Clinical trial NCT02781584
Conditions: Nonalcoholic Steatohepatitis (NASH) Nonalcoholic Fatty Liver Disease (NAFLD)
Sponsor: Gilead Sciences
Start date: 2016-06-13; Completion date: 2020-12-17
Enrollment: 220 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of selonsertib, firsocostat, cilofexor, fenofibrate and/or Vascepa® in adults with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

Detailed description:

Arms: arm 1: Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks. arm 2: Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks. arm 3: Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks. arm 4: Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks. arm 5: Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks. arm 6: Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks. arm 7: Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks. arm 8: Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks. arm 9: Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks. arm 10: Participants will receive fenofibrate (FENO) 48 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 48 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. arm 11: Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 145 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. arm 12: Participants will receive Vascepa® (VAS) 2 g capsule orally twice daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + VAS 2 g capsule twice daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. arm 13: Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + FENO 145 mg tablet orally once daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.
Interventions: intervention 1: SEL intervention 2: FIR intervention 3: CILO intervention 4: FENO intervention 5: VAS
Intervention descriptions: intervention 1: Administered orally once daily intervention 2: Administered orally once daily intervention 3: Administered orally once daily intervention 4: Administered orally once daily intervention 5: Administered orally two times daily

Protocol documents:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Regimens in Subjects with 
Nonalcoholic Steatohepatitis (NASH)
Name of Test Drug:
Selonsertib (SEL, GS-4997); GS-0976; GS-9674
Study Number:
GS-US-384-3914
Protocol Version (Date):
Amendment 11: 26 September 2018
Analysis Type:
Interim and Final Analysis, Cohorts 10-11
Analysis Plan Version:
1.0
Analysis Plan Date:
22 August 2019
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(fJ GILEAU 


