor
CDHFD
choline-deficient high-fat diet
CFR
Code of Federal Regulations
CI
confidence interval
c-Jun
c-Jun protein
CK 18
cytokeratin 18
Clast
last observed quantifiable plasma/serum concentration of the drug
CLcr
creatinine clearance
CLDQ-NAFLD
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease
Cmax
maximum observed plasma/serum concentration of drug
CMH
Cochran-Mantel-Haenszel
COL1A1
collagen type 1 alpha 1
CCI
CCI


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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
DKD
Diabetic Kidney Disease
dL
Deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
DRSP
Drospirenone
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EE
ethinyl estradiol
EFS
event-free survival
eg
Example
eGFR
estimated glomerular filtration rate
ELF™
Enhanced Liver Fibrosis 
ESA
erythropoiesis-stimulating agents
EU
European Union
EudraCT
European clinical trial database
F2
Moderate Fibrosis
F3
Bridging Fibrosis
F4
Compensated Cirrhosis
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
CCI
CCI
CCI


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FGF19
fibroblast growth factor 19
FSH
follicle stimulating hormone
fu
unbound fraction
FXR
farnesoid X receptor
GCP
Good Clinical Practice
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
gastrointestinal 
GMR
geometric mean ratio
GSI
Gilead Sciences, Inc.
HA
hyaluronic acid
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
HLT
high-level term
HOMA-IR
homeostatic assessment of insulin resistance
HR
hazard ratio
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ID
Identification
IDE
investigational device exemption
IEC
independent ethics committee
IMP
Investigational Medicinal Product
CCI


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IRB
institutional review board
IU
international units
IUD
intrauterine device
IV
Intravenous
IXRS
interactive mobile/web response system
JNK
c-Jun N-terminal kinase
kg
Kilogram
kPa
Kilopascal
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LEVO
Levonorgestrel
LLT
lower-level term
LOXL2
lysyl oxidase-like 2
LSM
least squares mean
M30
capsase-cleaved fragment of CK 18
M65
intact fragment of CK 18
MATE1
multidrug and toxin extrusion protein 1
MCV
mean corpuscular volume
MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-stage Liver Disease
mg
Milligram
MH
Mantel-Haenszel
min
Minute
mL
Milliliter
mm
Millimeter
mmHg
millimeter of Mercury
MPQR2
multidrug resistance-associated protein
MQC
morphometric quantitative collagen
MRI
magnetic resonance imaging
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
NCEP ATP III
National Cholesterol Education Program Adult Treatment Plan III
NOAEL
no observed adverse event level
CCI


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OATP
organic anion-transporting polypeptide
OCT1
organic cation transporter 1
OCT2
organic cation transporter 2
OL
Open-Label
OST-α
organic solute transporter alpha
OST-β
organic solute transporter beta
p38
mitogen-activated protein kinase p38
PAH
pulmonary arterial hypertension
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 
p-p38
phospho-p38
PPAR
Peroxisome Proliferator-Activated Receptor
PSC
primary sclerosing cholangitis
PSR
picrosirius red
PT
prothrombin time / Preferred Term
PTM
placebo to match
PVE
Pharmacovigilance & Epidemiology
PVR
pulmonary vascular resistance
Q
Quarter
QD
once daily
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to 
occur
QTc
QT interval corrected for heart rate
rBA
relative bioavailability
RBC
red blood cell count
RIF
Rifampin
RNA
ribonucleic acid
ROC
receiver operating characteristic
ROS
reactive oxygen species
SADR
serious adverse drug reaction
SAE
serious adverse event
SAF
steatosis, activity, fibrosis
SAP
statistical analysis plan
SAS®
Statistical Analysis System


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SD
standard deviation
SEL
Selonsertib
SF-36
Short Form 36 Health Survey
SIM
Simtuzumab
SOC
System Organ Class
SOP
standard operating procedure
SREBP-1c
sterol regulatory element binding protein-1c
SUSAR
Suspected Unexpected Serious Adverse Reaction
Sx
Symptoms of drug-related hepatotoxicity (eg, jaundice, right upper quadrant pain, nausea, 
vomiting, etc.)
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
TEAE
treatment-emergent adverse event
TGF-β
transforming growth factor beta
TIMP1
tissue inhibitor of metalloproteinase 1
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TPO
Thrombopoietin
UGT
UDP-glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
VAS
Visual Analog Scale
VORI
Voriconazole
WBC
white blood cell count
WPAI
Work Productivity and Activity Impairment Questionnaire 


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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 and metabolic syndrome that are leading to an increased incidence of 
NASH. Prevalence rates of hepatic steatosis or fatty liver, an entity that has been termed 
NAFLD, range from 6% to 37% worldwide {Ong 2007, Vernon 2011} with a recent pooled 
overall global prevalence of 25% reported {Younossi 2016}. NASH, the form of NAFLD 
associated with increased liver-related mortality, affects approximately 30% of all patients with 
NAFLD {Ong 2007, Williams 2011, Younossi 2016}. In the United States (US), it has been 
estimated that 2% to 5% of the population have NASH {Vernon 2011}, which is equivalent to 
approximately 16 million adults. Furthermore, as NASH is a manifestation of the metabolic 
syndrome, associated elevated cardiovascular risk factors (eg, atherosclerotic disease, cardiac 
arrhythmogenicity) likely coexist in patients with NASH {Dietrich 2014, Faramawi 2008, 
Voulgari 2010}. NASH represents a significant and growing unmet medical need for which there
are no currently approved therapies.
NASH is primarily thought to occur as the result of the metabolic syndrome: the impact of 
obesity, hepatic insulin resistance, and dyslipidemia. Fatty liver, or simple steatosis, is not 
sufficient to cause liver injury; it is the presence of inflammation and hepatocellular injury on the 
background of steatosis that produces NASH and may result in the progression to cirrhosis and 
its complications including end-stage liver disease. 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) with progressive liver fibrosis {Dowman 2010, Koek 2011, Rolo 2012, 
Sumida 2013}. The major pathways in NASH disease progression include those involved in 
metabolic dysfunction in the hepatocyte, activation of hepatic stellate cells, and activation and 
recruitment of macrophages leading to hepatic inflammation and fibrosis. Advanced fibrosis and 
cirrhosis are characterized by extensive collagen deposition and remodeling of the extracellular 
matrix. Additionally, there is evidence which suggests that lipotoxic intermediates of fatty acids 
likely contribute to the etiology of NASH {Neuschwander-Tetri 2010}.
Over time, NASH may result in progressive liver fibrosis, ultimately resulting in cirrhosis. 
Advanced liver fibrosis (bridging fibrosis or cirrhosis) is associated with increased morbidity and 
mortality {Ekstedt 2014, Yeh 2014}. Cirrhosis increases the risk of developing HCC and other 
complications of end-stage liver disease, including jaundice, fluid retention (edema and ascites), 
portal hypertension and variceal hemorrhage, impaired coagulation, and HE. Decompensated 
liver disease, as defined by the development of one of the above complications, has a high 
mortality rate and the only 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}.


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1.2.
Selonsertib (SEL)
1.2.1.
General Information for SEL
SEL is a potent and selective small molecule inhibitor of apoptosis signal-regulating kinase 1 
(ASK1). ASK1 is a ubiquitously expressed serine/threonine kinase that is primarily activated by 
pathological oxidative stress {Makie 2007, Takeda 2008, Tobiume 2002}. ASK1 in turn 
phosphorylates and activates mitogen-activated protein kinase (p38) and c-Jun N-terminal 
kinases (JNK). p38 and JNK mediate metabolic, pro-inflammatory, and pro-fibrotic changes in 
the liver, which are central to disease progression in NASH. By inhibiting ASK1 signaling in 
patients with NASH, SEL is expected to halt progressive liver fibrosis and reverse existing 
fibrosis, thus preventing the development of cirrhosis-related complications. The mechanism of 
ASK1 signaling in NASH is presented graphically in Figure 1-1.
Figure 1-1.
ASK1 Signaling in NASH
Increased ASK1 signaling is observed in liver biopsy specimens of patients with NASH, as 
demonstrated by increased levels of phosphorylated p38, which correlates with progression of 
fibrosis. ASK1 promotes a pathological cycle between oxidative stress, metabolic dysfunction, 
and hepatocellular damage and inflammation that ultimately promotes fibrosis and organ failure.
These effects are the result of known roles of p38 and JNK signaling in hepatocytes, 
macrophages, hepatic stellate cells and fibroblasts, which have been demonstrated in preclinical 
studies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Therefore, ASK1 signaling through p38 and JNK in hepatocytes, macrophages, and hepatic 
stellate cells promotes hepatocellular steatosis, apoptosis, necrosis, inflammation and fibrosis. 
SEL, by inhibiting oxidative stress-driven ASK1 signaling characteristic of NASH, is expected 
to halt progressive fibrosis and lead to regression of pre-existing fibrosis, thereby reducing 
progression to cirrhosis and its associated complications.
Please refer to the SEL Investigator’s Brochure (IB) for additional details.
1.2.2.
Nonclinical Pharmacology and Toxicology 
SEL has been extensively evaluated in nonclinical toxicology studies. Findings attributed to SEL 
administration were primarily related to the cardiovascular system (mild decrease blood pressure 
and mild QT interval corrected for heart rate [QTc] prolongation), gastrointestinal (GI) tract 
(profuse diarrhea), kidney (tubular basophilia, eosinophilic droplets, and pigment), and 
embryofetal effects (visceral and/or skeletal malformations) occurred at exposures that were in 
excess of the targeted human exposure at 18 mg/day. Self-limiting diarrhea has been observed in 
subjects across the clinical studies. However, the low grade and self-limiting nature of the 
diarrhea suggests the diarrhea in the clinical studies is different from what was observed in 
monkeys.
Please refer to the SEL IB for additional details.
1.2.3.
Clinical Trials of SEL
As of 28 November 2017, 15 Phase 1 and 2 clinical studies have been conducted/are ongoing in 
which 359 healthy subjects, 248 subjects with diabetic kidney disease (DKD), 113 subjects with 
pulmonary arterial hypertension (PAH), and 72 subjects with NASH have been dosed with SEL. 
In an ongoing Phase 2 study for severe alcoholic hepatitis (GS-US-416-2124), 50 additional 
subjects are planned for dosing. Phase 3 clinical studies have initiated in which an additional 
640 NASH subjects with bridging fibrosis (Study GS-US-384-1943) and 640 NASH subjects 
with cirrhosis (Study GS-US-384-1944) are planned to be dosed. 
Information on the completed and ongoing Phase 1 clinical studies and Phase 2 studies of DKD,
PAH, and alcoholic hepatitis can be found in the IB.
1.2.3.1.
Study GS-US-384-4266: A Phase 1 Drug Interaction Study Evaluating the Effect 
of Selonsertib on the Pharmacokinetics of a Representative Hormonal 
Contraceptive Medication, Ethinyl Estradiol/Levonorgestrel
Study GS-US-384-4266 was a Phase 1, open-label study designed to evaluate the safety of SEL 
and the effect of SEL on the PK of a representative hormonal contraceptive, ethinyl 
estradiol/levonorgestrel (EE/LEVO), in healthy female subjects of childbearing potential. 
Subjects received a single oral dose of EE/LEVO (0.03/0.15 mg) alone and coadministered with 
SEL following 14 days of once daily dosing of SEL 18 mg.


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1.2.3.1.1.
Subject Disposition 
A total of 16 subjects were enrolled. All 16 subjects (100%) completed the study.
1.2.3.1.2.
Safety Results
No deaths, SAEs, Grade 3 or 4 AEs, AEs leading to discontinuation of study drug or study 
participation, or pregnancies were reported during the study. A total of 5 of 16 subjects (31.3%) 
experienced at least 1 AE during the study. All of the events were Grade 1 in severity, and no AE 
was experienced by more than 1 subject. Two subjects (12.5%) experienced AEs considered by 
the investigator to be related to study drug (menstruation irregularity [EE/LEVO] and headache 
[EE/LEVO + SEL]), both of which resolved prior to the end of the study. No clinically 
meaningful changes in laboratory values were noted, and there were no notable changes in vital 
sign measurements.
1.2.3.1.3.
Pharmacokinetic Results
As shown in Table 1-1, similar systemic exposures (AUCinf, AUClast, and Cmax) of LEVO and EE 
were observed following administration of LEVO/EE alone or in combination with SEL (18 mg 
once daily). All 90% CIs of the GLSM ratios for AUCinf, AUClast, and Cmax were within the 
typical lack of PK alteration boundaries of 70% to 143%. No loss of contraceptive efficacy is 
expected upon administration of SEL with oral contraceptives like EE/LEVO.
Table 1-1.
Pharmacokinetic Results from Study GS-US-384-4266 Evaluating 
DDE between SEL 18 mg QD and Representative Hormonal 
Contraceptive, Ethinyl Estradiol/Levonorgestrel
Ethinyl Estradiol PK 
Parameter
Mean (% CV)
%GLSM Ratio (90% CI)
Test/Reference
SEL + EE 
(Test)
(N = 16 )
EE 
(Reference)
(N = 16)
AUCinf (h*ng/mL)
778.7
(29.2)
769.7
(45.6)
105.25
(94.72, 116.95)
AUClast (h*ng/mL)
700.0
(31.2)
623.5
(35.9)
113.71
(106.20, 121.75)
Cmax (ng/mL) (%)
88.8
(32.1)
74.2
(26.8)
117.76
(108.68,127.61)
Levonorgestrel PK 
Parameter
Mean (% CV)
%GLSM Ratio (90% CI)
Test/Reference
SEL + LEVO
(Test)
(N = 16)
LEVO
(Reference)
(N = 16)
AUCinf(h*ng/mL)
40.8
(45.7)
40.1
(42.9)
99.82
(89.49, 111.34)
AUClast (h*ng/mL)
37.2
(43.7)
36.4
(40.1)
100.39
(90.16, 111.78)
Cmax (ng/mL) (%)
3.7
(45.8)
3.3
(40.7)
112.74
(99.58, 127.64)


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1.2.3.2.
Study GS-US-384-1497: A Phase 2, Randomized, Open Label Study Evaluating 
the Safety, Tolerability, and Efficacy of Selonsertib alone or in Combination with 
Simtuzumab (SIM) in Subjects with Nonalcoholic Steatohepatitis (NASH) and 
Fibrosis (F2-F3)
This multicenter, randomized, open-label study evaluated the safety, tolerability, and efficacy of 
SEL (6 mg or 18 mg) alone or in combination with simtuzumab (SIM, a monoclonal antibody 
directed against lysyl oxidase-like 2 (LOXL2) evaluated for the treatment of NASH) versus SIM 
alone for 24 weeks in subjects with NASH and fibrosis stages F2 or F3. 
1.2.3.2.1.
Subject Disposition 
A total of 72 subjects were randomized; 67 subjects (93.1%) completed study treatment. Of the 
5 subjects who did not complete study treatment, 3 subjects discontinued due to AEs, 1 subject 
withdrew consent, and 1 subject was lost to follow-up.
1.2.3.2.2.
Safety Results 
Treatment with SEL (6 mg or 18 mg with or without SIM 125 mg) and SIM 125 mg was 
generally well tolerated. The 3 most common AEs were headache, nausea, and sinusitis. Most 
AEs were Grade 1 or Grade 2 in severity. Overall, 5 subjects had a Grade 3 AE; none of the 
Grade 3 AEs was reported in > 1 subject, and all but 1 were assessed as unrelated to study drug. 
No Grade 4 AEs were reported. Serious adverse events (SAEs) were reported for 5 subjects.
There were no trends in SAE type or time of onset, and no SAE was reported in > 1 subject. 
Overall, 1 subject had an SAE that was assessed as related to study drug, and 3 subjects had AEs 
leading to premature discontinuation of study drug. No subjects died during the study.
The majority of subjects in each treatment group had at least 1 graded laboratory abnormality. 
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. The most common 
Grade 3 laboratory abnormality was increased serum glucose. All of the subjects with Grade 3 
increased glucose had graded elevations in glucose at baseline and at every study visit thereafter;
all had a history of diabetes and were currently taking medication for diabetes. The only other 
Grade 3 laboratory abnormalities that were reported for ≥ 2 subjects were increased triglycerides 
(N = 3), increased ALT (N = 2), and increased aspartate aminotransferase (AST) (N = 2). 
Two subjects had Grade 4 increased gamma-glutamyl transferase (GGT). One of these subjects 
discontinued study drug due to Grade 1 increased hepatic enzymes. The other subject had 
elevated GGT throughout the study. 
Across treatment groups, no clinically relevant changes from baseline to Week 24 were observed 
in measures of liver biochemistry, including alkaline phosphatase, ALT, AST, GGT, and total 
bilirubin. For all treatment groups, median values for ALT, AST, and GGT were in the high 
normal or above normal ranges at baseline and Week 24, although values for those parameters 
tended to decrease from baseline to Week 24.


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No notable changes in vital sign measurements (temperature, pulse, systolic blood pressure, 
diastolic blood pressure, and respiration rate) or body weight were reported during the study. No 
trends in ECG findings suggestive of cardiac abnormalities were observed. No subject 
pregnancies were reported.
1.2.3.2.3.
Summary of Efficacy Results
Treatment with SEL in GS-US-384-1497 resulted in histologic improvements in subjects with 
biopsy proven NASH and F2-F3 fibrosis. Although the small size of the study precluded formal 
statistical comparisons between treatment groups, numerically superior improvements were also 
consistently observed in the following endpoints in SEL treated compared with SIM-treated 
subjects:

Subjects treated with SEL (18 or 6 mg) ± SIM 125 mg had a ≥ 1 stage decrease in NASH 
CRN fibrosis stage from baseline in 43.3 % and 29.6 % of subjects, respectively, compared 
with 20.0% of subjects treated with SIM 125 mg alone.

Subjects treated with SEL (18 or 6 mg) ± SIM 125 mg were less likely to have worsening of 
fibrosis (6.7% and 14.8%, respectively) or progression to cirrhosis (3.3% and 7.4%, 
respectively) compared with subjects treated with SIM 125 mg alone (40.0% with worsening 
of fibrosis and 20.0% with progression to cirrhosis).

Consistent with fibrosis stage improvement, subjects treated with SEL (18 or 6 mg) ± SIM 
125 mg had reductions in hepatic collagen content as measured by morphometric quantitative 
collagen (MQC) (−8.7% and −8.2%, respectively) versus an increase of 2.1% in subjects 
treated with SIM 125 mg alone.

Greater reductions in cytokeratin 18 (CK 18) capsase-cleaved fragment of CK 18 (M30) and 
intact fragment of CK 18 (M65) fractions in subjects treated with SEL (18 or 6 mg) ± SIM 
125 mg versus SIM 125 mg alone, indicate reduced rates of hepatocellular apoptosis and 
necrosis, and are consistent with improvements in fibrosis stage and liver biochemistry tests. 
The dose-dependent reductions in CK18 M30 and M65 fractions also support the mechanism 
of action of SEL.
Across all treatment groups, no clinically significant worsening in metabolic or cardiovascular 
risk factors from baseline and no significant change in weight were observed at Week 24.
Collectively, these data support that SEL treatment results in fibrosis regression, improvements 
in liver biochemistry, and reductions in hepatic fat, inflammation, and apoptosis in subjects with 
NASH and moderate to severe liver fibrosis.
For further information on SEL in Phase 2 NASH clinical trials, refer to the SEL IB.


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1.3.
GS-0976
1.3.1.
General Information for GS-0976
GS-0976 is a small molecule allosteric inhibitor of acetyl-CoA carboxylase (ACC). ACC 
catalyzes the conversion of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed 
step in fatty acid synthesis. GS-0976 is being developed for the treatment of NASH, a metabolic 
disorder characterized by dysregulated fatty acid metabolism.
Dysregulated fatty acid metabolism occurs via elevated fatty acid synthesis, impaired fatty acid 
oxidation, or both. Therefore, inhibition of fatty acid synthesis and/or stimulation of fatty acid 
oxidation have the potential to favorably affect several metabolic diseases and sequelae. ACC is 
a critical enzyme in both fatty acid synthesis and fatty acid oxidation. Due to this unique position 
in intermediary metabolism {Harwood 2005, Tong 2006}, pharmacologic inhibition of ACC 
presents an attractive strategy for limiting fatty acid synthesis in lipogenic tissues while 
simultaneously stimulating fatty acid oxidation in oxidative tissues {Harwood 2005}.
Please refer to the GS-0976 IB for additional details.
1.3.2.
Nonclinical Pharmacology and Toxicology
GS-0976 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 GS-0976 can reduce the 
de novo lipogenesis (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. In total, these studies confirm the potential for GS-0976 to impact 
important metabolic endpoints associated with NASH.
The nonclinical toxicologic profile of GS-0976 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. 
GS-0976 was well tolerated for 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 did, whereas they did at 3-times higher mean GS-0976 exposure. 
In the females, the lowest exposure where lens degeneration was observed was 5-times higher 
than the clinical exposure at 20 mg GS-0976. 


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In contrast, in the 13-week mouse study, there were no eye findings that were attributed to 
GS-0976 at exposures approximately 8-fold above the clinical exposure at 20 mg. While the 
relevance to humans of the lens degeneration observed in the mouse is currently unknown, the 
lack of eye findings attributable to GS-0976 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 GS-0976 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.
GS-0976 was not genotoxic and there was no embryo-fetal developmental toxicity at exposures 
approximately 50-times the clinical exposure. GS-0976 was considered non-corrosive and does 
not require classification as an eye irritant.
Based on the systemic concentrations of GS-0976 measured in the repeat-dose toxicity studies in 
mice, rat, and dog at the projected clinically efficacious area under the plasma/serum
concentration versus time curve (AUC) (88 ng•h/mL), the margins of exposure at the no 
observed AE levels (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 GS-0976.
Please refer to the GS-0976 IB for additional details.
1.3.3.
Clinical Trials of GS-0976
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 GS-0976 IB. 
1.3.3.1.
Study GS-US-426-4074: A Phase 1 Study to Evaluate Transporter and 
Cytochrome (CYP) 450-Mediated Drug-Drug Interactions Between GS-0976 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 GS-0976 (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 GS-0976, as assessed by 
changes in fractional DNL, will also be evaluated.
1.3.3.1.1.
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.


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1.3.3.1.2.
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.
1.3.3.1.3.
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 GS-0976 20 mg (N=28). 
Single doses of CsA and RIF significantly increased GS-0976 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 GS-0976 is a sensitive substrate of hepatic OATP 
with intestinal P-gp playing a minimal role in GS-0976 absorption as seen by a smaller increase 
in GS-0976 Cmax by CsA compared to single dose RIF.
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 GS-0976 
20 mg (N=14). Co-administration of GS-0976 with PBC resulted in a moderate increase in 
GS-0976 exposure (61%) indicating UGTs are involved in the metabolism of GS-0976. 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 GS-0976 
with VORI increased GS-0976 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 GS-0976 50 mg once daily on a sensitive 
CYP3A4 probe substrate (midazolam [MDZ] 2 mg: MDZ; N=12). Neither single dose nor 
multiple doses of GS-0976 altered MDZ exposure (90% CIs of the % geometric mean ration 
(GMR) for AUC and Cmax with lack of effect bounds of 70-143%) indicating GS-0976 is not an 
inhibitor or inducer of CYP3A4.
Cohort 6: Impact of single and multiple doses of GS-0976 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 GS-0976 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 GS-0976 slightly increased 
EE exposure (AUCinf increased ~34%) with no effect on DRSP exposure indicating GS-0976 


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does not induce enzymes/transporters involved in the clearance of DRSP or EE. No loss of 
contraceptive efficacy is expected upon administration of GS-0976 with oral contraceptives like 
DRSP/EE. The slight increase in EE exposure is not considered clinically significant and does 
not warrant dose modification.
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 
Evaluating DDIs with GS-0976 (20 mg or 50 mg)
Inhibitor/Inducer 
Drug
GS-0976
%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 GS-0976
%GMR (90% CIs)
MDZ + MD GS-0976
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
GS-0976 (50 mg)
111 
(99.8, 123)
102 
(91.6, 115)
102 
(91.4, 113)
106
(94.9, 119)
DRSP + SD GS-0976
%GMR (90% CIs)
DRSP + MD GS-0976
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
GS-0976 (50 mg)
96.4 
(86.5, 107)
103 
(91.5, 116)
105 
(94.0, 117)
116
(102, 131)
EE + SD GS-0976
%GMR (90% CIs)
EE + MD GS-0976
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
GS-0976 (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


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1.3.3.2.
Study GS-US-426-3988: A Phase 1 Open-Label, Parallel-Group, Single-Dose 
Study to Evaluate the Pharmacokinetics of GS-0976 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 GS-0976 in subjects with normal hepatic function 
and mild, moderate, or severe hepatic impairment (CP class A, B, or C, respectively). Up to 
60 subjects are planned for enrollment in 1 of 3 hepatic impairment cohorts: Cohort 1 
(mild hepatic impairment), Cohort 2 (moderate hepatic impairment), and Cohort 3 
(severe hepatic impairment). 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. Subjects in Cohorts 1 and 2 will receive a single oral dose of 
GS-0976 20 mg in a fasted state on Day 1. Subjects in Cohort 3 will receive a single oral dose of 
GS-0976 5 mg in a fasted state on Day 1.
1.3.3.2.1.
Subject Disposition and Demographics
As of 17 November 2017, a total of 36 subjects were dosed; 34 subjects had completed study 
treatment. No subjects prematurely discontinued study treatment. No subjects withdrew consent, 
and no subjects were lost to follow-up.
1.3.3.2.2.
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 were 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. 


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1.3.3.2.3.
Preliminary PK Results
Preliminary PK results from Cohorts 1 and 2 are presented below and in Table 1-3:

Cohort 1 (Mild Hepatic Impairment; CP A): GS-0976 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. GS-0976 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 GS-0976. 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.

Cohort 2 (Moderate Hepatic Impairment; CP B): GS-0976 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 GS-0976 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 
GS-0976 metabolism (ie, UGTs and CYP3A4). At a dose of 20 mg QD, GS-0976 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.


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Table 1-3.
GS-US-426-3988: Preliminary GS-0976 and GS-834773 PK 
Parameters Following a Single Dose of GS-0976 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)
Mild Hepatic 
Impairment (N=10)
%GMR
(90% CI)
1
GS-0976
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
GS-0976
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 
GS-0976, dose adjustments are not considered necessary in subjects with mild hepatic 
impairment.


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1.3.3.3.
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Safety, Tolerability, and Efficacy of GS-0976 in Subjects with Nonalcoholic 
Steatohepatitis (GS-US-426-3989)
Study GS-US-426-3989 is a completed Phase 2, randomized, double-blind, placebo-controlled 
study designed to evaluate the safety, tolerability, and efficacy of GS-0976 in subjects with 
NASH. To be eligible to participate, subjects were required to have a clinical diagnosis of 
NAFLD with imaging or a liver biopsy documenting fatty liver within 2 years prior to Screening, 
MRI-PDFF with ≥ 8% steatosis, and MRE with liver stiffness ≥2.5 kPa at Screening, or a 
historical liver biopsy within 12 months of Screening consistent with NASH and no documented 
weight loss > 5% between the date of the liver biopsy and Screening.
The primary endpoint was the safety of GS-0976. Exploratory efficacy endpoints included 
changes from baseline in steatosis as measured by MRI-PDFF, liver stiffness as measured by 
both MRE and FibroScan®, noninvasive markers of fibrosis including ELF™Test, markers of 
liver injury and function (ALT, AST, bilirubin, GGT and alkaline phosphatase [ALP]), 
homeostatic assessment of insulin resistance (HOMA-IR), serum lipid profiles, and HbA1c 
levels.
1.3.3.3.1.
Subject Disposition
A total of 127 subjects were randomized (50 in the GS-0976 20 mg group, 51 in the GS-0976 
5 mg group, and 26 in the placebo group). Of the 127 randomized subjects, 126 received at least 
1 dose of study drug (49 in the GS-0976 20 mg group, 51 in the GS-0976 5 mg group, and 26 in 
the placebo group).
A total of 121 subjects (96.0%) completed study drug treatment: 48 (98.0%) in the GS-0976 
20 mg group, 47 (92.2%) in the GS-0976 5 mg group, and 26 (100.0%) in the placebo group. A 
total of 118 subjects (93.7%) completed the study: 46 (93.9%) in the GS-0976 20 mg group, 
46 (90.2%) in the GS-0976 5 mg group, and 26 (100.0%) in the placebo group.
1.3.3.3.2.
Safety Results
Treatment with GS-0976 20 or 5 mg was generally well tolerated. The most common AEs in 
each treatment group were nausea, abdominal pain, and diarrhea (GS-0976 20 mg); diarrhea, 
headache, and hypertriglyceridemia (GS-0976 5 mg); and fatigue, sinusitis, nausea, chest 
discomfort, constipation, and dyspnea (placebo). Most AEs were Grade 1 or 2 in severity. 
Overall, 5 subjects had a Grade 3 AE; none of the Grade 3 AEs was reported in > 1 subject, and 
all but 1 were considered unrelated to study drug. One Grade 4 AE, which was not considered 
treatment-related, was reported. SAEs were reported for 4 subjects and included transient 
ischemic attack, sepsis, pyrexia, abdominal pain, HE, and diverticulitis. There were no trends in 
SAE type or time of onset, no SAE was reported in > 1 subject, and all SAEs were considered 
unrelated to study drug. Two subjects had AEs leading to premature discontinuation of study 
drug; for 1 of these subjects, the AEs leading to study drug discontinuation (pruritus, rash 
papular, and night sweats) were considered treatment-related. No deaths occurred during the 
study.


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The majority of subjects had at least 1 graded laboratory abnormality. The majority of laboratory 
abnormalities were Grade 1 or 2 in severity. Overall, the most common Grade 3 or 4 laboratory 
abnormalities in subjects receiving GS-0976 were elevated triglycerides (hypertriglyceridemia; 
16.0%, 16 of 100 subjects) and elevated glucose (hyperglycemia; 10.0%, 10 of 100 subjects), 
which only occurred in subjects who received GS-0976. The majority of subjects with Grade 3 or 
4 hypertriglyceridemia had a medical history of hyperlipidemia or hypertriglyceridemia, and had 
graded elevations in triglycerides at baseline. Grade 3 or 4 hyperglycemia was reported for 
10 subjects, all of whom had a medical history of diabetes and were taking medication for 
diabetes, and 7 of whom had HbA1c > 9.0% at baseline.
A total of 8 subjects met criteria for Drug Induced Liver Injury (DILI) monitoring, 4 of whom 
experienced liver-related laboratory abnormalities that were at least Grade 3 in severity, 
including Grade 3 elevated ALT, Grade 3 elevated AST, and/or Grade 3 elevated GGT. All 
4 subjects had graded abnormalities in the respective analytes at baseline. No AEs associated 
with the liver-related laboratory abnormalities were reported for any of the 4 subjects, and all 
4 subjects completed treatment with study drug.
No notable changes in vital sign measurements or body weight were reported during the study. 
No clinically significant ECG abnormalities were reported. No subject pregnancies were 
reported.
1.3.3.3.3.
Efficacy Results
Larger median (quarter (Q) 1, Q3) decreases from baseline in liver steatosis as measured by 
MRI-PDFF (in %) were observed in the GS-0976 groups compared with the placebo group, with 
the largest decrease in the GS-0976 20 mg group: −4.99 (−8.15, −0.78) in the GS-0976 20 mg 
group, −2.22 (−4.33, 0.07) in the GS-0976 5 mg group, and −0.94 (−1.94, 1.41) in the placebo 
group. These decreases corresponded with median (Q1, Q3) percent decreases of −28.9% 
(−47.7%, −11.9%) in the GS-0976 20 mg group, −13.0% (−28.5%, 0.6%) in the GS-0976 5 mg 
group, and −8.4% (−18.2%, 9.6%) in the placebo group. The difference (GS-0976 vs placebo) in 
least squares mean (LSM) change from baseline in MRI-PDFF at Week 12 was statistically 
significant for the GS-0976 20 mg group (−3.42% [95% CI: −5.73, −1.11; p = 0.004]). 
Larger proportions of subjects in both GS-0976 groups had at least 30% reduction in MRI-PDFF 
at Week 12 compared with the placebo group: 47.8% (22 of 46 subjects) in the GS-0976 20 mg 
group, 23.4% (11 of 47 subjects) in the GS-0976 5 mg group, and 15.4% (4 of 26 subjects) in the 
placebo group. The difference in proportions between the GS-0976 20 mg and placebo groups 
was statistically significant (31.8% [95% CI: 10.5%, 53.2%; p = 0.004]).
In contrast, no statistically significant differences between the GS-0976 groups and the placebo 
group were observed for the MRE endpoints. The proportions of subjects with at least 15% 
reduction in MRE at Week 12 were 32.6% (15 of 46 subjects) in the GS-0976 20 mg group, 
40.4% (19 of 47 subjects) in the GS-0976 5 mg group, and 34.6% (9 of 26 subjects) in the 
placebo group.


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At Week 12, larger median (Q1, Q3) percent decreases from baseline in liver stiffness by 
FibroScan® were observed in both GS-0976 groups compared with the placebo group: −11.1% 
(−34.1%, 13.5%) in the GS-0976 20 mg group, −8.4% (−29.7%, 8.8%) in the GS-0976 5 mg 
group, and −3.1% (−21.6%, 22.3%) in the placebo group.
Slightly smaller median percent decreases from baseline in ELF™Test score at Week 12 were 
observed in the GS-0976 groups compared with the placebo group: −0.8% (−4.5%, 2.1%) in the 
GS-0976 20 mg group, −0.9% (−5.0%, 3.0%) in the GS-0976 5 mg group, and −1.7% (−3.2%, 
0.7%) in the placebo group. At Week 12, median (Q1, Q3) percent changes from baseline in each 
component of ELF™Test score were as follows:

Hyaluronic acid (HA): −6.9% (−22.2%, 35.0%) in the GS-0976 20 mg group, −0.7% 
(−29.0%, 30.3%) in the GS-0976 5 mg group, and −15.3% (−25.4%, 20.9%) in the placebo 
group

Tissue inhibitor of metalloproteinase 1 (TIMP1): −7.9% (−17.2%, 0.1%) in the GS-0976 
20 mg group, −2.9% (−13.9%, 5.8%) in the GS-0976 5 mg group, and 1.5% (−9.0%, 10.6%) 
in the placebo group

Procollagen III amino terminal peptide (PIIINP): −13.9% (−23.6%, 9.4%) in the GS-0976 
20 mg group, −7.0% (−15.3%, 10.9%) in the GS-0976 5 mg group, and −0.5% (−7.9%, 
4.3%) in the placebo group.
Larger median (Q1, Q3) percent decreases from baseline in ALT at Week 12 were observed in 
both GS-0976 groups compared with the placebo group: −20.5% (−41.1%, 8.0%) in the GS-0976 
20 mg group, −9.8% (−26.2%, 5.1%) in the GS-0976 5 mg group, and −6.7% (−17.6%, 2.7%) in 
the placebo group. Larger median (Q1, Q3) percent decreases from baseline in AST were also 
observed in both GS-0976 groups compared with the placebo group: −5.6% (−38.6%, 19.4%) in 
the GS-0976 20 mg group, −9.3% (−18.2%, 6.3%) in the GS-0976 5 mg group, and −3.5% 
(−23.7%, 10.8%) in the placebo group. Changes from baseline in other liver biochemistry 
parameters (ALP, GGT, and total bilirubin) were not clinically relevant.
At Week 12, median (Q1, Q3) percent increases from baseline in triglycerides were observed in 
both GS-0976 groups compared with a decrease in the placebo group: 10.8% (−4.2%, 48.0%) in 
the GS-0976 20 mg group, 12.9% (−9.9%, 57.2%) in the GS-0976 5 mg group, and −4.3% 
(−18.3%, 16.5%) in the placebo group. No notable changes from baseline to Week 12 in other 
lipid parameters, HbA1c, or glucose were observed in any treatment group.
Please refer to the GS-0976 IB for additional details.
1.4.
GS-9674
1.4.1.
General Information for GS-9674
GS-9674 is a potent agonist of 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. 


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Please refer to the GS-9674 IB for additional details, including:

In vitro FXR agonism

Nonclinical in vivo efficacy studies

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology
1.4.2.
Nonclinical Pharmacology and Toxicology
In vivo pharmacology studies have demonstrated that GS-9674 preferentially activates intestinal 
FXR and reduces liver fibrosis. In cynomolgus monkeys, there was an increase in circulating 
FGF19 levels after oral dosing of GS-9674 but not after intravenous (IV) dosing despite greater 
exposure to GS-9674 after IV dosing. These data suggest that intestinal FXR agonism by 
GS-9674 causes FGF19 production, whereas low systemic free drug concentrations limit effects 
following IV administration of GS-9674. In addition, the oral administration of GS-9674 to 
monkeys directly activated intestinal FXR, as measured by the expression of FXR-target genes in 
the ileum (FGF19, organic solute transporter alpha (OSTα), organic solute transporter beta 
(OSTβ) mRNA). In a mouse model of NASH induced by a diet enriched in fat, cholesterol and 
sugar, GS-9674 reduced hepatic steatosis and normalized bile acid levels in plasma. In a 
CDHFD/sodium nitrite (NaNO2) rat model of liver fibrosis that utilizes “2 hits” to mimic the 
metabolic and oxidative stress components of NASH in humans, GS-9674 dose dependently 
reduced both biochemical and histological measures of liver fibrosis. Overall, the results from 
these pharmacology studies demonstrate that GS-9674 is a potent and selective agonist of 
intestinal FXR with the potential to benefit NASH patients by inducing FGF19 production.
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally for up to 26 and 39 weeks, respectively. Findings attributed to 
GS-9674 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 GS-9674. These 
findings were minimal to mild, non-adverse, and reversible after discontinuation of treatment. 
The 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 GS-9674 QD with 
food.
Please refer to the GS-9674 IB for additional details.
1.4.3.
Clinical Trials of GS-9674
As of 1 November 2017, 6 Phase 1 clinical studies have been completed or are ongoing and 
4 Phase 2 studies in subjects with NASH, PBC, and PSC are ongoing.
Information about completed and ongoing clinical studies can be found in the current GS-9674 
IB.


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1.4.3.1.
Study GS-US-454-4315: A Phase 1 Study to Evaluate the Relative Bioavailability 
and Food Effect of Single Agent Tablets and Fixed Dose Combinations of 
GS-9674, GS-0976, and/or Selonsertib in Healthy Subjects Study 
GS-US-454-4315 is an ongoing Phase 1 open-label, multiple cohort, crossover study to assess 
the relative bioavailability (rBA) (Part A) of fixed dose combination (FDC) tablets of GS-9674, 
GS-0976, and/or SEL compared to single agent tablets administered in combination in healthy 
subjects. Food effect was evaluated in Part A on SEL and GS-0976 administered as an FDC 
tablet (SEL/GS-0976) and GS-9674 and GS-0976 each administered as single agent tablets. 
Supratherapeutic exposure (Part B) of GS-9674 was also assessed. Approximately 90 subjects 
were enrolled into 4 pre-specified cohorts: Cohorts 1 to 3 in Part A and Cohort 4 in Part B.
1.4.3.1.1.
Subject Disposition 
Of the 90 enrolled subjects, all received at least 1 dose of study drug. A total of 89 of 90 subjects 
(98.9%) completed treatment with study drug and completed the study. One subject in Cohort 2 
prematurely discontinued the study due to an AE of urticaria.
1.4.3.1.2.
Preliminary Safety Results
Administration of GS-9674, SEL, and GS-0976 was generally well tolerated in healthy subjects. 
No deaths, SAEs, Grade 4 AEs, or pregnancies were reported during this study. 
One subject experienced a Grade 2 AE of acute urticaria on Day 13 following treatment with 
SEL + GS-0976 (single agent tablets) on Day 1 and SEL/GS-0976 (FDC) on Day 9. This led to 
the discontinuation of study participation, and this event was considered related to study drug by 
the investigator. 
A total of 12 of 90 subjects (13.3%) experienced at least 1 AE, and the most commonly reported 
AEs overall were lower abdominal pain (4 subjects, 4.4%) and headache (2 subjects, 2.2%). No 
trends in the overall frequency or type of AEs were observed between the FDC tablets and 
coadministration of their respective single agent tablets, between administration of therapy in the 
fed versus fasted state, and between supratherapeutic dosing of GS-9674 at 100 mg TID, with 
1.0 hr separation versus 0.5 hr separation. 
Overall, 6 of 90 subjects (6.7%) experienced an AE that was considered to be related to study 
drug by the investigator. The most commonly reported study drug-related AEs overall were 
lower abdominal pain (4 subjects, 4.4%) and headache (2 subjects, 2.2%). With the exception of 
the Grade 2 AE of acute urticaria, all other study drug-related AEs were Grade 1 in severity and 
did not require discontinuation from the study. 
A total of 47 of 90 subjects (52.2%) experienced a graded laboratory abnormality. The majority 
of laboratory abnormalities were Grade 1 or 2 in severity, and no Grade 4 laboratory 
abnormalities were observed. Eight of the 90 subjects (6.5%) had a Grade 3 laboratory 
abnormality: increased LDL cholesterol (2 subjects) and occult blood in urine (6 subjects). Both 
subjects who had a Grade 3 increased LDL cholesterol had Grade 1 or 2 increased LDL 


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cholesterol at baseline and at all other on-study measurements. The Grade 3 laboratory 
abnormalities of occult blood in urine were not associated with any AEs, all occurred in females 
of childbearing potential, and were deemed by the investigator to be due to menses. 
No notable changes in vital sign measurements or clinically significant ECG abnormalities were 
observed during the study.
1.4.3.1.3.
Preliminary PK Results
Preliminary results on the effect of food on GS-9674 PK are presented below and in Table 1-4.
The effect of food on GS-9674 single agent tablets has previously been evaluated using a 
moderate fat meal, which demonstrated a 33% to 35% decrease in GS-9674 exposure (AUC). 
The changes in the primary PK parameters for GS-9674 and its metabolite, GS-716070, 
following a single dose administration of GS-9674 single-agent tablet under fed (light meal or 
high-fat meal) versus fasting conditions were evaluated in this study and the preliminary results 
are summarized in the table below. Both SEL and GS-0976 have previously been shown to not 
significantly affect GS-9674 PK when administered as single agent tablets. Thus, comparison of 
GS-9674 PK following co-administration of GS-9674 with SEL or GS-0976 and a high-fat meal 
(Treatments A and G, respectively) to administration of GS-9674 alone in the fasted state 
(Treatment C) was considered acceptable to evaluate the effect of food on GS-9674 single agent 
tablets. Administration of GS-9674 alone (Treatment I) with a light meal decreased both AUCinf
and Cmax of GS-9674 (63% and 68%, respectively) as compared to administration of GS-9674 
alone (Treatment C) under fasted conditions. Administration of GS-9674 with a high-fat meal 
increased GS-9674 exposure (AUCinf) 37% to 42% as compared to fasted conditions with 
minimal changes in Cmax (-7% to 1%). Changes in PK of the metabolite, GS-716070, were 
similar to those of parent.


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Table 1-4.
GS-US-454-4315: Summary of Changes in Primary PK Parameters 
for GS-9674 and GS-716070 Following Administration of GS-9674 
Single Agent Tablets with a Light Meal or High-Fat Meal as 
Compared to Fasted State
Light Meal vs Fasted
(Treatment I vs C)
High-Fat Meal vs Fasted
(Treatment A vs C)
High-Fat Meal vs Fasted
(Treatment G vs C)
GS-9674
AUCinf
↓ 63%
↑ 42%
↑ 37%
AUClast
↓ 63%
↑ 44%
↑ 39%
Cmax
↓ 68%
↑ 1%a
↓ 7%
GS-716070
AUCinf
↓ 65%
↑ 34%
↑ 23%
AUClast
↓ 66%
↑ 37%
↑ 24%
Cmax
↓ 68%
↑ 1%a
↓ 11%
The 90% CIs of the %GLSM ratios for test versus reference treatments were within (↔), extended above (↑), or extended below 
(↓) the predefined lack of PK alteration boundaries of 70% to 143%. Percentages indicate the increase or decrease in the 
geometric mean for the respective PK parameter for test treatment relative to reference treatment.
a
The 90% CIs of the %GLSM ratio for test versus reference treatment extended both above and below the predefined lack of 
PK alteration boundaries of 70% to 143%.
1.4.3.2.
Study GS-US-402-3885: A Phase 1 Open-Label, Parallel-Group, Adaptive, 
Single-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of 
GS-9674 in Subjects with Normal and Impaired Hepatic Function
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 GS-9674 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 will receive a single oral dose of GS-9674 30 mg in the fed state on 
Day 1 with PD collected on Day -1 and Day 1.
1.4.3.2.1.
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 AE, withdrew consent, or were lost to follow-up.


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1.4.3.2.2.
Preliminary Safety Results 
Overall, 8.8% of subjects had a treatment-emergent adverse event (TEAE) of Grade 1 or 2. There 
was 1 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 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, 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.
1.4.3.2.3.
Preliminary PK Results
Preliminary PK results are presented below and in Table 1-5:

Cohort 1 (mild hepatic impairment; CP A): GS-9674 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). Both analytes had minor changes in plasma 
protein binding (unbound fraction [fu] increased ~30%). GS-9674 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 GS-9674. At a dose of 30 mg QD in subjects with mild hepatic impairment, exposure 
margins relative to preclinical NOAEL exposures for both parent and metabolite are expected 
to remain adequate.

Cohort 2 (moderate hepatic impairment; CP B): GS-9674 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. Plasma unbound fraction (fu) of GS-9674 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 metabolite, respectively. 


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Table 1-5.
GS-US-402-3885: Preliminary GS-9674 and GS-716070 PK 
Parameters Following a Single Dose of GS-9674 30 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
GS-9674
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)
2
GS-9674
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)
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 GS-9674. Changes in FGF19 and C4 following a single dose of GS-9674 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 
GS-9674, dose adjustments are not considered necessary in subjects with mild hepatic 
impairment.


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1.4.3.3.
Study GS-US-402-1852: A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH)
GS-US-402-1852 is an ongoing Phase 2, randomized, double-blind, placebo-controlled study 
evaluating the safety, tolerability, and efficacy of GS-9674 in subjects with NASH and fibrosis. 
Eligibility of potential subjects is based upon a clinical diagnosis of NAFLD, a historical liver 
biopsy within the previous 12 months consistent with NASH and non-cirrhotic fibrosis, or a
MRI-PDFF with ≥ 8% steatosis and MRE with liver stiffness ≥ 2.5 kPa.
1.4.3.3.1.
Subject Disposition 
As of September 2017, study GS-US-402-1852 randomized 140 subjects, with 128 active, 
8 completed, and 4 early terminated from the study. The number of subjects with ≥12 weeks of 
study drug exposure was 112/140 (80%) and 17/140 (12.1%) had completed 24 weeks of study 
drug treatment.
1.4.3.3.2.
Preliminary Safety Data
As of September 2017, four subjects have early terminated from the study due to AEs. 
One patient developed right upper quadrant pain two weeks into the study and was subsequently 
found to have a duodenal lymphoma. Three patients discontinued the study due to pruritus with 
resolution of symptoms after study drug discontinuation. 
1.5.
Combination Studies of SEL, GS-0976, and GS-9674
1.5.1.
Nonclinical Pharmacology, Pharmacokinetics, Drug Metabolism, and 
Toxicology
Given that ASK1, FXR, and ACC mediate distinct biological pathways and cellular mechanisms 
that contribute to NASH pathophysiology, it is hypothesized that combinations of SEL, 
GS-9674, and GS-0976 will provide greater benefit to reduce or reverse NASH progression. 
In support of this hypothesis, pairwise combinations of an ASK1 inhibitor, an FXR agonist, and 
an ACC inhibitor were well tolerated and caused a greater reduction in fibrosis compared to the 
respective single agents in a rat choline-deficient, high-fat diet (CDHFD) model of fibrosis. Rats 
were fed a CDHFD for 6 weeks to induce severe lipotoxicity in the liver and moderate fibrosis. 
The animals were then maintained on the CDHFD for another 6 weeks while being treated 
therapeutically with a vehicle control, ASK1 inhibitor, FXR agonist, ACC inhibitor or pairwise 
combinations of each drug. Fibrosis was assessed histologically by staining extracellular matrix 
with picrosirius red (PSR). Additionally, the number of activated hepatic stellate cells was 
quantified by staining liver sections with antibodies against SMA and desmin. Quantitative 
morphometry was performed to determine the percent positive area for each marker. Treatment 
with the ASK1 inhibitor monotherapy or FXR agonist monotherapy led to small and 
nonsignificant reductions in PSR area whereas the ACC inhibitor monotherapy led to a 
significant reduction in PSR area of about 50% relative to vehicle control animals. The FXR and 


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ASK1 combination significantly decreased PSR area by 69% relative to vehicle control animals, 
which was significantly greater efficacy than that for each respective single agent. Combinations 
of the ACC inhibitor with either the ASK1 inhibitor or the FXR agonist trended towards greater 
reduction in PSR % area than the ACC inhibitor alone, each reaching 60% reduction. All 
pairwise combinations significantly reduced alpha smooth muscle actin (-SMA) and desmin 
area to a greater extent than the single agents alone. In addition, all pairwise combinations led to 
greater reductions in plasma markers of fibrosis TIMP1 and PIIINP compared to each respective 
single agent. These data demonstrate that pairwise combinations of each of the agents increased 
anti-fibrotic efficacy assessed by multiple different markers. Therefore, combinations of SEL, 
GS-9674 and GS-0976 have the potential to induce a greater magnitude of fibrosis reversal in 
subjects with NASH. 
Pairwise combinations of an ASK1 inhibitor, an FXR agonist, and an ACC inhibitor also 
increased efficacy relative to the respective monotherapies in a mouse model of NASH. Mice 
were fed a diet high in fat, sugar and cholesterol for five months to induce hepatic steatosis and
expression of fibrogenesis-related genes as well as elevated plasma ALT levels. The animals 
were then treated for 28 days with a vehicle control, ASK1 inhibitor, FXR agonist, ACC 
inhibitor or pairwise combinations of each drug. All combinations resulted in significantly 
greater reductions in hepatic steatosis, hepatic cholesterol and triglyceride levels, and plasma 
ALT levels compared to animals treated with the respective monotherapies. In addition, the 
combination therapies caused a greater reduction in mRNA levels of genes associated with 
fibrogenesis collagen type 1 alpha 1 (COL1A1), TIMP1, and platelet-derived growth factor beta 
(PDGF-).
Pharmacodynamic analysis for ASK1, FXR, and ACC signaling confirmed that these targets 
regulate independent pathways that contribute to NASH pathogenesis. Treatment of mice with an 
ASK1 inhibitor did not agonize the FXR pathway or inhibit the ACC pathway. Similarly, 
treatment of mice with an FXR agonist did not impinge on the ASK1 or ACC pathways and the 
ACC inhibitor did not agonize the FXR pathway or inhibit the ASK1 pathway. Therefore, each 
agent is expected to cause a therapeutic benefit independent of the other monotherapies.
In a 13-week repeat-dose combination toxicity mouse study, GS-0976 and GS-9674, when 
administered separately or in combination, resulted in no adverse findings. The NOAEL for the 
combination groups was considered to be 20/3 mg/kg/day GS-9674/GS-0976, the highest dose 
group tested. Exposures of GS-0976 and GS-9674 in the highest combination mouse group were 
approximately 6-fold higher than the clinical exposure of each compound.
GS-0976 was also administered in combination with SEL to rats for 13 consecutive weeks. 
Microscopic findings of hyperkeratosis and hyperplasia, edema, ulceration, erosion, and/or focal 
squamous epithelial degeneration of the non-glandular stomach were observed at 30 mg/kg/day 
GS-0976 alone and in all combination groups. The non-glandular stomach findings occurred in a 
dose-dependent manner were considered adverse in the 5/10 and 15/30 mg/kg/day SEL/GS-0976 
groups. However, the findings do not have any relevance to humans since humans do not have a 
non-glandular stomach. In the lung, aggregates of macrophages, with or without interstitial 
mononuclear infiltrates and cholesterol clefts, were noted in all groups, including the vehicle 


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control group. While this finding was considered adverse in the high dose combination group 
due to increased incidence and severity, an increased occurrence after gavage dosing can also be 
indicative of mechanically induced reflux. The NOAEL for this study that is relevant to human 
safety is the 5/10 mg/kg/day SEL/GS-0976 group with corresponding SEL and GS-0976 
exposure margins of 5 and 36-times above the clinical exposures, respectively.
In a 13-week repeat dose combination toxicity study in monkeys, SEL and GS-9674 when 
administered separately or in combination resulted in no adverse findings. Observed findings 
with the combination (increases in platelets, shortened prothrombin time (PT) and activated 
partial thromboplastin time (aPTT), increases in alkaline phosphatase, decreases in serum bile 
acids, increases in liver weight and hepatocellular hypertrophy) were non-adverse and attributed 
to GS-9674 and were consistent with those observed with GS-9674 administered alone. There 
was no exacerbation of the findings when GS-9674 was dosed in combination with SEL. The 
NOAEL for the combination was 10/300 mg/kg/day SEL/GS-9674, the highest dose group 
tested. Exposures of SEL and GS-9674 in the highest combination group were 2- and 34-fold
higher, respectively, than the clinical exposures.
1.5.2.
Clinical Trials
1.5.2.1.
Study GS-US-402-2101: A Phase 1 Study to Evaluate Potential Drug-Drug 
Interactions Between GS-9674, SEL, and GS-0976
Study GS-US-402-2101 is a Phase 1, open-label, multiple-cohort, multiple-dose study designed 
to evaluate potential drug-drug interactions between SEL 18 mg, GS-9674 100 mg, and GS-0976 
20 mg in healthy subjects (Cohorts 3-5). Cohorts 1 and 2, designed to evaluate potential 
combination DDIs using a lower dose of GS-9674, and Cohort 6, designed to evaluate the 
potential DDIs between all three agents, were not conducted based on preliminary data from 
Cohorts 3 through 5. A total of 108 subjects were enrolled in Cohorts 3 through 5.
1.5.2.1.1.
Subject Disposition and Demographics
A total of 108 subjects were enrolled; 104 subjects completed study treatment. Four subjects
prematurely discontinued study treatment, with 1 subject prematurely discontinuing due to an 
AE. Two subjects withdrew consent and 1 subject was lost to follow-up. 
1.5.2.1.2.
Safety Results 
Administration of SEL, GS-0976 and GS-9674 was generally well tolerated in healthy subjects. 
No deaths, SAEs, Grade 4 AEs, or pregnancies were reported during this study. One subject 
experienced a Grade 3 AE of increased blood creatine phosphokinase during GS-9674 treatment 
that led to the discontinuation of study drug; this event was considered related to study drug by 
the investigator.


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A total of 31 of 108 subjects (28.7%) experienced at least 1 AE, and the most commonly 
reported AEs overall were headache (9 subjects, 8.3%), constipation (4 subjects, 3.7%), and 
dizziness (3 subjects, 2.8%). No trends in the overall frequency or type of AEs across the cohorts 
or between the single-agent and combination treatments within the cohorts in this small number 
of subjects were observed.
Overall, 24 of 108 subjects (22.2%) experienced an AE that was considered to be related to study 
drug by the investigator. The most commonly reported study drug-related AEs overall were 
headache (8 subjects, 7.4%), constipation (4 subjects, 3.7%), and dizziness (3 subjects, 2.8%). 
With the exception of a Grade 3 AE of increased blood creatine phosphokinase, all other study 
drug-related AEs were Grade 1 in severity and did not require modification of study drug dose.
A total of 70 of 108 subjects (64.8%) experienced a graded laboratory abnormality. The majority 
of laboratory abnormalities were Grade 1 or 2 in severity, and no Grade 4 laboratory 
abnormalities were observed. 7 of 108 subjects (6.5%) had a Grade 3 laboratory abnormality: 
increased LDL cholesterol (5 subjects), increased creatine phosphokinase (1 subject), and occult 
blood in urine (1 subject). All subjects who had a Grade 3 increased LDL cholesterol had 
Grade 1 or 2 LDL cholesterol at baseline and at all other on-study measurements. The Grade 3 
laboratory abnormality of increased creatine phosphokinase was associated with an AE that led 
to discontinuation of study drug. The Grade 3 laboratory abnormality of occult blood in urine 
was not associated with an AE and was considered not clinically significant by the investigator.
No notable changes in vital sign measurements or clinically significant ECG abnormalities were 
observed during the study.
1.5.2.1.3.
Summary of PK Results
The changes in the primary PK parameters for SEL, GS-9674, and GS-0976 and their respective 
metabolites (GS-607509, GS-716070, and GS-834773) following once-daily administration of 
SEL, GS-9674, and/or GS-0976 in combination for 7 days compared with the single agent for 
7 days are summarized in the Table 1-6. None of modest changes observed were considered 
clinically significant, and no dose modifications were needed upon co-administration of SEL, 
GS-9674, and/or GS-0976.


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Table 1-6.
GS-US-402-2101: Changes in primary PK parameters for SEL, 
GS-9674, and GS-0976 and their respective metabolites (GS-607509, 
GS-716070, and GS-834773) following once daily administration of 
SEL, GS-9674, and/or GS-0976 in combination for 7 days compared 
with the single agent for 7 days
Cohort 3: SEL+GS-0976
GS-0976
GS-834773
SEL
GS-607509
AUCtau
↔
↔
↔
↔
Cmax
↔
↔
↔
↔
Ctau
↑ 38%
↑ 69%
↔
↓ 9%
Cohort 4: GS-9674+SEL
GS-9674
GS-716070
SEL
GS-607509
AUCtau
↔
↔
↔
↑ 28%
Cmax
↑ 25%
↑ 26%
↔
↑ 28%
Ctau
↑ 25%
↔
↔
↑ 24%
Cohort 5: GS-9674+GS-0976
GS-9674
GS-716070
GS-0976
GS-834773
AUCtau
↔
↔
↔
↔
Cmax
↔
↔
↔
↔
Ctau
↑ 59%
↑ 24%
↓ 24%
↑ 3%a
The 90% CIs of the %GLSM ratios for test versus reference treatments were within (↔), extended above (↑), or extended below 
(↓) the predefined lack of PK alteration boundaries of 70% to 143%. Percentages indicate the increase or decrease in the 
geometric mean for the respective PK parameter for test treatment relative to reference treatment.
a
The 90% CIs of the %GLSM ratio for test versus reference treatment extended both above and below the predefined lack of 
PK alteration boundaries of 70% to 143%.
1.5.2.2.
Study GS-US-384-3914: A Proof of Concept, Open-Label Study Evaluating the 
Safety, Tolerability, and Efficacy of Regimens in Subjects with Nonalcoholic 
Steatohepatitis (NASH)
Study GS-US-384-3914 is an ongoing proof of concept, open-label, multiple-cohort study 
designed to evaluate the safety and efficacy of SEL 18 mg, GS-0976 20 mg, and GS-9674 30 mg
alone and in combination in subjects with NASH. Cohorts 1 through 6 include subjects with 
NASH and stage 2 to 3 fibrosis as evaluated by a MRE ≥ 2.88 kPa and an MRI-PDFF ≥10% or a 
historical biopsy (by NASH CRN criteria or equivalent) within 12 months of Screening. 
Cohorts 1 through 3 are monotherapy cohorts, and Cohorts 4 through 6 are combination cohorts.
Cohorts 7 and 8 includes subjects with cirrhosis due to NASH as evaluated by MRE ≥4.67 kPa, 
FibroScan® ≥ 14 kPa, FibroTest® ≥ 0.75, or a historical biopsy consistent with stage 4 fibrosis 
(by NASH CRN criteria or equivalent) within 12 months of Screening. All cohorts were planned 
to receive study drug for 12 weeks duration.


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1.5.2.2.1.
Cohort 1 (SEL), Cohort 2 (GS-0976) and Cohort 3 (GS-9674) Subject Disposition 
and Demographics
As of January 12, 2018, a total of 30 subjects were enrolled (N=10 for each cohort) and all had 
completed study treatment. No subjects prematurely discontinued study drug, withdrew consent, 
or were lost to follow-up. 
1.5.2.2.2.
Preliminary Safety Results 
Fifty percent (50% [5/10]) of subjects had a TEAE in Cohorts 1 and 3, and 60% (6/10) of 
subjects had an AE in Cohort 2. There were no Grade 3 or 4 AEs, and no SAEs. In Cohort 1 and 
Cohort 2, the most common AEs occurred in the system organ class of GI disorders, with 20% 
(2/10) of subjects in each cohort experiencing this type of AE. In Cohort 3, the system organ 
class of infections and infestations included the most common AEs at 40% (4/10). 
One subject in Cohort 1 had a Grade 4 hyperuricemia. There was one subject in Cohort 2 who 
had a Grade 3 lab abnormality of hypertriglyceridemia. There was one subject in Cohort 1 and 
two subjects in Cohort 3 who had Grade 3 hyperglycemia. One subject in Cohort 2 had a Grade 3 
elevation of ALT and AST (Study Day 112), after stopping the study drug at Day 84. This was in 
the context of a viral illness. There was no concurrent increase in bilirubin or INR, and the ALT 
and AST decreased on repeat testing. In Cohort 3, there were two subjects with Grade 3 ALT 
and AST. These subjects’ lab abnormalities were not associated with changes in bilirubin or 
INR. The subjects were asymptomatic and continued study drug with a decrease in their liver 
biochemistry while on treatment. 
1.5.2.2.3.
Cohort 4 (SEL + GS-9674), Cohort 5 (SEL + GS-0976) and Cohort 6 
(GS-0976 + GS-9674) Subject Disposition and Demographics
As of January 12, 2018, a total of 60 subjects were enrolled (N=20 for each cohort). In Cohorts 4 
and 5, all subjects had completed treatment. In Cohort 6, 16 subjects had completed study drug 
dosing, and the remaining 3 subjects had been dosed for at least 8 weeks. No subjects have 
prematurely discontinued study drug due to AE. One subject in Cohort 6 withdrew consent on 
Day 62, but this was not related to an AE.
1.5.2.2.4.
Preliminary Safety Results 
In Cohort 4, 25% (5/20) of subjects experienced a TEAE, and one subject had a Grade 3 
treatment-emergent SAE (TESAE). This serious event was cellulitis and was not-related to study 
drug. In Cohort 5, 40% (8/20) of subjects experienced a TEAE, but these were all Grade 1 or 2. 
One subject had a Grade 2 SAE of a tooth abscess that was not-related to study drug. In 
Cohort 6, 50% (10/20) of subjects experienced an AE. Most of these AEs were Grade 1 or 2, and 
one subject experienced a Grade 3 serious event of a urinary tract infection (UTI), which was 
deemed not-related to study drug. The most common AEs were in the system organ class of 
infections and infestations (15%, 3/20) for Cohort 4, GI disorders for Cohort 5 (20%, 4/20), and 
infections and infestations (25%, 5/20) for Cohort 6. 


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No subjects in Cohorts 4 through 6 have discontinued study drug due to AEs. One subject in 
Cohort 6 had an interruption of drug while hospitalized due to the AE of a UTI. This UTI was 
exacerbated by excessive diuresis and subsequent electrolyte abnormalities, nausea, and 
dizziness. None of these events were deemed related to the study drug, and the subject continued 
on study drug after initiating treatment for the UTI.
Cohorts 4 and 5 each had two subjects (10%, 2/20) with Grade 3 hyperglycemia. One subject in 
Cohort 5 had an asymptomatic Grade 3 elevation in GGT with no concurrent elevation in other 
liver biochemistry laboratory values. In Cohort 6, 10% (2/20) of subjects have had Grade 3 
hypertriglyceridemia. In Cohort 5 10% (2/20) of subject have had Grade 4 hypertriglyceridemia. 
All subjects were asymptomatic and were started on lipid lowering medication (fish oil or 
fibrate) with a decrease in their triglyceride levels. 
The safety parameters in the 6 cohorts for this study as of January 12, 2018 have demonstrated 
that there is no clinically significant increase in the percentages of AEs (Table 1-7) or Grade 3 or 
above lab abnormalities (Table 1-8) for any combination of study drugs compared to the 
monotherapy. There has been one SAE in each of Cohort 4, Cohort 5, and Cohort 6, but these 
have been unrelated to study drug and not resulted in the discontinuation of either subject from 
the study. Grade 3 or above triglyceride elevations have been present in both monotherapy and 
combination cohorts including GS-0976 in similar percentages and all subjects have been 
asymptomatic. 
1.5.2.2.5.
Cohort 7 (GS-0976) and Cohort 8 (GS-9674) Subject Disposition and 
Demographics 
As of January 12, 2018, a total of 20 cirrhotic subjects were enrolled (N=10 for each cohort). In 
Cohort 7, 10 subjects had completed 12 weeks of study drug. In Cohort 8, 8 subjects had 
completed 12 weeks of treatment, and the remaining 1 ongoing subject had taken at least 
8 weeks of study drug. One subject in Cohort 8 prematurely discontinued study drug due to an 
AE.
1.5.2.2.6.
Preliminary Safety Results 
In Cohort 7, 80% (8/10) subjects experienced a treatment emergent AE, and one of these was a 
Grade 3 SAE of intestinal obstruction that was deemed not-related to study drug. In Cohort 8, 
70% (7/10) subjects experienced a treatment emergent AE, and all of these were Grade 1 or 2 in 
severity. In Cohort 8, one subject experienced Grade 2 worsening of pruritus that led to study 
drug discontinuation. In Cohort 7, the largest percentage of AEs occurred in the system organ 
class of infections and infestations (30%, 3/10). In Cohort 8, the system organ classes of skin and 
subcutaneous tissue disorders and GI disorders both had the largest incidence (30%, 3/10 for 
each class). 
In Cohort 7, 4 subjects (40%) experienced Grade 3 laboratory abnormalities. One subject had a 
transient decrease in their neutrophils. Two subjects had hyperglycemia, and one of these 
hyperglycemia subjects had concurrent Grade 3 hyponatremia that resolved with improved 
glycemic control. One subject had asymptomatic hypertriglyceridemia that resolved with fibrate 


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treatment. In Cohort 8, 3 subjects (30%) had Grade 3 lab abnormalities. One subject had a 
transient hypophosphatemia and one subject had hyperglycemia. One subject had an increase in 
their INR on Day 84 that was believed to be a lab error and normalized on repeat testing without 
intervention. Also, there were no concurrent changes in liver biochemistry testing with this 
transient increase in INR.
The safety parameters of these subjects demonstrate that both GS-0976 and GS-9674 can be 
dosed safely in subjects with cirrhosis due to NASH for 12 weeks duration. The single SAE in 
these cohorts was not-related to study drug GS-0976, and the subject who discontinued GS-9674
had Grade 2 worsening of pre-existing pruritus. The laboratory abnormalities of hyperglycemia 
and hypertriglyceridemia were due to poor baseline metabolic control and were asymptomatic.
There are no clinically significant trends in safety parameters when comparing subjects with 
moderate fibrosis (ie, Cohorts 2 and 3) and cirrhosis (ie, Cohorts 7 and 8) in terms of AEs 
(Table 1-7) or Grade 3 or above lab abnormalities (Table 1-8) dosed with either GS-0976 or 
GS-9674.
Table 1-7.
GS-US-384-3914: Safety Summary
n (%)
Cohort 1
SEL
(N=10)
Cohort 2
GS-0976 
(N=10)
Cohort 3
GS-9674 
(N=10)
Cohort 4
SEL+
GS-9674
(N=20)
Cohort 5
SEL+
GS-0976
(N=20)
Cohort 6
GS-0976+
GS-9764
(N=20)
Cohort 7
GS-0976 
[F4]
(N=10)
Cohort 8
GS-9674 
[F4]
(N=10)
TEAEs
5 (50%)
6 (60%)
5 (50%)
5 (25%)
8 (40%)
10 (42.9%)
8 (80%)
7 (70%)
TEAEs 
Grade 3 
or above 
0
0
0
1 (5%)*
0
1 (5%)+
1 (10%)#
0
TESAEs 
0
0
0
1(5%)*
1(5%)@
1 (5%)+
1 (10%)#
0
Treatment 
D/C due 
to AE
0
0
0
0
0
0
0
1 (10%)^
*
Unrelated cellulitis from an insect bite 
+
Unrelated urinary tract infection
# 
Unrelated intestinal obstruction
^
Grade 2 worsening pruritus 
@
Unrelated tooth abscess


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Table 1-8.
GS-US-384-3914: Treatment-Emergent Grade 3 and 4 Lab 
Abnormality Summary
n (%)
Cohort 1
SEL
(N=10)
Cohort 2
GS-0976 
(N=10)
Cohort 3
GS-9674 
(N=10)
Cohort 4
SEL+
GS-9674
(N=20)
Cohort 5
SEL+
GS-0976
(N=20)
Cohort 6
GS-0976+
GS-9764
(N=20)
Cohort 7
GS-0976 
[F4]
(N=10)
Cohort 8
GS-9674 
[F4]
(N=10)
Total
2 (20%)
2 (20%)
4 (40%)
2 (10%)
4 (20%)
2 (10%)
4 (40%)
3 (30%)
ALT
0
1 (10%)
2 (20%)
0
0
0
0
0
AST
0
1 (10%)
2 (20%)
0
0
0
0
0
GGT
0
0
0
0
1 (5%)
0
0
0
Urate
1 (10%)
0
0
0
0
0
0
0
Triglycerides
0
1 (10%)
0
0
2 (10%)
2 (10%)
1 (10%)
0
Glucose
1 (10%)
0
2 (20%)
2 (10%)
2 (10%)
0
2 (20%)
1 (10%)
Neutrophils 
(Decreased)
0
0
0
0
0
0
1 (10%)
0
Hypophosphatemia
0
0
0
0
0
0
0
1 (10%)
Hyponatremia
0
0
0
0
0
0
1 (10%)
0
Increased INR
0
0
0
0
0
0
0
1 (10%)
1.6.
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 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 needed to 
achieve optimal therapeutic benefit, particularly in patients with advanced fibrosis.
ASK1 inhibition with SEL reduces oxidative stress-induced hepatocyte apoptosis, inflammation 
and fibrogenesis by reducing activation of JNK and p38 stress-response kinases. Thus, SEL is 
postulated to halt several instigating triggers for NASH. ASK1 inhibition reduces hepatic 
steatosis and fibrosis in obese mice fed a fat and carbohydrate rich diet, and reduces liver fibrosis 


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in rats fed a choline-deficient, high-fat diet. In a completed Phase 2 study in subjects with NASH 
(GS-US-384-1497), SEL dose-dependently reduced liver fibrosis, demonstrating that ASK1 
inhibition causes regression of liver fibrosis in humans. Increased rates of hepatic DNL and 
insufficient fatty acid oxidation lead to hepatic steatosis and associated lipotoxicity, which are 
also implicated in the etiology and progression of NASH. By inhibiting ACC, GS-0976 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), GS-0976 led to improvement in hepatic steatosis, liver biochemistry, and 
markers of fibrosis. 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 GS-9674 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), GS-9674 led to statistically significant reductions in hepatic 
steatosis and GGT, and thus, GS-9674 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 ASK1 inhibitor and ACC inhibitor, ASK1 inhibitor and FXR agonist, and 
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 SEL and GS-9674, SEL and GS-0976, or GS-9674 and GS-0976. 
NASH with fibrosis is a condition with a high risk of progression to cirrhosis which may lead to 
end-stage liver disease and increases the risk of HCC. Thus, reversing the fibrotic process in 
addition to ameliorating the metabolic dysfunction that drives NASH pathogenesis is paramount 
to improving the prognosis of this condition. 
The current gold standard for assessing fibrosis is liver biopsy. As such, improvement in liver 
fibrosis without worsening of NASH as assessed by liver biopsy will be evaluated as the primary 
efficacy parameter in this 48-week study. However, liver biopsy has numerous limitations 
including its invasiveness and the potential for serious complications, which deter many patients 
from seeking evaluation for NAFLD or enrolling in clinical trials of novel therapies. Liver 
biopsy is also limited by cost, sampling error, and variability in histopathological interpretation. 
Due to these limitations, the development and validation of noninvasive markers of liver injury
has emerged as a clinical and research priority. To further the development of such tools, this
study will also incorporate noninvasive endpoints for the assessment of fibrosis including serum 
markers (eg, ELF™test, FibroSURE/FibroTest®, pro-C3) and imaging (eg, liver stiffness by 
FibroScan® and MRE). Noninvasive markers of other histological lesions such as hepatic fat by 
MRI-PDFF and hepatocellular apoptosis by CK18 will also be measured. A key exploratory 
objective of the study is to correlate these markers with liver histology at baseline and determine 
their utility for monitoring histological responses that occur during the course of the study.
Moreover, a subset of patients will be enrolled in the study based entirely on noninvasive 
markers of fibrosis; specifically a liver stiffness by FibroScan® XL probe ≥ 14.0 kPa and ELF™
test score ≥9.8 during screening. These criteria have been selected to increase the likelihood of 
enrolling patients with advanced fibrosis (F3-F4) rather than those with mild fibrosis (F0-F2), in 


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whom the urgency for treatment is lower {Miele 2017, Shadab Siddiqui 2017}. This novel 
approach will help inform the design of future clinical trials in NASH based entirely on 
noninvasive parameters for enrollment and the evaluation of treatment response. 
1.6.1.
Rationale for Dose Selection of SEL
SEL 18 mg once daily was selected for evaluation in this study based on a combination of safety 
and efficacy data in the Phase 2 NASH study (GS-US-384-1497) as well as PK/PD modeling of 
predicted inhibition of p38 phosphorylation. In study GS-US-384-1497, SEL 6 mg and 18 mg 
(± SIM 125 mg) for 24 weeks were evaluated. While both doses demonstrated a ≥1-stage 
decrease in NASH CRN fibrosis stage from baseline at a rate higher than subjects treated with 
SIM alone (20%) or compared to historical placebo response rates, SEL 18 mg (± SIM 125 mg) 
had a slightly higher response rate (43%) than SEL 6 mg (± SIM 125 mg) (30%). In addition, an 
exposure-response relationship was identified for SEL exposure and percent change from 
baseline of blood phosphorylated p38 measured in subjects in Phase 2 studies in PAH and DKD 
after administration of SEL 2 mg, 6 mg, or 18 mg once daily. Utilizing this model, plasma SEL
AUCtau observed in the NASH subjects after administration of SEL 18 mg ± SIM 125 mg was 
associated with 78% (7.5%) of maximal inhibition (Emax) of phosphorylated p38 [mean (%CV)]. 
A study of SEL in subjects with cirrhosis and hepatic impairment demonstrated no clinically 
relevant differences in SEL exposure which allows for treatment without dose adjustment in 
patients with advanced fibrosis. Across the clinical development program, SEL has been 
well-tolerated in Phase 1 and Phase 2 studies up to 48 weeks in duration with no clear 
dose-safety relationships for incidences or severity of AEs or laboratory abnormalities. Thus, the 
efficacy and safety profile of SEL support dosing of 18 mg once daily in this study.
1.6.2.
Rationale for Dose Selection of GS-0976
The dose of GS-0976 chosen for evaluation in this study, 20 mg QD, is supported by the safety, 
tolerability and effects of GS-0976 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 GS-0976 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 GS-0976 up to 1000 mg or multiple daily doses (10 days) of GS-0976 
up to 200 mg were administered. In healthy but overweight or obese subjects, a single GS-0976
dose of 20 mg resulted in a mean inhibition of fractional DNL of 71%. In study 
GS-US-426-3989, GS-0976 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.
GS-0976 20 mg also had larger reductions in liver biochemistry (ie, ALT) and serum markers of
fibrosis (ie, TIMP-1 and 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 GS-0976 20 mg for 12 weeks in the proof of 
concept study described above with similar safety as subjects with less advanced fibrosis.


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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. GS-0976 exposures in non-cirrhotic subjects are expected to remain > 48- and 
206-fold lower than the GS-0976 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, GS-0976 exposures in subjects with mild hepatic impairment (CP A) are 
expected to remain ≥22 and ≥105-fold lower than the GS-0976 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 
GS-0976, dose adjustments are not considered necessary for subjects with compensated cirrhosis 
in this study.
1.6.3.
Rationale for Dose Selection of GS-9674
A GS-9674 dose of 30 mg administered without regard to food has been selected for this study 
based on PK, PD, safety, and efficacy data from Phase 1 studies in healthy subjects and subjects 
with hepatic impairment (GS-US-402-1851, GS-US-454-4315, and GS-US-402-3885) and 
Phase 2 studies in subjects with NASH with or without cirrhosis (GS-US-402-1852 and 
GS-US-384-3914). GS-9674 exposure at this dose is expected to provide sufficient FXR 
agonism and result in histologic improvements in subjects with NASH.
In the Phase 1 study GS-US-402-1851, GS-9674 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 GS-9674 doses 
evaluated, doses ≥ 30 mg provided comparable intestinal FXR agonism as assessed by increases 
in FGF19 exposure. Food effect data in studies GS-US-402-1851 and GS-US-454-4315 shows 
that fasted exposure is contained within the range of exposures observed across meal types. 
In ongoing studies, subjects with stage 1 to 3 fibrosis and compensated cirrhosis due to NASH 
have been dosed with 30 mg GS-9674 for 12 weeks with food, without regard to meal type. In 
non-cirrhotic NASH subjects 30 mg GS-9674 was well tolerated and associated with significant 
decreases in hepatic fat as assessed by MRI-PDFF and liver biochemistry (ie, GGT) over 
12 weeks (GS-US-384-3914). Though GS-9674 exposures are increased in mild hepatic 
impairment (1.8-fold), GS-9674 30 mg was well tolerated following 12 weeks of treatment in 
subjects with compensated cirrhosis due to NASH (GS-US-384-3914). Additionally, adequate 
exposure margins (12- to 30-fold relative to preclinical NOAEL exposures) are expected after 
30 mg GS-9674 administration to subjects with compensated cirrhosis due to NASH. Data 
supports that no GS-9674 dose adjustment is required for compensated cirrhosis in this study.
1.6.4.
Rationale for Dose Selection of Combinations
SEL, GS-9674, and GS-0976 can be co-administered without dose modification. This is based on 
the available preclinical and clinical safety information of each single agent, as well as the 
combinations. The PK results from study GS-US-402-2101 showed no clinically meaningful 
changes in SEL, GS-9674, and GS-0976 exposure when co-administered (Section 1.5.2.1). In 
study GS-US-384-3914 described above (Section 1.5.2.2), combinations of SEL 18 mg once 
daily, GS-9674 30 mg once daily, and GS-0976 20 mg once daily, alone or in combination, were
dosed in subjects with mild to advanced fibrosis due to NASH, with safety profiles that are 
similar to the monotherapies.


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1.7.
Risk/Benefit Assessment for the Study
This study will provide information regarding the safety and efficacy of SEL, GS-0976, 
GS-9674, alone or in combination for the treatment of patients with bridging fibrosis and 
compensated cirrhosis due to NASH. These patients are at the highest risk for clinical 
complications related to their liver disease. As there are currently no approved therapies for 
NASH, there is a large unmet medical need for this growing population of patients.
The potential benefits of SEL for the treatment of NASH were shown in the Phase 2 study 
GS-US-384-1497. As described above, fibrosis regression was observed in a greater proportion 
of SEL-treated versus SIM-treated subjects after only 24 weeks of treatment. Although this study 
did not include a placebo control arm, these response rates to SEL are substantially higher than 
reported in the placebo groups of Phase 2 trials for other compounds in development for NASH 
{Neuschwander-Tetri 2014, Ratziu 2016}. In addition, reductions in liver biochemistries
(eg, ALT, AST, GGT), liver fat content by MRI-PDFF, lobular inflammation, liver stiffness by 
MRE, and biomarkers of apoptosis and necrosis (serum CK-18 M30 and M65 levels) were 
observed, particularly in fibrosis responders.
The potential benefits of GS-0976 for the treatment of NASH were shown in the Phase 2 study 
GS-US-426-3989. As described above, significant and clinically meaningful reductions in 
hepatic fat by MRI-PDFF and decreases in ALT, TIMP-1, and PIIINP were observed in the 
subjects who received GS-0976 20 mg for only 12 weeks of treatment. Based on these results, 
improvements in liver histology including hepatic fibrosis would be expected to ensue in studies 
of longer duration. A subset of subjects who received GS-0976 in the Phase 2 study had 
asymptomatic Grade 3 or 4 elevations in triglycerides that resolved spontaneously or with 
treatment with fibrates or fish oil. These subjects had abnormal triglycerides at baseline, and so 
strategies to mitigate this risk in the proposed study will consist of exclusion criteria for 
triglyceride elevations above 250 mg/dL and close monitoring of lipid testing with a plan to 
initiate treatment with fibrates or fish oil if clinically indicated (see Figure 7-3).
Subjects randomized to GS-9674 may benefit from an improvement in their underlying NASH 
which may manifest as improvements in liver biochemistry, hepatic steatosis, and fibrosis. In the 
proof of concept study (GS-US-384-3914), 10 subjects with mild to moderate fibrosis and 
10 subjects with cirrhosis due to NASH have been dosed with GS-9674 for 12 weeks. These 
subjects have shown decreases in hepatic fat by MRI-PDFF and liver biochemistry (ie, GGT). 
One subject with cirrhosis discontinued the study due to worsening pruritus, and to mitigate this 
potential risk with GS-9674, close monitoring of clinical signs and symptoms with a plan to 
initiate treatment for pruritus if clinically indicated has been recommended (see Section 7.5.5). In 
the Phase 1 study, 94 subjects have received GS-9674 in single or multiple doses (14 days) up to 
300 mg. All TEAEs were mild to moderate (Grade 1 or 2), and overall, the rate of any AEs was 
similar between subjects treated with GS-9674 or placebo. The predominant toxicities were 
anemia, back pain, diarrhea, and headache. Grade 2 or 3 elevations in serum ALT were seen in 
five (5%) GS-9674 treated subjects and one (4%) placebo treated subject. Grade 2 or 3 
ALT elevations that occurred on-treatment were observed in 2/23 (9%) twice daily (BID) treated 
subjects, but none of the 71 subjects who received QD GS-9674 dosing. In these cases, 


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elevations in serum bilirubin or prolongation of INR were not observed, serum ALT levels 
normalized upon treatment cessation, and no evidence of drug hypersensitivity syndrome 
(eg, fever, rash, eosinophilia) was noted. In nonclinical studies, effects on the liver have been 
limited to non-adverse mild increases in alkaline phosphatase and liver weights and minimal 
hepatocellular hypertrophy that are likely a pharmacological response to FXR agonism. There 
were no elevations in liver transaminases or changes in liver pathology (degeneration/necrosis) 
in the nonclinical studies to suggest direct cellular damage. In order to mitigate the potential risk 
of hepatotoxicity with GS-9674, QD dosing of GS-9674 has been chosen for this study. 
Moreover, close monitoring of liver biochemistry values will be performed and parameters for 
discontinuation of the study drugs due to liver test abnormalities have been defined 
(see Section 7.5) and will be closely followed.
Subjects with advanced fibrosis who are randomized to the placebo control arm in the study may 
benefit from frequent medical monitoring and close assessment of their NASH (eg, surveillance 
for HCC and hepatic decompensation) and associated pathologies during the duration of placebo 
treatment. 
Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-hepatic laboratory abnormalities are also defined and will be closely followed.
Overall, the nonclinical and preliminary clinical data show a positive benefit/risk ratio in support 
of the study in subjects with bridging fibrosis and compensated cirrhosis due to NASH. 
Appropriate safety monitoring will be conducted throughout the study to further characterize the 
safety profile of SEL, GS-0976, and GS-9674, alone or in combination, in this patient 
population. 
In summary, there are no approved treatment options available for patients with NASH. Based 
on clinical experience with SEL, GS-0976, and GS-9674, alone or in combination, the 
risk/benefit ratio is positive and supports the continued evaluation of these monotherapies and 
combination therapies in this patient population. 
1.8.
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 prima1y objectives of this study are: 
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• 
To assess the safety and tolerability of SEL, GS-0976, and GS-9674, administered alone or in 
combination, in subjects with bridging fibrosis or compensated cinhosis due to NASH 
• 
To evaluate changes in liver fibrosis, as measured by the NASH CRN classification, without 
worsening of NASH (defined as any increase in hepatocellular ballooning or lobular 
inflammation) 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
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STUDY DESIGN 
3.1. 
Study Design 
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This is a Phase 2, randomized, double-blind, placebo-contrnlled study evaluating the safety and 
efficacy of SEL, GS-0976, GS-9674, and combinations in subjects with bridging fibrosis or 
compensated cinhosis due to NASH. 
The overall study design is presented graphically in Figure 3-1. 
Figure 3-1. 
Overall Study Design 
3.2. 
8 Weeks 
48 Weeks 
C 
QO 
.2 
.!: 
1v 
C 
N 
CII 
'e 
0 
.., 
"CJ 
Ill 
C 
IV 
a: 
A: SEL 18 mg+ GS-097620 mg+ PTM GS-967430 mg (N N 70) 
8: SEL 18 mg+ PTM GS-0976 20 ma + GS-9674 30 ma (N N 70) 
C: SEL18 mg + PTM GS-097620 mg+ PTM GS.9674 30mg (N N 35) 
D: PTM SEL 18 mg+ GS-0976 20 mg + PTM GS-9674 30 ma (N N 35) 
E: PTM SEL 18 mg+ PTM GS-0976 20 mg+ GS-9674 30 mg (N N 35) 
F: PTM SEL 18 mg+ PTM GS-097620 m, + PTM GS-9674 30 mg (N N 35) 
G: PTM SEL 18 mg + GS-0976 20 mg + GS·9674 30 mg (N N 70) 
Study Treatments 
Subjects meeting the study's ent:Iy criteria will be assigned randomly in a 2:2:1:1:1:1:2 ratio to 
1 of 7 ti·eatment groups (Group A, Group B, Group C, Group D, Group E, Group F, or Group G), 
with approximately 70 subjects in each combination ti·eatment group and approximately 35 
subjects in each single agent or placebo group, as shown in Figure 3-1. Randomization will be 
sti·atified by the presence or absence of diabetes mellitus, as detennined by medical histo1y or 
based on the Screening lab values if previously undiagnosed (HbAlc 
6.5% or fasting plasma 
glucose~ 126 mg/dL) and by the presence or absence of cinhosis (F4) as detennined by the 
centi·al biopsy reader at Screening. 
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Study chugs will be administered for a total of 48 weeks from the Day 1 visit. Dosage and 
administration of the study chugs and reference products are described in Section 5.2.4. 
3.3. 
Duration of Study 
Paiiicipation can last up to 60 weeks, which includes an 8-week Screening period, a 48-week 
On-Treatment period, and a 4-week Follow-Up period. 
3.4. 
End of Study 
End of study is considered to be completion of the 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 350 subjects with bridging fibrosis and compensated 
cirrhosis due to NASH. Approximately 60% of the enrolled subject population will have 
cirrhosis on the Screening liver biopsy, and approximately 40% of these subjects will have 
cirrhosis due to NASH with < 5% steatosis. Approximately 70 subjects who do not have 
historical liver biopsies may be enrolled based on noninvasive fibrosis markers (FibroScan® and 
ELF™Test score) regardless of fibrosis stage determined on the Screening liver biopsy.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Males and non-pregnant, non-lactating females between 18 – 80 years of age inclusive, based 
on the date of the Screening visit;
2) Willing and able to give written informed consent prior to any study specific procedures 
being performed;
3) Bridging fibrosis or cirrhosis due to NASH as defined by one of the following; all subjects 
must not have documented weight loss > 5% between the date of the biopsy and Screening:
a) NASH (defined as the presence of a steatosis grade ≥ 1, hepatocellular ballooning grade 
≥ 1, and lobular inflammation grade ≥ 1, according to the NAS) and bridging 
fibrosis (F3) within 6 months of Screening, in the opinion of the central reader; 
b) Compensated cirrhosis (F4) due to NASH (defined as the presence of a steatosis grade
≥1, hepatocellular ballooning grade ≥ 1, and lobular inflammation grade ≥1, according 
to the NAS) within 12 months of Screening, in the opinion of the central reader;
c) Compensated cirrhosis (F4) due to NASH with < 5% steatosis (defined as a steatosis 
grade of 0, hepatocellular ballooning grade ≥ 1, and lobular inflammation grade ≥ 1, 
according to the NAS) within 12 months of Screening, in the opinion of the central 
reader; and at least two of the following criteria for metabolic syndrome, modified from 
the NCEP ATP III, 2005 Guidelines at Screening:
i)
Fasting glucose ≥100 mg/dL or receiving drug treatment for elevated glucose;
ii) Fasting HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women or receiving 
drug treatment for low HDL cholesterol;
iii) Fasting triglycerides ≥150 mg/dL or receiving drug treatment for elevated 
triglycerides;


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iv) Waist circumference ≥102 cm for men or ≥88 cm for women or BMI ≥30 kg/m2;
v) Systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or
receiving drug treatment for hypertension;
d) In subjects who have never had a liver biopsy, liver stiffness by FibroScan® XL probe 
≥14.0 kPa, Enhanced Liver Fibrosis (ELF™) Test score ≥ 9.8, and at least two of the 
criteria for metabolic syndrome modified from the NCEP ATP III Guidelines, at 
Screening. In subjects eligible based on this criterion, a liver biopsy must be performed 
during Screening and must be deemed evaluable for fibrosis stage and NAS by the central 
reader; however, the reported stage of fibrosis will not determine eligibility for the study;
4) Screening laboratory parameters, as determined by the central laboratory:
a) eGFR ≥60 mL/min, as calculated by the Cockcroft-Gault equation;
b) HbA1c ≤ 9.5% (or serum fructosamine ≤381 µmol if HbA1c is unable to be resulted);
c) Hemoglobin ≥ 10.6 g/dL;
d) INR ≤ 1.4, unless due to therapeutic anticoagulation;
e) Total bilirubin ≤ 1.3 x ULN, unless due to an alternate etiology such as Gilbert’s 
syndrome or hemolytic anemia;
f)
Platelet count ≥ 125,000/µL;
g) Serum triglyceride level ≤250 mg/dL;
h) ALT < 5 x ULN;
5) BMI ≥ 18 kg/m2 at Screening;
6) Female subjects of childbearing potential (see definition in Appendix 3) must have a negative 
pregnancy test at Screening and Day 1;
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) Known hypersensitivity to SEL, GS-0976, GS-9674, the metabolites, or formulation 
excipients;
2) Prior history of decompensated liver disease including ascites, HE, or variceal bleeding;
3) CP score > 6 at Screening, unless due to an alternate etiology such as Gilbert’s syndrome or 
therapeutic anticoagulation;


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4) MELD score > 12 at Screening, unless due to an alternate etiology such as therapeutic 
anticoagulation;
5) Chronic HBV infection (HBsAg positive);
6) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection 
less than 2 years prior to the Screening visit are not eligible;
7) Other causes of liver disease based on medical history and/or centralized review of liver 
histology, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, 
autoimmune disorders (eg, PBC, 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) Current or prior history of HCC;
10) Any weight reduction surgery within 2 years prior to Screening or malabsorptive weight loss 
surgery (eg, Roux-en-Y or distal gastric bypass) at any time prior to Screening. Weight 
reduction surgery is disallowed during the study;
11) Intestinal resection that could result in malabsorption of study drugs;
12) Weight loss > 10% within 6 months prior to Screening;
13) HIV infection;
14) History of symptomatic chronic pulmonary disease (eg, chronic obstructive pulmonary 
disease, interstitial lung disease) within 6 months prior to Screening;
15) 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 Screening;
b) Transient ischemic attack or cerebrovascular accident within 6 months prior to Screening;
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 Screening;


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16) Males who habitually drink greater than 21 oz/week of alcohol or females who habitually 
drink greater than 14/oz week of alcohol (1 oz/30 mL of alcohol is present in:
a 12 oz/360 mL beer, a 4 oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40 proof 
alcohol);
17) Positive urine drug screen for amphetamines, cocaine or opiates (eg, heroin, morphine) at 
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 
6 months prior to Screening may be included in the study. Subjects with a positive urine drug 
screen due to prescription medication (eg, opioids, methylphenidate) are eligible if the 
prescription and diagnosis are reviewed and approved by the investigator;
18) Use of any prohibited concomitant medication as described in Section 5.3. 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 
6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must 
be on a stable dose for at least 3 months prior to the diagnostic liver biopsy;
19) History of a malignancy within 5 years of Screening with the following exceptions:
a) Adequately treated carcinoma in situ of the cervix;
b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer;
20) Unable to safely undergo a liver biopsy;
21) Concurrent participation in another therapeutic clinical study;
22) Presence of any laboratory abnormality or condition that could, in the opinion of the 
investigator, compromise the subject’s ability to participate in the study, including a history 
of substance abuse and/or a psychiatric condition requiring hospitalization and/or emergency 
room visit within 2 years of Screening;
23) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Mobile/Web Response System (IXRS) will be used for centralized randomization 
and treatment assignment. Randomization will be stratified by the presence or absence of 
diabetes mellitus, as determined by medical history or based on the Screening lab values if 
previously undiagnosed (HbA1c ≥ 6.5% or fasting plasma glucose ≥126 mg/dL), and the 
presence or absence of cirrhosis (F4) as determined by the central biopsy reader at Screening. 
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IXRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment.
Study drugs will be dispensed in a blinded fashion to the subjects.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS for that 
subject. Gilead recommends but does not require that the investigator contact the Gilead medical 
monitor before breaking the blind. Treatment assignment should remain blinded unless that 
knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation, along with the date on which the 
treatment assignment was obtained. The investigator is requested to contact the Gilead medical 
monitor promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
In the event that GS-US-384-1943 and GS-US-384-1944 demonstrate lack of efficacy and are 
discontinued after the Week 48 Interim Analysis, unblinding of the SEL monotherapy treatment 
group will occur. Unblinded SEL monotherapy treatment assignments will be generated by the 
external reporting statistician. Investigators will receive subject-specific SEL monotherapy 
treatment assignments upon applicable regulatory authority and IRB/IEC/EC approval to 
discontinue subjects from study drug and complete assessments for premature discontinuation 
from study (refer to Section 6.8).
The rationale for unblinding must be clearly explained in source documentation, along with the 
date on which treatment assignment was obtained.


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The Pharmacovigilance & Epidemiology (PVE) department at Gilead Sciences may 
independently unblind cases for expedited reporting of suspected unexpected serious adverse 
reactions (SUSARs).
5.2.
Description and Handling of SEL, GS-0976, GS-9674
5.2.1.
Formulation
5.2.1.1.
Selonsertib (SEL) 18 mg
SEL will be supplied as 18 mg strength tablets. The tablets are round, film-coated gray tablets 
debossed with an underscored “18” on one side and “GSI” on the other side. In addition to the 
active ingredient, SEL tablets contain the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, 
polyethylene glycol, titanium dioxide, talc, and iron oxide black. 
PTM SEL tablets are identical in size, shape, color and appearance to their corresponding 
strength of active SEL tablets and contain the same inactive ingredients. 
5.2.1.2.
GS-0976 20 mg
GS-0976 will be supplied as 20 mg strength tablets. The tablets are round, plain-faced, 
film-coated white tablets containing 20 mg of GS-0976. In addition to the active ingredient, 
GS-0976 tablets contain the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, polyethylene glycol, and talc, which are common pharmaceutical excipients.
PTM GS-0976 tablets are identical in size, shape, color and appearance to their corresponding 
strength of active GS-0976 tablets and contain the same inactive ingredients. 
5.2.1.3.
GS-9674 30 mg
GS-9674 will be supplied as 30 mg strength tablets. The tablets are capsule-shaped, plain-faced, 
film-coated orange tablets. The tablets contain GS-9674-02 (tromethamine salt) and inactive 
ingredients microcrystalline cellulose, mannitol, crospovidone, magnesium stearate, and 
film-coating material comprised of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, 
yellow iron oxide, red iron oxide, and ferrosoferric oxide. 
PTM GS-9674 tablets are identical in size, shape, color, and appearance to their corresponding 
strengths of active GS-9674 tablets. PTM GS-9674 tablets contain the following ingredients: 
microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, 
and film-coating material comprised of polyvinyl alcohol, polyethylene glycol, talc, titanium 
dioxide, yellow iron oxide, red iron oxide, and ferrosoferric oxide.


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5.2.2.
Packaging and Labeling
SEL and PTM SEL 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 fitted with an 
induction-sealed and aluminum-faced liner.
GS-0976 and PTM GS-0976 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.
GS-9674 and PTM GS-9674 tablets are packaged in white, HDPE bottles. Each bottle contains 
30 tablets, a 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 drugs 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) and/or other local regulations.
5.2.3.
Storage and Handling
SEL, PTM SEL, GS-0976, PTM GS-0976, GS-9674, and PTM GS-9674 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 drugs should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.2.4.
Dosage and Administration
The administration of study drugs will be recorded in the source documentation and in the eCRF.
SEL, PTM SEL, GS-0976, PTM GS-0976, GS-9674, and PTM GS-9674 tablets will be provided 
by Gilead Sciences. Subjects will take one tablet of each drug (or PTM) together at 
approximately the same time each day. Drugs should be taken with or without food, and
swallowed whole with water. A dose will be considered missed if the subject cannot take the
complete 3 tablet 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.


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Study drug dosing and administration will occur as follows, based on treatment group 
randomization:

Treatment Group A: one SEL 18 mg tablet, one GS-0976 20 mg tablet, and one PTM 
GS-9674 30 mg tablet administered orally once daily with or without food

Treatment Group B: one SEL 18 mg tablet, one PTM GS-0976 20 mg tablet, one GS-9674 
30 mg tablet administered orally once daily with or without food

Treatment Group C: one SEL 18 mg tablet, one PTM GS-0976 20 mg tablet, and one PTM 
GS-9674 30 mg tablet administered orally once daily with or without food

Treatment Group D: one PTM SEL 18 mg tablet, one GS-0976 20 mg tablet, and one PTM 
GS-9674 30 mg tablet administered orally once daily with or without food

Treatment Group E: one PTM SEL 18 mg tablet, one PTM GS-0976 20 mg tablet, and 
one GS-9674 30 mg tablet administered orally once daily with or without food

Treatment Group F: one PTM SEL 18 mg tablet, one PTM GS-0976 20 mg tablet, and 
one PTM GS-9674 30 mg tablet administered orally once daily with or without food

Treatment Group G: one PTM SEL 18 mg tablet, one GS-0976 20 mg tablet, and 
one GS-9674 30 mg tablet administered orally once daily with or without food
5.3.
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 Screening and any taken during the study
until the end of the follow-up period.
Caution should be exercised when co-administering sensitive P-gp substrates with narrow 
therapeutic index (eg, digoxin) with study drugs, as it may increase the concentrations of these 
agents. The Investigator should review the prescribing information of the concomitant 
medication for guidance on co-administration with a weak P-gp inhibitor. 
Subjects on Vitamin E ≥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 6 months 
prior to the diagnostic liver biopsy. Subjects on antidiabetic medication(s) must be on stable 
dose(s) for at least 3 months prior to the diagnostic liver biopsy. If possible, the doses of these 
medications should remain stable through the end of treatment.
Any investigational medication within 30 days or within 5 half-lives prior to Screening and 
throughout the study (eg, obeticholic acid, elafibranor, and cenicriviroc) is prohibited. Subjects 
enrolled in the current protocol may participate concurrently in a HepQuant™ sponsored 
investigational device study at participating US sites only (Investigational Device Exemption 
# G170034/S002), once approved by the applicable IRB/IEC.


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The following medications are prohibited for all treatment groups, from 30 days prior to Day 1 
up to and including the day of the last dose of study drugs:

Chronic systemic immunosuppressants including but not limited to: corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for ≤ 2 weeks total is allowed.

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents [ESAs]; granulocyte 
colony stimulating factor [GCSF]; thrombopoietin [TPO] mimetics)

Any medication or supplement prescribed for weight loss

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 representative medications that are prohibited or which should be used with caution 
are listed below in Table 5-1.
Table 5-1.
List of Representative Disallowed and Use with Caution Medicationsa
Agents Disallowed
Drug Class
Disallowed 30 days prior to Day 1 through the end of treatment
Immunosuppressants
Chronic systemic corticosteroidsb, tacrolimus, sirolimus, cyclosporine, 
mycophenolate mofetil, and methotrexate
Acid Reducing Agents
H2-Receptor antagonistsd
Antibioticsc
azithromycin, clarithromycin, erythromycin
Anticonvulsantsc
phenobarbital, phenytoin, carbamazepine, oxcarbazepine
Antimycobacterialsc
rifamycins, isoniazid
Endothelian Receptor Antagonistsc
Bosentan
Herbal/Natural Supplementsc
St. John’s Wort, Echinacea, milk thistle (ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Otherc
gemfibrozil, modafinil
Agents to be used with Caution
Drug Class
Agents to be used with Caution from 30 days prior to Day 1 through end of 
treatment
Cardiac Medicationse
digoxinf, dabigatran etexilate, aliskiren
Acid Reducing Agents
antacidsg
Bile Acid Sequestrantsh
cholestyramine, colestipol, colesevelem
a
Not all of these example medications may be approved in each of the countries 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
May result in an increase or decrease in the concentration of study drugs.
d
H2-Receptor antagonists can be taken up to 3 days prior to Day 1.
e
SEL may increase the exposure of these medications.


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f
For subjects on digoxin at start of study: obtain digoxin level prior to starting study drug and at the Week 1 Visit with 
digoxin level checks during the study period per Investigator discretion. Monitor and adjust digoxin dose as necessary based 
on prescribing information.
g
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours 
(before or after) study drug administration.
h
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) study drug administration.
5.4.
Accountability for SEL, GS-0976, and GS-9674
The Investigator is responsible for ensuring adequate accountability of all used and unused 
Investigational Medicinal Product (IMP). This includes acknowledgement of receipt of each 
shipment of IMP (quantity and condition). All used and unused IMP dispensed to subjects must 
be returned to the site.
IMP accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.4.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used (empty bottles) and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. A 
copy of the site’s SOP will be obtained for central files. Where possible, study drugs will be 
destroyed at the site. Upon study completion, a copy of the Investigational Drug Accountability 
records must be filed at the site. Another copy will be returned to Gilead Sciences. If drug is 
destroyed on site, the Investigator must maintain accurate records for all study drug bottles 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and person who disposed of the drug. All study drug records must be maintained 
at the site and copies must be submitted to Gilead Sciences at the end of the study.


Selonsertib, GS-0976, GS-9674
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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 Site Operations 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
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.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 8 weeks before randomization to determine eligibility for 
participation in the study. The Screening period may be extended under special circumstances 
with the explicit approval of the Gilead Medical Monitor.
Screening laboratory tests may be repeated once within the Screening period, at the discretion of 
the Investigator, prior to Randomization.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Screening visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at Screening:

Obtain written informed consent prior to initiation of any Screening procedures

Obtain Screening number from IXRS

Obtain medical history

Record all concomitant medications that the subject has taken within 30 days prior to 
Screening

Complete PE

Vital signs, body weight, and height

Assess ascites and HE
CCI


Selonsertib, GS-0976, GS-9674 
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• 
12-Lead ECG 
I 
• 
Obtain blood samples for: 
-
Chemist:Iy 
-
Hematology 
-
Coagulation 
-
Insulin and lipids 
-
HIV-1, HBV, and HCV serology 
-
HbAlc (if unable to be resulted, sernm fiuctosamine will be tested) 
-
Sernm pregnancy test (for females of childbearing potential) 
I 
• 
Collect urine samples for: 
Final 
Amendment4 
-
Urine drng screen for amphetamines, cocaine and opiates (ie, heroin, morphine) 
I 
• 
Perfo1m liver biopsy (if required) and provide liver tissue for centi·al reading. A historical 
biopsy that meets eligibility criteria may be accepted as the Screening biopsy if the sample is 
deemed acceptable for interpretation by the cent:I'al reader. The historical sample must be 
within 6 months of Screening for F3 subjects and within 12 months of Screening for 
F4 subjects. 
I 
• 
Record in the source documents and eCRFs all SAEs and any AEs related to protocol 
mandated procedures that occun ed after signing of the consent f01m. All other untoward 
medical occunences observed during the Screening period, including exacerbation or 
changes in medical histo1y are to be captured on the medical histo1y eCRF. See Section 7 
Adverse Events and Toxicity Management for additional details. 
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Final 
Amendment4 
• 
Confom subject's liver histological findings, including fibrosis stage, on the centrally 
read biopsy repo1i 
I 
• 
Review and document the subject's eligibility status 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic after Screening for randomization into the study. 
6.3. 
Day 1 Assessments 
All Day 1 assessments must be completed before subject dispensation/dosing of study diugs. 
6.3.1. 
Day 1: Randomization and Assessments 
Subjects returning to the clinic for randomization at Day 1 should be instmcted to fast (no food 
or di·ink, except water), sta1iing from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensme an approximate 8-hom fast prior to the blood sample collection under 
fasting condition the next morning. 
After review of inclusion and exclusion criteria to confom continued eligibility, subjects will be 
randomized to stud diu assi nment and receive a Sub'ect Identification Number via the IXRS. 
The following will be perfonned and documented at the Day 1 visit prior to dosing: 
I 
• 
Lifestyle questionnaire 
I 
• 
Symptom di·iven PE 
• 
Vital signs and body weight 
I 
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Assess ascites and HE 
• 
Provide lifestyle modification counseling 
• 
Obtain blood samples for: 
-
Chemist:Iy 
-
Hematology 
-
Coagulation 
-
Insulin and lipids 
-
HbAlc 
I 
Final 
Amendment4 
Note: For subjects on digoxin at staii of study: obtain digoxin level prior to staii ing study 
dmg and at the Week 1 Visit, with digoxin level checks during the study period per 
Investigator discretion. Monitor and adjust digoxin dose as necessaiy based on 
prescribing infonnation. 
• 
Collect urine samples for: 
-
Albumin 
-
Creatinine 
-
Albmnin/creatinine ratio 
-
Pregnancy test (for females of childbearing potential only) 
I 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs related to protocol mandated procedures occuning since the 
Screening visit 
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• 
Dispense study chugs and provide instruction on appropriate dosing and administr·ation; 
subject will take the Day 1 dose of study ch11gs on-site at the end of the visit, with or without 
food 
I 
I 
6.4. 
6.4.1. 
On-Treatment Assessments 
Week 1 Visit (± 3 days) 
Subjects should be instructed to fast (no food or ch·ink, except water), starting from 
midnight (00:00) or earlier, as appropriate, on the evening prior to the Week 1 visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning. 
The following assessments will be perfonned and documented at this visit: 
• 
Lifestyle questionnaire 
Note: It is recommended that the questionnaire be completed prior to any study procedures 
being perfo1med and prior to the subject seeing a health care provider. 
• 
Symptom ch·iven PE 
• 
Vital signs and body weight 
• 
Assess ascites and HE 
• 
Obtain blood samples for: 
-
Chemistry 
-
Hematology 
-
Coagulation 
Note: For subjects on digoxin at staii of study: obtain digoxin level prior to staiiing study 
chug and at the Week 1 Visit, with digoxin level checks during the study period per 
Investigator discretion. Monitor and adjust digoxin dose as necessaiy based on 
prescribing infonnation. 
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Final 
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• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs occmTing since the previous visit 
• 
Review of study chug dosing compliance (pill count) and provide instruction on appropriate 
dosing and achninish'ation 
I 
I 
6.4.2. 
Week 4, Week 12, and Week 36 Visits (±3 days) 
Subjects should be instructed to fast (no food or ch·ink, except water), sta1ting from 
midnight (00:00) or earlier, as appropriate, on the evening prior to the visit to ensme an 
approximate 8-hom fast prior to the blood sample collection the next morning. 
The following will be perfo1med and documented at this visit: 
I 
• 
Lifestyle questionnaire 
I 
Note: It is recommended that the questionnaires be completed prior to any study procedmes 
being perfo1med and prior to the subject seeing a health care provider. 
• 
Symptom ch·iven PE 
• 
Vital signs and body weight 
I 
• 
Assess ascites and HE 
• 
Provide lifestyle modification counseling 
• 
Obtain blood samples for: 
-
Chemistry 
-
Hematology 
-
Coagulation 
-
Insulin and lipids 
-
HbAlc 
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Collect urine samples for: 
-
Albumin (Weeks 12, 36) 
-
Creatinine (Weeks 12, 36) 
-
Albumin/creatinine ratio (Weeks 12, 36) 
-
Biomarkers (Weeks 12, 36) 
-
Pregnancy test (for females of childbearing potential only) 
Final 
Amendment4 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs occmTing since the previous visit 
• 
Review of study drng dosing compliance (pill count) 
• 
Dispense study drng and provide instrnction on appropriate dosing and administration 
I 
I 
6.4.3. 
Week 8, Week 16, Week 20, Week 28, Week 32, Week 40, and Week 44 Visits 
(±3 days) 
Subjects should be instructed to fast (no food or drink, except water), staiiing from midnight 
(00:00) or eai·lier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning. 
The following will be perfonned and documented at this visit: 
• 
Lifestyle questionnaire 
Note: It is recommended the questionnaire be completed prior to any study procedures being 
perfo1med and prior to the subject seeing a health care provider. 
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Gilead Sciences, Inc. 
• 
Vital signs and body weight 
• 
Symptom driven PE 
• 
Assess ascites and HE 
• 
Lifestyle modification counseling 
• 
Obtain blood samples for: 
-
Chemistiy 
-
Hematology 
-
Coagulation 
I 
I 
• 
Collect urine samples for: 
-
Pregnancy test (for females of childbearing potential only) 
Final 
Amendment4 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any SAEs and all AEs occuning since the previous visit 
• 
Review of study chug dosing compliance (pill count) 
• 
Dispense study chugs to the subject and provide instrnction on appropriate dosing and 
administi·ation 
I 
I 
6.4.4. 
Week 24 and Week 48 (±7 days) 
I 
• 
Lifestyle questionnaire 
I 
Note: It is recommended the questionnaires be completed prior to any study procedures being 
perfo1med and prior to the subject seeing a health care provider. 
• 
Vital signs and body weight 
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Complete PE 
• 
Hip and waist circumference 
• 
12-lead ECG (Week 48 only) 
• 
Assess ascites and HE 
• 
Lifestyle modification counseling 
• 
Obtain blood samples for: 
I 
-
Chemist:Iy 
-
Hematology 
-
Coagulation 
-
Insulin and lipids 
-
HbAlc 
I 
I 
I 
I 
• 
Collect urine samples for: 
-
Albumin 
-
Creatinine 
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I 
I 
-
Albumin/creatinine ratio 
-
Pregnancy test (for females of childbearing potential only) 
• 
Liver biopsy and provide liver tissue for central reading (Week 48 only) 
Final 
Amendment4 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs occmTing since the previous visit 
• 
Review of study drng dosing compliance (pill count) 
• 
Dispense study drng and provide instrnction on appropriate dosing and administration 
(Week 24 only) 
I 
I 
Note: Subjects should not exceed the allowed dosing period of 48 weeks (336 days). All 
effo1i should be made for the Week 48 visit to coincide with the subject's last dose of study 
diug. If it is not possible to schedule the Week 48 visit on Day 336 of dosing, detailed dosing 
instructions should be provided to subjects on the precise day to complete their dosing before 
or after their Week 48 visit. 
6.4.5. 
Early Termination (ET) Visit 
I 
• 
Lifestyle questionnaire 
I 
Note: It is recommended that the questionnaires be completed prior to any study procedmes 
being perfo1med and prior to the subject seeing a health care provider. 
• 
Complete PE 
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Vital signs and body weight 
I 
• 
12-lead ECG 
• 
Assess ascites and HE 
• 
Lifestyle modification counseling 
• 
Obtain blood samples for: 
-
Chemist:Iy 
-
Hematology 
-
Coagulation 
-
Insulin and lipids 
-
HbAlc 
-
ELFn1 Test 
• 
Collect urine samples for: 
-
Albumin 
-
Creatinine 
-
Albumin/creatinine ratio 
-
Pregnancy test (for females of childbearing potential only) 
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Final 
Amendment4 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs occmTing since the previous visit 
• 
Review of study drng dosing compliance (pill count) 
• 
At the discretion of the Investigator, perfonn the following assessments: 
I 
I 
-
Liver biopsy and provide liver tissue for central reading 
6.4.6. 
Unscheduled Visits 
Additional unscheduled assessments may be perfo1med at the discretion of the Investigator. 
At a minimum, the following will be perfonned and documented: 
• 
Symptom driven PE 
• 
Obtain blood samples for: 
-
Chemistiy 
-
Hematology 
-
eGFR 
• 
Record vital signs and body weight 
• 
Record all concomitant mediations that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occuning since the previous visit 
If the Unscheduled visit is perfonned for the sole pmpose of disti·ibution of study dmg, the 
assessments noted above do not need to be perfonned. 
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Amendment 4
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6.5.
Post-treatment Assessments
6.5.1.
Follow-Up Visit (±5 days)
Subjects will return for a Follow-Up visit four weeks after the date of last dose of study drug.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Follow-Up visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

Symptom driven PE

Vital signs and body weight

12-lead ECG

Obtain blood samples for:
Chemistry
Hematology
Coagulation 
Insulin and lipids
HbA1c 

Collect urine samples for:
Albumin 
Creatinine 
Albumin/creatinine ratio
Pregnancy test (for females of childbearing potential only)
CCI
CCI
CCI


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Final 
Amendment4 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record all SAEs and any AEs occmTing since the previous visit 
I 
6.6. 
Criteria for Discontinuation of Study Drug 
Study chugs must be discontinued in the following instances: 
• 
Subject progression to decompensated cnThosis, as defined by any of the following: 
-
Clinically apparent ascites requii·ing treatment 
-
HE of Grade 2 or above (according to the West Haven criteria as defined in Appendix 4) 
requii·ing treatment 
-
Portal hype1i ension-related upper gastrointestinal bleeding identified by endoscopy and 
requii·ing hospitalization, including events of bleeding from esophageal varices, gastric 
varices, and po1ial hype1iensive gastropathy 
I 
• 
Liver transplantation 
• 
Subject develops an SAE consisting of a serious hypersensitivity reaction to study chug 
• 
IntercmTent illness that would, in the judgment of the Investigator, affect assessments of 
clinical sta.tus to a significant degree. Following resolution of intercunent 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 procedmes 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 dming the study; refer to Appendix 3 
• 
Discontinuation of the study or treatment groups at the request of Gilead, a regulato1y 
agency, or an IRB/IEC/EC. 
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6.7. 
Interruption of Study Drug 
Final 
Amendment4 
If dosing is intenupted (ie, as a result of an AE), the subject must stop dosing of all three study 
diugs. Eve1y attempt should be made to keep the subject in the study and continue to perfo1m 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 withdi·awn from 
the study. 
6.8. 
Assessments for Premature Discontinuation from Study 
Subjects prematurely discontinuing from the study ( eg, as a result of an AE or a treatment group 
closure) should have an ET visit upon discontinuing, as well as a Follow-Up visit 4 weeks after 
the date of the last dose of study diugs (refer to Section 6.4.5 and 6.5.1). Discussion with the 
Medical Monitor is recommended. 
The subject will be considered off-study after the completion of these visits. 
If these visits are not possible or acceptable to the subject or Investigator, the subject may be 
withdi·awn from the study. 
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6.11. 
6.11.1. 
Description of Assessments 
Clinical Laboratory Analytes 
Final 
Amendment4 
Fasting is required prior to all study visits. Subjects should be instmcted to fast (no food or drink, 
except water), staiiing from midnight (00:00) or eai·lier, as appropriate, on the evening prior to 
the visit to ensure an approximate 8-hour fast prior to the blood sample collection the next 
morning. Please refer to the Covance Laborato1y Manual or the individual subject Covance 
laborato1y repo1i for gender and age specific reference ranges. 
Chemistiy: 
, bicai·bonate, blood urea niti·ogen (BUN), calcium, chloride, 
creatinin-
te dehydrogenase (LDH)~
esium, phosphoms, potassium, 
sodium,_
, total protein, uric acid,1111, eGFR as calculated by the 
Cockcroft-Gault equation, and creatine phosphokinase (CPK) 
Hematology: 
Hematocrit (Hct), hemoglobin (Hgb ), platelet count, red blood cell count (RBC), white blood 
cell count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neutl'ophils, eosinophils, basophils, and mean co1puscular volume (MCV) 
Coagulation Panel: 
INR, PT, and activated paiiial thromboplastin time (APTT) 
Additional Tests: 
HIV-1 antibody (reflex to HIV-1 RNA), HBV (HBsAg), HCVantibody (reflex to HCV RNA), 
semm pregnancy testing, FSH, eGFR as calculated by MDRD, homeostasis model assessment of 
insulin resistance (HOMA-IR, based on fasting glucose and insulin), C-peptide, lipid panel 
(cholesterol, high-density lipoprotein [HDL], LDL, ti·iglycerides, and other lipid tests), free fatty 
acids, digoxin testing, HbAlc (semm fmctosamine will be tested if HbAlc is unable to be 
resulted) 
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Urine Samples: 
Final 
Amendment4 
Urine will be collected for albumin, creatinine, albumin/creatinine ratio,~ 
(for amphetamines, cocaine, methadone, and opiates), pregnancy testin-
6.11.2. 
Physical Examination 
A complete PE should include source documentation of general appearance, and the following 
body systems: head, neck, and thyroid; eyes (including an ophthalmoscopic examination), ears, 
nose, throat, mouth, and tongue; chest ( excluding breasts); respirato1y ; cardiovascular; lymph 
nodes; abdomen; skin, hair, nails; musculoskeletal; neurological. 
The focus of a symptom driven PE will be determined by the Investigator based on subject 
complaint. For example, if a subject complains of a cough, a lung exam should be perfonned. If 
consistent with pneumonia (rales/crackles on exam) then an AE would be documented. 
All complete and symptom driven examinations should include assessments to detennine the 
presence of ascites and HE, and a pulmonaiy examination with questioning regarding pulmona1y 
symptoms. 
6.11.3. 
Vital Sign 
Assessment of vital signs will include measurement of resting blood pressure, pulse, respirato1y 
rate 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 aim suppo1i ed 
so that the midpoint of the manometer cuff is at heaii level; 
• 
Use a mercmy sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial a1ie1y; 
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Measure and record the blood pressure to the nearest 2 millimeter of mercmy (nnnHg) mark on 
the manometer or to the nearest whole number on an automatic device. 
6.11.4. 
Medical History 
Medical histo1y , including details regarding illnesses and allergies, date(s) of onset, whether a 
condition(s) is cmTently ongoing, and medication histo1y, will be collected on all subjects during 
Screening. 
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6.11.6.
Creatinine Clearance
Creatinine clearance will be calculated by the Central Laboratory, using the Cockcroft-Gault 
equation {Cockcroft 1976}.
Male:
CLcr (mL/min) = [140 −age (years)] BW(kg)
                                                        72 Scr
Female: CLcr (mL/min) = [140 −age (years)] BW(kg) 0.85
                                                        72 Scr
Scr = serum creatinine (mg/dL)
Actual body weight will be used for the CLcr.
CCI


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6.11.7. 
Pregnancy Testing 
Final 
Amendment4 
All females of childbearing potential will have a sernm pregnancy test at Screening; FSH may be 
tested to determine a female subject's postmenopausal state (refer to Appendix 3). All females of 
childbearing potential will have a urine pregnancy test at Day 1 (prior to dosing) and eve1y 
4 weeks thereafter. In the event of a positive pregnancy result, subjects will be instructed to stop 
study diugs immediately (if applicable) and complete a sernm pregnancy test. 
6.11.9. 
Health Related Quality of Life (HRQoL) 
It is recommended that these questionnaires be completed prior to the clinical and laborato1y 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself. 
6.11.9.1. 
Sho1t Fonn 36 Health Survey (SF-36) 
The SF-36 asks 36 questions to measure functional health and well-being from the subject's 
point of view. It consists of eight health domains: physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health. These health 
domain scales conti·ibute to the physical health and mental health summa1y measures. 
6.11.9.2. 
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. 
6.11.9.3. 
Work Productivity and Activity Impainnent (WPAI) 
The WPAI questionnaire asks questions regarding the effect of NASH on a person's ability to 
work and perfo1m regular activities. 
6.11.9.4. 
EuroQol Five Dimensions (EQ-5D) 
The EQ-5D questionnaire is a standard measure of health status developed by the EuroQol 
Group to provide a simple, generic measure of health for clinical and econoinical appraisal {The 
EuroQol Group 1990}. The EQ-5D is not disease specific and has been validated in numerous 
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/discomfo1t, 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 dimensions are combined into a 5-digit number to describe the subject's health state. The VAS 
records the subject's health on a 0-100 mm VAS scale, with 0 indicating "the worst health you 
can imagine" and 100 indicating "the best health you can imagine". 
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6.11.10. 
Pruritus Assessments 
Final 
Amendment4 
It is recommended that these questionnaires be completed prior to the clinical and laborato1y 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself. 
6.11.10.1. 
Visual Analogue Scale- Itch (VAS-itch) 
The VAS-itch is a tool for measuring the intensity of pmritus. 
6.11.10.2. 
5-D itch 
The 5-D itch is multidimensional measure of itching that allows changes in chronic prnritus to be 
detected over time. The questionnaire measures the degree, duration, direction, disability, and 
distribution of prnritus. 
6.11.11. 
Electrocardiogram 
Standard 12-lead ECG assessments will be perfo1med. The Investigator will review the ECGs for 
any clinically significant abno1malities to ensure subject safety. Abno1mal ECG findings that are 
considered clinically significant by the Investigator and meet the definition of an AE should be 
repo1i ed and recorded in the AE eCRF page. 
- ... 
-
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6.11.15. 
Liver Biopsy 
Final 
Amendment4 
All possible attempts should be made to acquire a liver biopsy specimen of at least 2.0 cm in 
length to ensure accurate staging of fibrosis and other histological lesions. It is recommended 
that a 16 gauge needle is used to collect the tissue sample. A historical biopsy within 6 months of 
the Screening visit (that is consistent with NASH and bridging fibrosis [F3]) or within 12 months 
of the Screening visit (that is consistent with NASH andcinhosis (F4) or cinhosis due to NASH 
with < 5% steatosis [F4, NAS steatosis grade = O]) may be accepted as the Screening biopsy. The 
liver biopsy sample must be deemed adequate for evaluation by the central reader for inclusion. 
Liver biopsies will be sent to a centrnl laborato1y and then read by a central reader. The central 
reader will read all Screening biopsies for eligibility. This assessment will include an assessment 
of the adequacy of the specimen as well as the fibrosis stage and a detennination that the biopsy 
is consistent with NASH or cinhosis due to NASH with < 5% steatosis. If liver biopsy results are 
deemed unevaluable by the central reader, a repeat biopsy may be perfo1m ed at the discretion of 
the Investigator. 
If a liver biopsy is peifonned per standard of care outside of protocol mandated assessments, all 
possible attempts should be made to submit the biopsy specimen to the central reader for 
evaluation. 
Please refer to the Site Operations Manual for additional infonnation. 
6.11.16. 
Lifestyle Modification Counseling 
Lifestyle modifications such as weight loss via diet and increased exercise can be effective in the 
treatment of NASH. At each study visit, all subjects will receive counseling regarding lifestyle 
modifications including the maintenance of a healthy diet and paiiicipation in regulai· exercise. 
6.11.17. 
Lifestyle Questionnaire 
This questionnaire will assess the quantity of alcohol intake, dieta1y patterns, and physical 
activity of subjects before staiiing study mu gs and between study visits. 
It is recommended that this questionnaire be completed prior to the clinical and laborato1y 
assessments. The subject should read the questionnaire by himself/herself and record the answers 
by himself/herself. 
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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 post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. 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 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that 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 were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
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; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 IMP 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 Section 7.2.2.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The Investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The Investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. 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.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
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.
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.
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 drugs, the following types of events 
should be reported on the eCRF: all SAEs and adverse events related to protocol-mandated 
procedures.
Adverse Events
Following initiation of study drug, until 30 days after last administration of study drugs, all AEs 
regardless of cause or relationship, must be collected and 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 may request that certain AEs be followed beyond the protocol defined follow-up 
period.


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Serious Adverse Events 
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All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
paiiicipate in the study (ie, signing the infonned consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead PVE as instmcted. This also includes any SAEs resulting from 
protocol-associated procedures perfonned after infonned consent is signed. 
Any SAEs and deaths that occur after the Follow-Up visit but within 30 days of the last dose of 
study diugs, regardless of causality, should also be repo1ied. 
Investigators ai·e 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 paiiicipation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and repo1i 
the event to Gilead PVE. 
Electronic Serious Adverse Event (eSAE) Repo1iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PVE within 24 hours of the Investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
fo1m and submit within 24 hours: 
Gilead Sciences PVE: 
Fax: 
Email: 
PD 
PD 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. If an SAE has 
been repo1ied via a paper f 01m because the eCRF database has been locked, no fmiher action 
1s necessa1y. 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, and other 
documents ai·e 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 tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1is. 
• 
Any medications necessaiy for tr·eatment 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. 
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Gilead Medical Monitor contact info1mation is as follows: 
Name:PPD 
Telephone: 
Mobile: 
Fax: 
Email: 
7.4. 
PD 
PPD 
PPD 
PPU 
Gilead Reporting Requirements 
Final 
Amendment4 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other countiy-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulato1y agencies reports of SAEs, serious adverse dmg reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulato1y 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
cmTent regulations. 
Assessment of expectedness for SAEs will be dete1mined by Gilead using reference safety 
info1mation specified in the IB or relevant local label as applicable. 
All Investigators will receive a safety letter notifying them of relevant SUSAR repo1is associated 
with any study IMP. The Investigator should notify the IRB or IEC of SU SAR repo1is as soon as 
is practical, where this is required by local regulato1y agencies, and in accordance with the local 
institutional policy. 
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7.5.2. 
Close Observation 
Close observation includes: 
I 
• 
Obtaining a more detailed histo1y of symptoms and prior or concmTent disease 
Final 
Amendment4 
• 
Obtaining a histo1y of concomitant diug use (including nonprescription medications and 
herbal and dietaiy supplement prepai·ations), alcohol use, recreational dmg use, and special 
diets 
• 
Obtaining a histo1y of exposme to environmental chemical agents 
• 
Ruling out other causes of liver disease as needed ( obtain viral hepatitis panel, imaging for 
evaluation of biliaiy 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 abno1malities stabilize or study mugs have been discontinued and the 
subject is asymptomatic 
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During a period of close observation for DILI, study diugs can be continued, if desired, at the 
discretion of both the Medical Monitor and Investigator. 
If study diu gs 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 abnonnal laborato1y values have 
resolved or returned to baseline levels or they are considered iITeversible, or until there is a 
satisfacto1y explanation for the changes observed. 
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Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laborato1y abno1malities should be confnmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days ofreceipt of the original test results. For AEs associated with 
laborato1y abno1malities, 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 laborato1y abnonnality. 
Any questions regarding toxicity management should be directed to the Medical Monitor. 
- -
7.5.4. 
Hypertriglyceridemia 
Although some randoinized subjects will have baseline dyslipideinia, some subjects may 
experience fmther elevations in their triglycerides. Figure 7-3 describes the recommended 
monitoring and intervention strategy for subjects that meet the criteria for on-treatment 
hype1triglycerideinia of Grade 3 or 4 (~ 500 mg/d.L). 
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Figure 7-3. 
Algorithm for Monitoring and Treatment of Hypertriglyceridemia 
-
7.6. 
7.6.1. 
Triglycerides Grade 3 or 4 
(~ 500 mgldL) 
Repeat fasting testing 
-
within 72 hours of -
receipt of results 
If repeat fasting testing 
If repeat fasting testing 
is .: 500 mg/dL 
Start fenofibrate 145 mg 
PO daily or equivalent if 
fenofibrate is not available 
If patient has a contraindication, cannot 
tolerate a fibrate, or a fibrate is not available, 
start Vascepa 2000 mg PO twice daily or 
equivalent if Vascepa is not available 
Repeat fasting testing 7 to 14 
days after initiation of treatment 
Special Situations Reports 
Definitions of Special Situations 
is < 500 mg/dL 
No treatment 
modifications 
Special situation repo1is include all repo1is of medication enor, abuse, misuse, overdose, repo1is 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
repo1is regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding. 
Medication enor is any unintentional enor in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
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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.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The Investigator should report pregnancies in female study subjects that are identified after 
initiation of study drugs and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the paper 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 
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 
Section 7.3. 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 or 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: 
PPD
PPD
PPD
PPD


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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 or 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.
7.6.2.2.
Reporting Other Special Situations
Site personnel must record all other special situations data in the eCRF database and from there 
transmit the special situations information to Gilead PVE within 24 hours of the Investigator’s 
knowledge of the event. Detailed instructions can be found in the eCRF completion guidelines.
All special situations data will be recorded in the eCRF database within the timelines outlined in 
the eCRF completion guideline.
If it is not possible to record and submit the special situations information electronically, because 
the eCRF database cannot be accessed or is not available (including at study start), record the 
information on the paper special situations report form and submit by e-mail or fax within 
24 hours of the investigator’s knowledge of the event to Gilead PVE. Gilead PVE contact 
information is as follows: Email: 
 and Fax: 
As soon as it is possible to do so, any special situations reported via paper must be transcribed 
into the eCRF database according to instructions in the eCRF completion guidelines. If any 
special situations have been reported via a paper form because the eCRF database has been 
locked, no further action is necessary.
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.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
Details will be provided in the statistical analysis plan (SAP). 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are: 
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• 
To assess the safety and tolerability of SEL, GS-097 6, and GS-967 4, administered alone or in 
combination, in subjects with bridging fibrosis or compensated cinhosis due to NASH 
• 
To evaluate changes in liver fibrosis, as measured by the NASH CRN classification, without 
worsening of NASH (defined as any increase in hepatocellular ballooning or lobular 
inflammation) 
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8.1.2. 
8.1.2.1. 
Endpoints 
Primary Endpoint 
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The prima1y endpoints are the safety and anti-fibrotic effects of SEL, GS-0976, and GS-9674, 
administered alone or in combination, in subjects with bridging fibrosis or compensated cinhosis 
due to NASH. Safety endpoints include AEs and laborato1y evaluations. 
Anti-fibrotic response will be evaluated by the propo1i ion of subjects at Week 48 who achieve a 
I-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH ( defined as a~ I-point increase in hepatocellular ballooning or lobular 
inflammation). 
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8.2. 
Analysis Conventions 
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All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfo1med using Statistical Analysis System (SAS®) software (SAS Institute, Caiy, 
No1th Carolina, USA). 
8.3. 
8.3.1. 
Analysis Sets 
Efficacy 
The prima1y analysis set for efficacy analyses will be the Full Analysis Set (FAS) which includes 
all subjects who were randomized into the study and received at least one dose of study diugs. 
Subjects who receive study diugs other than that to which they were randomized for the entire 
duration of treatment will be analyzed according to the treatment group to which they were 
randomized. 
8.3.2. 
Safety 
The prima1y analysis set for safety analyses will include all subjects who received at least 
one dose of study diugs. Subjects who received study diug other than that to which they were 
randomized for the entire duration of treatment will be analyzed according to the study diugs 
received. 
All data collected during treatment plus 30 days after last dose of study diugs will be included in 
the safety summaries. 
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8.3.2.2.
Biomarkers
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessary baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest.
8.4.
Interim Analysis
An administrative interim analysis will be performed after all randomized subjects have 
completed Week 24 assessments or prematurely discontinued the study.
8.5.
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 drugs, the subject will be included in 
a summary of AEs according to the treatment received; otherwise, if the subject is not dosed then 
they will be excluded from the summary. 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 summary 
statistics for that time point. If the subject is missing a pre-dose value, then the subject will be 
excluded from the calculation of summary statistics for the pre-dose value and the change from 
pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a Screening result, if available. If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a Screening result, if available.
Further details of data handling conventions and transformation will be provided in the SAP.
8.6.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, BMI, waist-to-hip ratio,
randomization stratification groups (presence or absence of diabetes, fibrosis stage F3 or F4),
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8. 7. 
Efficacy Analysis 
8.7.1. 
Primary Efficacy Endpoints Analysis 
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The point estimates and 95% confidence intervals for the propo1iion of subjects who achieve a 
:::: I-stage improvement in fibrosis without worsening of NASH at Week 48 will be calculated by 
treatment group. 
8.8. 
Safety Analysis 
All safety data collected on or after the date that study diugs were first dispensed up to the date 
of last dose of study di11gs plus 30 days will be summarized by treatment group. Data for the 
pretreatment and follow-up periods will be included in data listings. 
8.8.1. 
Extent of Exposure 
Data of a subject's extent of exposure to study diugs will be generated from the study di11gs 
adininistration eCRF data. Exposure data will be summarized by treatment group. 
8.8.2. 
Adverse Events 
Clinical and laborato1y AEs will be coded using the Medical Dictionaiy for Regulato1y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Te1m (HLGT), 
High-Level Te1m (HLT), Prefened Te1m (PT), and Lower-Level Te1m (LLT) will be attached to 
the clinical database. AE severity will be graded using the CTCAE. 
Events will be summarized on the basis of the date of onset for the event. A TEAE will be 
defined as one or both of the following: 
• 
Any AEs with an onset date on or after the study diugs staii date and no later than 30 days 
after pe1manent discontinuation of study diugs 
• 
Any AEs leading to premature discontinuation of study di11gs 
Summai·ies (number and percentage of subjects) ofTEAEs by SOC and PT will be provided by 
treatment group. Treatment-emergent AEs will also be summai·ized by relationship to study 
diugs and severity. In addition, TEAEs leading to premature discontinuation of study diu gs and 
study will be summarized and listed. 
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (Yes/No). 
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8.8.3. 
Laboratory Evaluations 
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Selected laborato1y data will be summarized (n, mean, SD, median, QI, Q3, minimum, and 
maximum) by treatment group and study visit along with the coITesponding change from 
baseline values. 
Graded laborato1y abnonnalities will be defined using the grading scheme in the CTCAE. 
Grading of laborato1y abnonnalities for analysis purposes will be defined in the Statistical 
Analysis Plan. 
The incidence of treatment-emergent laborato1y 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 dmgs plus 30 days, will be summarized by treatment group. If baseline data 
are missing, then any graded abnonnality (ie, at least a Grade I) will be considered 
treatment-emergent. 
• 
8.11. 
Sample Size 
Due to the explorato1y nature of this study, no fo1m al power calculations were used to dete1mine 
sample size. The number of subjects was chosen based on clinical experience with other similar 
proof of concept studies; however, with a sample size of approximately 70 subjects in each 
active combination treatment aim and approximately 3 5 in the placebo aim, the study has over 
80% power to detect a difference in the propo1iion of subjects with a~ I-stage improvement in 
fibrosis without worsening of NASH of25% or more at Week 48 at a significance level of 
0.05 (two-sided), assuming the proportion of subjects that meet the endpoint in the placebo ann 
is 7.2%. 
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8.12.
Data Monitoring Committee
An independent, external multidisciplinary data monitoring committee (DMC) that consists of at 
least two hepatologists and a statistician will review the progress of the study and perform 
interim reviews of safety data. The initial meeting of the DMC will occur after 35 subjects
(approximately 5 per treatment group) have completed their Week 4 assessments and will meet 
at a minimum interval of every 6 months thereafter. The DMC will provide recommendations to 
Gilead whether the nature, frequency, and severity of adverse effects associated with study 
treatment warrant the early termination of the study in the best interests of the participants, 
whether the study should continue as planned, or the study should continue with modifications. 
The DMC may also provide recommendations as needed regarding study design.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
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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 Harmonisation (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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval
The Investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, ICF, 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/IEC/EC. The Investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC has been documented and provided as a letter to the 
Investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
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 IRB/IEC/EC-approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC/EC
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only partial date of birth (as applicable in
certain countries), another unique identifier (as allowed by local law), and an identification code
will be recorded on any form or biological sample submitted to the Sponsor, IRB/IEC/EC, 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 
IB, this protocol, eCRFs, the IMP, 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.
9.1.5.
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/IEC/EC and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.
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, PE, and confirmation of 
diagnosis (to support inclusion and exclusion criteria)


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
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 drugs, including dates of dispensing and 
return

Record of all AEs 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.
9.1.6.
Electronic 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. eCRFs 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 


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eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the 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 captures 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 (eg, 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 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, study drugs should be destroyed at the site. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. 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 drugs are destroyed on site, the investigator must maintain accurate records for all study 
drugs 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. Refer to the Pharmacy Binder for study drug disposal/return instructions. The 
study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC/EC, or to regulatory authority or health authority 
inspectors.


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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 9.1.4).
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 (eg, 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 authorities, IRBs, IECs, and ECs. 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.
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Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy 
in chronic liver disease: 2014 Practice Guideline by the American Association for 


Selonsertib, GS-0976, GS-9674
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Gilead Sciences, Inc.
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the Study of Liver Diseases and the European Association for the Study of the 
Liver. Hepatology 2014;60 (2):715-35.
Voulgari C, Tentolouris N, Papadogiannis D, Moyssakis I, Perrea D, Kyriaki D, et al. Increased 
left ventricular arrhythmogenicity in metabolic syndrome and relationship with 
myocardial performance, risk factors for atherosclerosis, and low-grade 
inflammation. Metabolism: clinical and experimental 2010;59 (2):159-65.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of 
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely 
middle-aged population utilizing ultrasound and liver biopsy: a prospective study. 
Gastroenterology 2011;140 (1):124-31.
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.
Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of 
nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, 
incidence, and outcomes. Hepatology 2016;64 (1):73-84.
Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, et al. Activation of the nuclear 
receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc 
Natl Acad Sci U S A 2006;103 (4):1006-11.


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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.
West Haven Criteria


Selonsertib, GS-0976, GS-9674 
Protocol GS-US-454-4378 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment4 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and 
Efficacy of Selonsertib, GS-0976, GS-9674, and Combinations in Subjects with Bridging (F3) 
Fibrosis or Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis (NASH) 
GS-US-454-4378, Amendment 4, 25 April 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
tpPD 
PPD 
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 
CONFIDENTIAL 
Page 124 
25 April 2019 


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Appendix 2.
Study Procedures Table
Assessments
Screening
Day
1
On-Treatment Visits
ET
Follow-Up
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 48
Clinical Assessments
Written Informed 
Consent
X
Determine 
Eligibility
X
X
Medical History
X
Physical 
Examination
Xa
X
X
X
X
X
X
X
Xa
X
X
X
X
X
Xa
Xa
X
Vital Signs 
including Body 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
Assess Ascites 
and HE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abdominal 
Ultrasound
Xb
X
X
X
Liver Biopsy 
Xe
X
Xd
 
 
 
 
CCI
CCI
CCI
CCI


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Assessments
Screening
Day
1
On-Treatment Visits
ET
Follow-Up
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 48
Lifestyle 
Questionnaire 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle 
Modification 
Counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study 
Drugs
X
X
X
X
X
X
X
X
X
X
X
X
Review of Study 
Drug Dosing 
Compliance (Pill 
Count)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, 
Hematology, 
Coagulation
X
Xj
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids 
X
X
X
X
X
X
X
X
X
HbA1c
Xk
X
X
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, 
HCV Serology
X
CCI
CCI


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Assessments
Screening
Day
1
On-Treatment Visits
ET
Follow-Up
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 48
Pregnancy 
Testingn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug Screen
X
Urine Collection 
(albumin, 
creatinine, 
albumin/creatinine 
ratio)
X
X
X
X
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Selonsertib, GS-0976, GS-9674 
Protocol GS-US-454-4378 
Gilead Sciences, Inc. 
a 
Complete PE 
b 
Historical ultrasound within 3 months inclusive to the date of Screening ma 
r 
d 
e r 
t 
I 
J 
k 
' 
n 
' 
CONFIDENTIAL 
On-Treatment Visits 
Page 128 
Final 
Amendment4 
25 April 2019 


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Gilead Sciences, Inc.
Amendment 4
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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 of 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
SEL is contraindicated in pregnancy as a malformation effect is suspected, based on non-clinical 
data. In rats and rabbits, SEL administration was associated with effects on embryo-fetal 
development at maternally toxic doses. This included total litter loss, increased resorptions and 
post implantation loss, reduced fetal weights, and visceral and skeletal malformations and 
variations. Embryofetal effects were observed in rats and rabbits at exposures (AUC24hr) that 
were 62- and 12-fold higher, respectively, than the projected SEL exposure at the proposed 
human dose of 18 mg/day. The NOELs for embryofetal development in rats and rabbits were 
15 and 10 mg/kg/day, respectively. The SEL exposure margins at these doses as compared to the 
maximum proposed human dose are 12- and 3-fold, respectively.
Preclinical data indicate that SEL is unlikely to reduce the exposure of hormonal contraceptives 
through induction of human drug metabolizing enzymes or drug transporters. This is supported 
by clinical DDI data, which demonstrated multiple doses of SEL did not result in exposure 
changes of a representative oral hormonal contraceptive, indicating no loss of contraceptive 
efficacy is expected upon administration of SEL with hormonal contraceptives.


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No formal studies have been conducted to evaluate the reproductive toxicity of GS-0976; 
therefore, the reproductive toxicity of GS-0976 in humans is unknown. However, mutant mice 
lacking ACC1, one of the targets of GS-0976, are embryonically lethal. Therefore, GS-0976 is 
contraindicated in pregnancy.
Preclinical data in human hepatocytes indicate that GS-0976 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 GS-0976 with hormonal contraceptives. Please refer to Section 1.3.3.1 and the 
latest version of the Investigator’s Brochure for additional information.
GS-9674 has not yet been studied in pregnant women. In 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 the 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 GS-9674. The NOEL for embryo/fetal 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 between GS-9674 and hormones used for 
contraception. 
Please refer to the latest version of the Investigator’s Brochure for additional information.
b) 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. Pregnancy tests will be 
performed at monthly intervals thereafter. Female subjects must agree to one of the following 
from Screening until 90 days 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


Selonsertib, GS-0976, GS-9674
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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)
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 90 days after the last dose of study drug.
3) 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 90 days 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 90 days 
after the last dose of study drug.
4) 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.


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Amendment 4
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5) 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 90 days 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 pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.6.2.1.


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Amendment 4
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Appendix 4.
West Haven Criteria
http://www.mdcalc.com/hepatic-encephalopathy-grades-stages/
Grade of Hepatic 
Encephalopathy
Description
Suggested Operative Criteria
Grade I
Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction
Altered sleep rhythm
Despite oriented in time and space 
(see below), the patient appears to have some 
cognitive/ behavioral decay with respect to his 
or her standard on clinical examination or to 
the caregivers
Grade II
Lethargy or apathy
Disorientation for time
Obvious personality change
Inappropriate behavior
Dyspraxia
Asterixis
Disoriented for time (at least 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: 
Study Title: 
Name of Test Drug: 
Study Number: 
(rJ GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety and Efficacy of Selonse1iib 
(GS-4997), GS-0976, GS-9674, and Combinations in 
Subjects with Bridging (F3) Fibrosis or Compensated 
Cinhosis (F4) due to Nonalcoholic Steatohepatitis (NASH) 
Selonse1iib (SEL, GS-4997), GS-0976 and GS-9674 
GS-US-454-4378 
Protocol Version (Date): 
Original: 
08 Januaiy 2018 
31 Januaiy 2018 
22 Febrnaiy 2018 
10 May2018 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
25 April 2019 
Analysis Type: 
Interim and Final 
Analysis Plan Version: 
1.0 
Analysis Plan Date: 
22 May 2019 
Analysis Plan Author(s): 
IPIPD 
IPIPD 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


SEL, GS-0976, GS-9674 
GS-US-454-4378 
Statistical Analysis Plan - Interim and Final Analyses 
Version 1.0 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................................................. 1 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF TABLES ......................................................................................................................................................... 4 
LIST OF FIGURES ....................................................................................................................................................... 4 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
PHARMACOKINETIC ABBREVIATIONS ................................................................................................................ 7 
1. 
INTRODUCTION ................................................................................................................................................ 8 
1. 1. 
Study Objectives ...................................................................................................................................... 8 
1.2. 
Study Design ............................................................................................................................................ 9 
1. 2. 1. 
Study Treatments .................................................................................................................. 10 
1.2.2. 
Duration of Study ................................................................................................................. 11 
1.2.3. 
End of Study ......................................................................................................................... 11 
1.2.4. 
Post Study Care .................................................................................................................... 11 
1.3. 
Sample Size and Power .......................................................................................................................... 11 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 12 
2. 1. 
Interi1n Analyses .................................................................................................................................... 12 
2.1. 1. 
DMC Interim Analyses ........................................................................................................ 12 
2.1.2. 
Week 24 Analysis ................................................................................................................. 12 
2.2. 
Final Analysis ........................................................................................................................................ 12 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 13 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
3.8. 
Analysis Sets .......................................................................................................................................... 13 
3.1. 1. 
All Randomized Analysis Set ............................................................................................... 13 
3.1.2. 
Full Analysis Set .................................................................................................................. 13 
3.1.3. 
Safe Anal sis Set. .............................................................................................................. 13 
Subject Grouping ................................................................................................................................... 14 
Strata and Covariates .............................................................................................................................. 14 
Examination of Subject Subgroups ........................................................................................................ 14 
Multiple Co1nparisons ............................................................................................................................ 15 
Missing Data and Outliers ...................................................................................................................... 15 
3.6.1. 
Missing Data ........................................................................................................................ 15 
3.6.2. 
Outliers ................................................................................................................................. 15 
Data Handling Conventions and Transfo1mations ................................................................................. 15 
Analysis Visit Windows ......................................................................................................................... 17 
3.8.1. 
Definition of Study Day ....................................................................................................... 17 
3.8.2. 
Analysis Visit Windows ....................................................................................................... 17 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 20 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 22 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 22 
4.2. 
Extent of Study Thug Exposw-e and Adherence ..................................................................................... 23 
4.2.1. 
Duration of Exposw·e to Study D1ug .................................................................................... 23 
4.2.2. 
Adherence to Study D1ug ..................................................................................................... 23 
4.3. 
Protocol Deviations ................................................................................................................................ 24 
CONFIDENTIAL 
Page2 
22 May 2019 


SEL, GS-0976, GS-9674 
GS-US-454-4378 
Statistical Analysis Plan - Interim and Final Analyses 
Version 1.0 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 25 
5. 1. 
Demographics ........................................................................................................................................ 25 
5.2. 
Baseline Characteristics ......................................................................................................................... 25 
5.3. 
Medical Histo1y ...................................................................................................................................... 27 
6. 
EFFICACY ANALYSES ................................................................................................................................... 28 
6.1. 
6.3. 
Change From Protocol-Specified Efficacy Analyses ............................................................................. 35 
7. 
SAFETY ANALYSES ........................................................................................................................................ 36 
7. 1. 
Adverse Events and Deaths .................................................................................................................... 36 
7.1. 1. 
Adverse Event Dictiona1y .................................................................................................... 36 
7.1.2. 
Adverse Event Severity ........................................................................................................ 36 
7.1.3. 
Relationship of Adverse Events to Study Drng .................................................................... 36 
7.1.4. 
Serious Adverse Events ........................................................................................................ 36 
7.1.5. 
Treatinent-Emergent Adverse Events ................................................................................... 36 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 37 
7.1.7. 
Additional Analysis of Adverse Events ............................................................................... 38 
7 .2. 
Laborato1y Evaluations .......................................................................................................................... 38 
7.2.1. 
Summaries ofNumeric Laborat01y Results ......................................................................... 39 
7.2.2. 
Graded Laborato1y Values ................................................................................................... 39 
7.2.3. 
Liver-related Laborato1y Evaluations ................................................................................... 41 
7.3. 
Vital Signs .............................................................................................................................................. 42 
7.4. 
Prior and Concoinitant Medications ....................................................................................................... 42 
7.4.1. 
Prior Medications ................................................................................................................. 42 
7.4.2. 
Concoinitant Medications ..................................................................................................... 43 
7.5. 
Electrocardiogram Results ..................................................................................................................... 43 
7 .5. 1. 
Investigator Electi·ocardiogram Assessment ........................................................................ 43 
7.6. 
Other Safety Measures ........................................................................................................................... 44 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 44 
I 
9. 
REFERENCES ................................................................................................................................................... 48 
10. SOFTWARE ....................................................................................................................................................... 49 
11. SAP REVISION .................................................................................................................................................. 50 
12. APPENDICES .................................................................................................................................................... 51 
Appendix 1. 
Schedule of Assessments ........................................................................................................ 52 
... 
CTCAE Grade for Laborato1 Para1neters ............................................................................. 56 
CONFIDENTIAL 
Page3 
22 May 2019 


SEL, GS-0976, GS-9674 
GS-US-454-4378 
Statistical Analysis Plan - Interim and Final Analyses 
Version 1.0 
LIST OF TABLES 
Table 3-1. -
Anal sis Visit Windows for Chemistiy, Hematology, Coagulation,_ 
, Glucose, Vital Si s, and Bod Wei ht ..................................................................... 18 
--
Table 3-5. 
LIST OF FIGURES 
Figure 1-1. 
Overall Study Design ............................................................................................................. 10 
CONFIDENTIAL 
Page4 
22 May 2019 


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Statistical Analysis Plan – Interim and Final Analyses
Version 1.0
CONFIDENTIAL
Page 5
22 May 2019
LIST OF ABBREVIATIONS
AE
adverse event
ANCOVA
analysis of covariance
APRI
AST to platelet ratio index
α-SMA
α-smooth muscle actin
BLQ
below the limit of quantitation
BMI
body mass index
CAP
controlled attenuation parameter
CI
confidence interval
CLDQ
chronic liver disease questionnaire
CK-18
cytokeratin-18
CMH
Cochran-Mantel-Haenszel
 
CRP
C-reactive protein
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FIB-4
fibrosis-4
FU
Follow-up
Hgb
hemoglobin
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HLT
high-level term
HOMA-IR
homeostasis model assessment of insulin resistance
ID 
identification
IFG 
impaired fasting glucose
LDL
low density lipoprotein
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI• -• 
-
-• --
-
• 


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Statistical Analysis Plan – Interim and Final Analyses
Version 1.0
CONFIDENTIAL
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LLT
lower-level term
LOQ
limit of quantitation
MedDRA
medical dictionary for regulatory activities
MELD
model for end-stage liver disease
MH
Mantel-Haenszel
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD activity score
NASH
nonalcoholic steatohepatitis
PIIINP
procollagen III N-terminal propeptide
PT
preferred term
PTM
placebo-to-match
QoL
quality of life
Q1, Q3
first quartile, third quartile
SAF
steatosis, activity and fibrosis
SAP
statistical analysis plan
SD
standard deviation
SEL 
selonsertib
SF-36
Short Form (36) Health Survey
SI (units)
international system of units
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TIMP1
tissue inhibitor of metalloproteinase 1
VLDL
very low density lipoprotein
ULN
upper limit of normal
WBC
white blood cell count
WHO
World Health Organization
WPAI
work productivity and activity impairment questionnaire
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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 2 
by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve


SEL, GS-0976, GS-9674 
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L 
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 (TFLs) in the administrative interim 
analysis at Week 24 and the final analysis and clinical study repo1i (CSR) at Week 48 for 
Study GS-US-454-4378. This SAP is based on the study protocol Amendment 4 dated 
25 April 2019 and the electronic case repo1i f01m (eCRF). The SAP will be finalized before 
interim analysis database finalization. Any changes made after the finalization of the SAP will be 
documented in the CSR. 
1.1. 
Study Objectives 
The prima1y objectives of this study are as follows: 
• 
To assess the safety and tolerability of selonse1iib (SEL, GS-4997), GS-0976, and GS-9674, 
administered alone or in combination, in subjects with bridging fibrosis or compensated 
cinhosis due to NASH 
• 
To evaluate changes in liver fibrosis, as measured by the NASH Clinical Research Network 
(CRN) classification, without worsening of NASH (defined as any increase in hepatocellular 
ballooning or lobular inflammation) 
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1.2. 
Study Design 
Version 1.0 
This is a Phase 2, randomized, double-blind, placebo-contrnlled study evaluating the safety and 
efficacy of SEL, GS-0976, GS-9674, and combinations in subjects with bridging fibrosis or 
compensated cinhosis due to NASH. 
The overall study design is presented graphically in Figure 1-1. The complete schedule of 
assessments can be found in Appendix 1. 
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Figure 1-1. 
Overall Study Design 
8Week.s 
48 Weeks 
A: SEL 18 mg+ GS-0976 20 mg + PTM GS-9674 30 mg {N N 70) 
8: SEL 18 mg + PTM GS-0976 20 mg+ GS-9674 30 mg (N N 70) 
C 
C: SEL 18 mg+ PTM GS-0976 20 mg+ PTM GS-9674 30 mg (N N 3S) 
011 
0 
.!: 
i 
C 
N 
QI 
... ·e 
0 
u 
,, 
Ill 
C 
0 : PTM SEL 18 mg + GS-097620 mg + PTM GS-967430 mg (N N 35) 
E: PTM SEL 18 mg + PTM GS-0976 20 mg + GS-9674 30 mg (N N 3S) 
F: PTM SEL 18 mg+ PTM GS-0976 20 mg+ PTM GS-9674 30 mg (N N 3S) 
G: PTM SEL 18 mg+ GS-097620 mg+ GS-9674 30 mg (N N 70) 
1.2.1. 
Study Treatments 
Version 1.0 
Subjects meeting the study's entiy criteria will be assigned randomly in a 2:2: 1: 1: 1: 1 :2 ratio to 
1 of 7 ti·eatment groups (Group A, Group B, Group C, Group D, Group E, Group F, or Group G), 
with approximately 70 subjects in each combination u-eatment group and approximately 
35 subjects in each single agent or placebo group, as shown in Figure 1-1. Randomization will be 
sti·atified by the presence or absence of diabetes mellitus, as detennined by medical histo1y or 
based on the screening lab values if previously undiagnosed (hemoglobin Ale [HbAlc] :::: 6.5% 
or fasting plasma glucose :::: 126 mg/d.L) and by the presence or absence of cinhosis (F4) as 
detennined by the centi·al biopsy reader at screening. 
Study mugs will be adininistered for a total of 48 weeks from the Day 1 visit. Dosage and 
adininisti·ation of the study di11gs and reference products are described in the protocol. 
Because Study GS-US-384-1943 and GS-US-384-1944 demonsti·ated lack of efficacy and are 
discontinued after the Week 48 futerim Analysis, subjects from the SEL monotherapy ti·eatment 
group (A) will be unblinded and discontinued from the study. 
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1.2.2.
Duration of Study
Participation can last up to 60 weeks, which includes an 8-week Screening period, a 48-week 
On-Treatment period, and a 4-week Follow-Up period.
1.2.3.
End of Study
End of study is considered to be completion of the Follow-Up visit.
1.2.4.
Post Study Care
There is no offered post study care.
1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. The number of subjects was chosen based on clinical experience with other similar 
proof-of-concept studies; however, with a sample size of approximately 70 subjects in each 
active combination treatment arm and approximately 35 subjects in the placebo arm, the study 
has over 80% power to detect a difference in the proportion of subjects with a ≥1-stage 
improvement in fibrosis without worsening of NASH of 25% or more at Week 48 at a 
significance level of 0.05 (two-sided), assuming the proportion of subjects that meet the endpoint 
in the placebo arm is 7.2%.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
DMC Interim Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will
recommend to the sponsor if 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 35 subjects (approximately 5 per treatment group) have 
completed assessments through Week 4. Additional meetings will be scheduled approximately 
every 6 months.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, or discontinuation of select treatment group, Gilead retains final 
decision-making authority on all aspects of the study.
2.1.2.
Week 24 Analysis
An administrative interim analysis will be performed after all randomized subjects have 
completed Week 24 assessments or prematurely discontinued the study.
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the study blind will be 
broken and the final analysis of the data will be performed.


SEL, GS-0976, GS-9674 
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Statistical Analysis Plan - Interim and Final Analyses 
Version 1.0 
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 catego1y will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quaiiile (Ql), 
third quaiiile (Q3), minimum, and maximum will be presented. 
All statistical tests will be 2-sided and perfo1med at the 5% significance level unless othe1w ise 
specified. 
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
so1ied by subject ID number, visit date, and time (if applicable). Data. collected on log fo1ms, 
such as AEs, will be presented in chronological order within the subject. The treatment group to 
which subjects were randomized will be used in the listings. Age, sex at bnih, race, and ethnicity 
will be included in the listings, as space pe1mits. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and then· definitions 
are provided in this section. Subjects included in each analysis set will be detennined before the 
study blind is broken for analysis. The analysis set will be identified and included as a subtitle of 
each table, figure, and listing. 
A listing of reasons for exclusion from analysis sets will be provided by subject. 
3.1.1. 
All Randomized Analysis Set 
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 subjects who took at least 1 dose of study dmg and 
were randomized into the study. This is the primaiy 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 diug. This is the 
prima1y analysis set for safety analyses. 
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3.2. 
Subject Grouping 
Version 1.0 
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 the actual treatment received. The actual ti·eatment received will differ from the 
randomized ti·eatment only when their actual ti·eatment differs from randomized ti·eatment for the 
entire u-eatment duration. 
For the PK Analysis Set, subjects will be grouped according to the actual ti·eatment they 
received. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to ti·eatment groups via the interactive voice or web response 
system (IXRS) using a sti·atified randomization schedule. Sti·atification will be based on the 
following variables: 
• 
Presence or absence of diabetes mellitus as detennined by medical histo1y or based on the 
screening laborato1y values if previously undiagnosed (HbAl c:::: 6.5% or fasting plasma 
glucose:::: 126 mg/dL) 
• 
Presence or absence of cinhosis (F4 vs. Non-F4) as detennined by the centi·al biopsy reader 
at screening 
If there are discrepancies in sti·atification factor values between the IXRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. 
Efficacy endpoints will be evaluated using the presence or absence of diabetes mellitus at 
baseline, and the presence or absence of cinhosis at baseline, as sti·atification factors for 
analyses, as specified in Section 6. 
For efficacy endpoints, the baseline value of the efficacy variable(s) will be included as a 
covariate in the efficacy analysis model, as appropriate. 
3.4. 
Examination of Subject Subgroups 
Subgrouping of subjects based on the randomization sti·atification factors of presence or absence 
of diabetes mellitus and cinhosis at baseline will be explored for subgroup analyses. 
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The primary efficacy endpoint(s) will be examined using the following subgroups:

Subjects with diabetes mellitus at baseline;

Subjects without diabetes mellitus at baseline;

Subjects with cirrhosis (F4) at baseline;

Subjects without cirrhosis (Non-F4) at baseline;
For the comparison of treatment difference between 2 treatment groups in each subgroup, only 
the point estimate and 95% confidence interval (CI) will be presented.
3.5.
Multiple Comparisons
All efficacy endpoints are exploratory in nature and may be tested using 2-sided tests at the 5% 
significance level without multiplicity adjustment.
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. Exceptions are presented in this document.
For missing last dosing 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 7.1.5.2, and for
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, 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


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Statistical Analysis Plan - Interim and Final Analyses 
Version 1.0 
In general, age (in years) on the date of the first dose of study drng will be used for analyses and 
presentation in listings. If age at Day 1 is not available for a subject, then age derived based on 
date of bi1i h and the Day 1 visit date will be used instead. If an emolled subject was not dosed 
with any study diug, the randomization date will be used instead of the first dosing date of study 
diug. For screen failures, the date the info1med consent was signed will be used for age 
calculation. 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 bi1i h and the 
date of the measurement or event, unless othe1wise 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 repo1ied in the fo1m of"< x" (where xis 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 summaiy statistics. An exception to this rnle is any value repo1ied as < 1 or < 0.1, 
etc. For values repo1ied as < 1 or < 0.1, a value of0.9 or 0.09, respectively, will be used to 
calculate summaiy statistics. 
• 
A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is repo1ied in the fo1m of"> x" (where xis 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 repo1ied in the fonn of 
":'.S x" or "::::: x" (where xis considered the LOQ). 
Natural logai·ithm transfo1mation will be used for plasma/blood concentrations and analysis of 
PK pai·ameters. Plasma concentration values that ai·e below the limit of quantitation (BLQ) will 
be presented as "BLQ" in the concentration data listing. Values that ai·e BLQ will be treated as 
0 at predose time points, and one-half the value of the LOQ at postbaseline time points. 
The following conventions will be used for the presentation of summaiy and order statistics: 
• If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as "BLQ." 
• If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and QI values will be displayed as "BLQ." 
• If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, QI, and median values will be displayed as "BLQ." 
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• If more than 7 5% of the subjects have a concentrntion data value of BLQ for a given time 
point, the minimum, Ql , median, and Q3 values will be displayed as "BLQ." 
• If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Ql , median, Q3, and maximum) will be displayed as "BLQ." 
3.8. 
3.8.1. 
Analysis Visit Windows 
Definition of Study Day 
Study day will be calculated from the first dosing date of study chug and derived as follows: 
• 
For postdose study days: Assessment Date - First Dosing Date+ 1 
• 
For predose study days: Assessment Date - First Dosing Date 
Therefore, Study Day 1 is the day of first dose of study ch11g administration. 
3.8.2. 
Analysis Visit Windows 
Subject visits might not occur on protocol-specified days. Therefore, for the pmpose of analysis, 
observations will be assigned to analysis windows. 
Selected safety and efficacy data, unless othe1wise specified, collected up to and including the 
last dosing date + 30 days, will be mapped according to the following analysis windows unless 
the nominal visit name is Follow-Up (FU). 
The analysis windows for select measures are provided in Table 3-1 to Table 3-5. 
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Table 3-1.
Analysis Visit Windows for Chemistry, Hematology, Coagulation, 
 
, Glucose, Vital Signs, and Body Weight
Nominal Visit
Nominal Study 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
182
Week 28
197
183
210
Week 32
225
211
238
Week 36
253
239
266
Week 40
281
267
294
Week 44
309
295
322
Week 48
337
323
≥337
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Table 3-5.
Analysis Visit Windows for Biopsy Data and electrocardiogram 
(ECG)
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 48
337
2
≥337
Data relating to unscheduled visits and early termination (ET) visits may be assigned to a
particular visit or time point based on the visit windows. The following conventions will be 
followed:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

Data collected on a follow-up visit (including ET FU visit) will be summarized as a separate 
visit, and labeled “Follow-up Visit”
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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. 
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rnles if a single value is needed: 
• 
For baseline, the last nonmissing value on or prior to the first dosing date of study drng 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, nonnal 
will be selected over abnonnal for safety ECG findings) for categorical data. 
• 
Baseline values for liver tests (ALT, AST, total bilirnbin, and direct bilirnbin) will be 
determined by averaging the values obtained between and including Screening and Day 1. 
I 
• 
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 
othe1wise specified. 
• 
For sennn creatinine, if both enzymatic and regular creatinine are collected from the same 
blood sample and are analyzable, regular creatinine will be chosen for analysis. 
Postbaseline histology endpoints will be selected in each visit window according to the following 
rnles: 
• 
Histology endpoints will be derived based on parameters collected from one biopsy sampling 
date if all parameters needed are available. 
• 
When multiple values of an endpoint are derived from biopsy samples obtained on different 
dates in one visit window, the value closest to the nominal day will be chosen for analysis. 
When two values are equidistant from the nominal day, the later value will be selected. 
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
When an endpoint cannot be derived due to missing parameter(s) from one biopsy sampling 
date, histology parameters from different biopsy sampling dates in that visit window will be 
used to derive the endpoint. Nonmissing value of each individual parameter closest to the 
nominal day for that visit window will be selected. When two records are equidistant from 
the nominal day, the later record will be selected. 

When an endpoint cannot be derived based on all biopsy samples in a visit window, the 
histology endpoint will be considered missing.
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each country and
investigator within a country, and overall. The summary will present the number and percentage 
of subjects enrolled. 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 by randomization stratum. The denominator for the 
percentage of subjects in the stratum will be the total number of enrolled 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. This summary will 
present the number of subjects screened, the number of subjects randomized, and the number of 
subjects in each of the categories listed below:

Safety Analysis Set 

Full Analysis Set

Pharmacokinetic Analysis Set (final analysis only)

Continuing study drug (Week 24 analysis only)

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Continuing study (Week 24 analysis only)

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 bottle ID
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
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1 and divided by 7, regardless of any temporary interruptions in study drug 
administration, and will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the 
last study drug dosing 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 analyses or the last available 
date in the database snapshot for subjects who were still on treatment at the time of an interim 
analysis..
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: 1 day, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 
36 weeks and 48 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
The total number of tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability eCRF using the following formula:
Total Number of Tablets Administered =
 No. of Tablets Dispensed − No. of Tablets Returned
When calculating total number of tablets administered according to the formula above, for
subjects in the active drug monotherapy and combination therapy groups, number of tablets of 
the active drugs will be included, and the placebo-to-match (PTM) tablets are not counted; all 
tablets will be counted when calculating total number of tablets administered for subjects in the 
placebo group.


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The level of on-treatment adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered during a subject’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






For each subject, the total number of days on treatment is calculated as the last dosing date minus 
first dosing date plus 1. For subjects in the placebo group, total number of study drug expected to 
be administered will be equal to the number of days on treatment multiplied by 3. For subjects on 
SEL/GS-0976/GS-9674 monotherapy groups, total number of study drug expected to be 
administered will be the same as number of days on treatment. For subjects on combinations, 
total number of study drug expected to be administered will be the number of days on treatment 
multiplies by 2.
At interim analyses, if the subject is ongoing, the number of tablets administered and expected to 
be administered on treatment will be calculated based on study drug accountability data.
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75%, ≥ 75 to < 90%, ≥ 90%) will be provided 
by treatment group for the Safety Analysis Set. No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately 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 enrolled 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) will be summarized by treatment 
group and overall using descriptive statistics for age, and using number and percentage of 
subjects for sex, race, and ethnicity. 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.
Baseline Characteristics
Baseline characteristics include:

Body weight (in kg),

Height (in cm),

Body mass index (BMI; in kg/m2), 

BMI category (< 18 kg/m2 [if applicable], 18 to < 25 kg/m2, 25 to < 30 kg/m2, and 
≥30 kg/m2),

Diabetes mellitus (absence or presence),

HOMA-IR,

HbA1c (%),
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
Platelets (103 /uL),

AST to platelet ratio index (APRI),

Fibrosis-4 (FIB-4),

Ishak fibrosis stage,

NASH CRN fibrosis stage,

Cirrhosis status (cirrhotic or non-cirrhotic),

Hepatic collagen content (%),

α-smooth muscle actin (α-SMA) (%)
 
 
 

Lobular inflammation grade,

Hepatocellular ballooning grade,
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Emolled based on non-invasive criteria, 
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Smoking Status. 
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These baseline characteristics will be summarized by ti·eatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summaiy of baseline characteristics will be provided for the Safety 
Analysis Set. No fonnal statistical testing is planned. 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order. 
5.3. 
Medical History 
General medical histo1y data will be collected at screening. General medical histo1y data will be 
coded using the cunent version of medical dictionaiy for regulato1y activities (MedDRA). 
System organ class (SOC), high-level group te1m (HLGT), high-level te1m (HLT), prefened 
tenn (PT), and lower-level te1m (LLT) will be provided in the medical histo1y dataset. 
General medical histo1y data will be listed. 
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6.
EFFICACY ANALYSES
All efficacy analyses are exploratory.
6.1.
Histology Response Efficacy Endpoints
6.1.1.
Definition of Histology Response Efficacy Endpoints
The histology efficacy endpoints include:
1) The proportion of subjects who achieve a ≥1-stage improvement in fibrosis (according to the 
NASH CRN classification) without worsening of NASH (defined as a ≥ 1-point increase in 
hepatocellular ballooning or lobular inflammation) at Week 48;
2) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis (according to the NASH 
CRN classification) at Week 48; 
3) Proportion of subjects who have NASH resolution (defined as lobular inflammation of 0 or 1 
from at least 1 at baseline and hepatocellular ballooning reduced to 0 from at least 1 at 
baseline; both criteria are necessary conditions) without worsening of fibrosis at Week 48;
4) Proportion of subjects with bridging fibrosis (F3) or less at baseline who progress to cirrhosis 
(F4) at Week 48;
5) Proportion of subjects with at least 1-point improvement in NAS elements, and those with at 
least 2-point improvement in NAS at Week 48.
6.1.2.
Analysis of Histology Response Efficacy Endpoint
The 95% CI for proportion of subjects who met the endpoint in each treatment group based on 
the Clopper-Pearson method will be calculated. 
A stratified Mantel-Haenszel (MH) test will be used to compare the differences in proportions of 
subjects who met the endpoint between each active arm (SEL, GS-0976, GS-9674, SEL + 
GS-0976, SEL + GS-9674, GS-0976 + GS-9674) and placebo, adjusting for presence or absence 
of cirrhosis and diabetes mellitus at baseline. The p-value and 95% CI of the difference in 
proportions between each active arm and placebo will be constructed based on stratum-adjusted 
MH proportions as follows {Koch 1989}:
pA – pB Z(1-α/2 )* SE(pA – pB),
where 

(pA – pB) = 

h
h
h
w
d
w
, is the stratum-adjusted MH proportion difference, where 
h
d
=
Bh
Ah
p
p

is the difference in the proportion of subjects who met the endpoint between 
SEL (GS-0976, GS-9674, SEL + GS-0976, SEL + GS-9674, GS-0976 + GS-9674) and 
placebo in stratum h.


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
h
w =
Bh
Ah
Bh
Ah
n
n
n
n

, is the weight based on the harmonic mean of sample size per treatment group 
for each stratum where 
Ah
n
and 
Bh
n are the sample sizes of SEL (GS-0976, GS-9674, SEL + 
GS-0976, SEL + GS-9674, GS-0976 + GS-9674) and placebo in stratum h.

SE( –  ) = 
2
*
*
*
*
)
(
1
)
1(
1
)
1(











h
Bh
Bh
Bh
Ah
Ah
Ah
w
n
p
p
n
p
p
w
, where 

1
5.0
*



Ah
Ah
Ah
n
m
p
and 
1
5.0
*



Bh
Bh
Bh
n
m
p
, and 

 ! and  ! are the number of subjects who met the endpoint in SEL (GS-0976, GS-9674, 
SEL + GS-0976, SEL + GS-9674, GS-0976 + GS-9674) and placebo in stratum h.

α = 0.05 for the calculation of 95% CI 

Z(1-α/2 ) = Z0.975 is the 97.5th percentile of the normal distribution

Z score = 
(#$%#&)
()(*$+*&)
If the computed lower confidence bound is less than –1, the lower bound is defined as –1. If the 
computed upper confidence bound is greater than 1, then the upper bound is defined as 1. 
The point estimates, 95% CIs, and corresponding p-values based on Z test for the differences in 
proportions between each active arm and placebo will be calculated. Additionally, point 
estimates, 95% CIs, and p-values for the difference in proportions between combination groups 
and the mono treatment groups forming the combination will be also calculated.
Subjects missing data regarding fibrosis stage or NAS elements used to define worsening of 
NASH (hepatocellular ballooning and lobular inflammation) at Week 48 will be excluded from 
the analysis. For NASH resolution, subjects with baseline lobular inflammation and 
hepatocellular ballooning grades of 1 or above, and who had change in fibrosis available 
(for baseline non-F4 subjects) or who had baseline fibrosis stage of F4 are included. For the 
analysis of subjects progressed to cirrhosis, only subjects with non-F4 CRN fibrosis stage at 
baseline are to be included. 
Forest plots of the treatment differences in proportion of subjects who met each histology 
endpoint will be generated for the subgroup analyses as described in Section 3.4
6.1.3.
Sensitivity Analysis of Histology Response Efficacy Endpoints
The histology response efficacy endpoints defined in Section 6.1.1 will also be analyzed on the 
FAS Analysis Set excluding subjects from sites with major compliance issues, as sensitivity 
analysis.
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6.3. 
Change From Protocol-Specified Efficacy Analyses 
Version 1.0 
A few subjects were emolled into the study with baseline fibrosis stage FO - F2. In the 
description of subgroups, and the planned analyses for F3 subjects, "F3" subjects were replaced 
by "non-F4" subjects, to include the FO - F2 subjects together with the F3 subjects. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. The AE dataset will provide SOC, HLGT, HLT, PT, and LLT.
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) criteria 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 eCRF 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.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
and Epidemiology Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
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.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent 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 dosing date of 
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 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 dosing date of study drug, will be considered to be treatment emergent. 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 dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and treatment group:

TEAEs by severity grade

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher

All TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

TE Treatment-related AEs of Grade 2 or higher

All TE treatment-related AEs by severity grade

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to death (ie, outcome of death)

All TEAEs leading to temporary dose interruption of study drug


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A brief, high-level sunnna1y of AEs described above will be provided by ti·eatment group and by 
the number and percentage of subjects who experienced the above AEs. All deaths observed in 
the study will also be included in this sUilllnaiy. 
Multiple events will be counted only once per subject in each sUilllnaiy. Adverse events will be 
smnmai·ized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For smnmaries by 
severity grade, the most severe grade will be used for those AEs that occmTed more than once in 
an individual subject during the study. 
In addition to the above sUilllnaiy tables, all TEAEs, TE SAEs and TE ti·eatment-related AEs, TE 
ti·eatment-related SAEs will be smnmai·ized by PT only, in descending order of total frequency. 
In addition, data listings will be provided for the following: 
• 
All AEs, indicating whether the event is u-eatment emergent 
• 
All AEs of Grade 3 or higher 
• 
SAEs 
• 
Deaths 
• 
AEs leading to premature discontinuation of study diug 
• 
AEs leading to temporaiy dose intenuption of study di11g 
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I 
7.2. 
Laboratory Evaluations 
Laborato1y data. collected during the study will be analyzed and smnmarized using both 
quantitative and qualitative methods. Smnmai·ies of laborato1y data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study di11g plus 30 days 
for subjects who have pennanently discontinued study di11g, or all available data at the time of 
the database snapshot for subjects who were ongoing at the time of an interim analysis. The 
analysis will be based on values repo1ied 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 pmpose of 
calculating summaiy statistics as specified in Section 3. 7. 
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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 urinalysis 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
Descriptive statistics will be provided by treatment group for creatinine, creatinine clearance 
(Cockroft-Gault), white blood cells (WBC), neutrophils, lymphocytes, hemoglobin, platelets, and 
free fatty acid 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 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
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 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. 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 treatment 
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Treatment-emergent laboratory abnormalities are defined as values within the reference range at 
baseline, but which become lower or higher than the reference range 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. If 
the relevant baseline laboratory value is missing, any postbaseline laboratory value that is lower 
or higher than the reference range will be considered treatment emergent.
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. If the relevant baseline laboratory value is missing, any Grade 3 or 4
values observed within the timeframe specified above will be considered treatment-emergent 
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.
The following summaries (number and percentage of subjects) for treatment-emergent 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 dosing date.
A by-subject listing of treatment-emergent 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.


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7.2.3.
Liver-related Laboratory Evaluations
Subjects will be grouped according to their baseline ALT/AST level; ≤upper limit of reference 
range (ULN) or > ULN, respectively. Liver-related abnormalities after initial study drug dosing 
will be examined and summarized using the number and percentage of subjects who were 
reported to have the following laboratory test values for postbaseline measurements:
For subjects with ALT/AST ≤ULN

Subjects meeting criteria for close observation
o
ALT/AST > 3 ULN

Subjects meeting criteria for study drug withheld
o
ALT/AST > 8 × ULN
o
ALT/AST > 5 × ULN for 2 weeks
o
ALT/AST > 3 × ULN and total bilirubin > 2 × ULN
o
ALT/AST > 3 × ULN and direct bilirubin > 2 × Baseline (in subjects with 
Gilbert’s syndrome)
o
ALT/AST > 3 × ULN and INR > 1.5 (if not on anticoagulation)
For subjects with ALT/AST > ULN

Subjects meeting criteria for close observation
o
ALT/AST > 2 Baseline
o
ALT/AST > 300 U/L

Subjects meeting criteria for study drug withheld
o
ALT/AST > 8 × Baseline 
o
ALT/AST > 500 U/L
o
ALT/AST > 3 × Baseline and total bilirubin > 2 × ULN 
o
ALT/AST > 3 × Baseline and direct bilirubin > 2 x Baseline (in subjects with 
Gilbert’s syndrome)
o
ALT/AST > 300 U/L, and total bilirubin > 2 × ULN 
o
ALT/AST > 300 U/L, and direct bilirubin > 2 x Baseline (in subjects with 
Gilbert’s syndrome)
o
ALT/AST > 3 × Baseline and INR > 1.5 (if not on anticoagulation)
o
ALT/AST > 300 U/L and INR > 1.5 (if not on anticoagulation)


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The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total or direct 
bilirubin, 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 nonmissing 
postbaseline values 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.
7.3.
Vital Signs
Descriptive statistics will be provided by treatment group for vital signs (Systolic Blood Pressure 
[mmHg], Diastolic Blood Pressure [mmHg], Respiratory Rate [breaths/min], Pulse Rate 
[beats/min], Temperature [°C]) 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 study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. 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, 
will be 
provided separately.
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 medications 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.
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For the purposes of analysis, any medication with a start date prior to the first dosing date of 
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 unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are 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 medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the 
last dosing date of study drug will also be considered concomitant. Medications with a stop date 
prior to the date of first dosing date of study drug or a start date after the last dosing date of 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 postbaseline 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. 


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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.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes From Protocol-Specified Safety Analyses
In addition to the protocol-specified analyses as described in Section 7.1 through 7.6, select 
safety endpoints will be analyzed in the Safety Analysis Set excluding subjects from sites with 
major compliance issues.


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9.
REFERENCES
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J 
Dermatol 2010;162 (3):587-93.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21. 


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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Appendix 1. 
APPENDICES 
Schedule of Assessments 
CTCAE Grade for Laborato1 
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Appendix 1.
Schedule of Assessments
Assessments
Screening
Day 
1
On-Treatment Visits
ET
Follow-Up
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Clinical Assessments
Written Informed 
Consent
X
Determine 
Eligibility
X
X
Medical History
X
Physical 
Examination
Xa
X
X
X
X
X
X
X
Xa
X
X
X
X
X
Xa
Xa
X
Vital Signs 
including Body 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
Assess Ascites 
and HE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abdominal 
Ultrasound
Xb
X
X
X
Liver Biopsy 
Xe
X
Xd
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Assessments
Screening
Day 
1
On-Treatment Visits
ET
Follow-Up
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Lifestyle 
Questionnaire 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle 
Modification 
Counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study 
Drugs
X
X
X
X
X
X
X
X
X
X
X
X
Review of Study 
Drug Dosing 
Compliance (Pill 
Count)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, 
Hematology, 
Coagulation
X
Xj
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids 
X
X
X
X
X
X
X
X
X
HbA1c
Xk
X
X
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, 
HCV Serology
X
Pregnancy 
Testingn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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UrineDmg 
Screen 
Urine Collection 
(albumin, 
creatinine, 
albumin/creatinine 
ratio) 
a 
Complete PE 
X 
X 
X 
b 
Historical ultrasound within 3 months inclusive to the date of Screening ma 
r 
X 
X 
X 
I 
e 
6 months of the Screening for F3 and within 12 months of the Screening for F4) may be accepted as the Screening biopsy 
r 
g 
upon con umation of subject's eligibility; may be completed up to 7 days before or 3 days after Day 1 
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Appendix 2.
CTCAE 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
-
-
Blood bicarbonate 
decreased
<LLN and no intervention 
initiated
-
-
-
-
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
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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
-
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
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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
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


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SAP GS-US-454-4378 v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
23-May-2019
20:26:08
Clinical Research eSigned 28-May-2019
17:56:44
PPD
PPD--