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Statistical Analysis Plan - Cohorts 10-11 
Version 1.0 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF T ABLES ......................................................................................................................................................... 4 
LIST OF ABBREVIA TIONS ........................................................................................................................................ 5 
PHARMACOKJNETIC ABBREVIATIONS ................................................................................................................ 7 
I. 
INTRODUCTION ................................................................................................................................................ 8 
1.1. 
Study Objectives ...................................................................................................................................... 8 
1.2. 
Study Design ............................................................................................................................................ 9 
1.3. 
Sample Size and Power .......................................................................................................................... I 0 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 11 
2.1. 
Interim Analyses .................................................................................................................................... 11 
2.1.1. 
DMC Interim Analysis ......................................................................................................... 11 
2.1.2. 
Week 12 Interim Analysis .................................................................................................... 11 
2.2. 
Final Analysis ........................................................................................................................................ 11 
3. 
GENERAL CONSIDERATIONS FOR DAT A ANALYSES ............................................................................ 12 
3.1. 
Study Phases .......................................................................................................................................... 12 
3. I. I. 
Pre-treatment Phase .............................................................................................................. 12 
3.1.2. 
Treatment Phase ................................................................................................................... 12 
3.1.3. 
EntireStudy .......................................................................................................................... 12 
3.2. 
Analysis Sets .......................................................................................................................................... 12 
3.2.1. 
All Randomized Analysis Set ............................................................................................... 13 
3.2.2. 
Full Analysis Set .................................................................................................................. 13 
3.2.3. 
Safe 
Anal sis Set ............................................................................................................... 13 
3 .2.6. 
Pre-treatment Safety Analysis Set ........................................................................................ 13 
3.3. 
Subject Grouping ................................................................................................................................... 13 
3.4. 
Strata and Covariates .............................................................................................................................. 14 
3.5. 
Examination of Subject Subgroups ........................................................................................................ 14 
3.6. 
Multiple Comparisons ............................................................................................................................ 14 
3.7. 
Missing Data and Outliers ...................................................................................................................... 15 
3.7.1. 
Missing Data ........................................................................................................................ 15 
3.7.2. 
Outliers ................................................................................................................................. 15 
3.8. 
Data Handling Conventions and Transformations ................................................................................. 15 
3.9. 
Analysis Visit Windows ......................................................................................................................... 17 
3 .9. I. 
Definition of Study Day ....................................................................................................... 17 
3.9.1.1. 
Study Day in Pre-treatment Phase .................................................................. 17 
3.9.1.2. 
Study Day in Treatment Phase ........................................................................ 17 
3 .9 .2. 
Analysis Visit Windows ....................................................................................................... 17 
3 .9 .2.1. 
Analysis Windows for Pre-treatment Phase .................................................... 18 
3.9.2.2. 
Analysis Visit Window for Treatment Phase .................................................. 18 
3.9.2.3. 
Analysis Windows for Entire Study ............................................................... 19 
3.9.3. 
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 Dtug Exposure and Adherence ..................................................................................... 23 
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4.2.1. 
Duration of Exposure to Study Dtug .................................................................................... 23 
4.2.2. 
Adherence to Study Drug ..................................................................................................... 24 
4.3. 
Protocol Deviations ................................................................................................................................ 24 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 26 
5.1. 
Demographics ........................................................................................................................................ 26 
5.2. 
Other Baseline Characteristics ............................................................................................................... 26 
5.3. 
Medical History ...................................................................................................................................... 28 
I 
7. 
SAFETY ANALYSES ........................................................................................................................................ 34 
7.1. 
Adverse Events and Deaths .................................................................................................................... 34 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 34 
7.1.2. 
Adverse Event Severity ........................................................................................................ 34 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 34 
7 .1.4. 
Serious Adverse Events ........................................................................................................ 34 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 34 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 34 
7.1.5.2. 
Incomplete Dates ............................................................................................ 35 
7 .1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 36 
7 .1.6.1. 
Summaries of Adverse Events and Deaths in The Treatment 
Phase ............................................................................................................... 36 
7.1.6.2. 
Summaries of Adverse Events and Deaths in The Pre-
Treatment Phase .............................................................................................. 37 
7.1.6.3. 
Summaries of Adverse Events and Deaths in The Entire 
Study ............................................................................................................... 38 
7 .2. 
Laboratory Evaluations .......................................................................................................................... 38 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 39 
7 .2.1.1. 
Summaries of Numeric Laboratory Results in the Treatment 
Phase ............................................................................................................... 39 
7 .2.1.2. 
Summaries of Numeric Laboratory Results in the Pre-
Treatment Phase and in the Entire Study ........................................................ 39 
7.2.2. 
Graded Laboratory Values ................................................................................................... 40 
7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 40 
7.2.2.2. 
Treatment-Emergent Marked Laboratory Abnormalities ............................... 41 
7 .2.2.3. 
Summaries of Laboratory Abnormalities ........................................................ 41 
7 .2.3. 
Liver-related Laboratory Evaluations ................................................................................... 42 
7 .2.4. 
Additional Summary of Laboratoty Value ........................................................................... 43 
7.3. 
Yitai Signs .............................................................................................................................................. 44 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 44 
7.4.1. 
Prior Medications ................................................................................................................. 44 
7.4.2. 
Concomitant Medications ..................................................................................................... 45 
7.5. 
Electrocardiogram Results ..................................................................................................................... 46 
7 .5.1. 
Investigator Electrocardiogram Assessment ........................................................................ 46 
7.6. 
Other Safety Measures ........................................................................................................................... 46 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 46 
I 
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I 
9. 
REFERENCES ................................................................................................................................................... 50 
10. SOFTWARE ....................................................................................................................................................... 51 
11 . SAP REVISION .................................................................................................................................................. 52 
12. APPENDICES .................................................................................................................................................... 53 
Appendix I. 
Appendix 2. 
Appendix 3. 
Appendix 4. 
Appendix 5. 
Table 3-1. 
Table 3-2. 
Table 3-3. 
Table 3-4. -
CONFIDENTIAL 
Schedule of Assessment for GS-US-384-3914 Cohorts IO and 11 ........................................ 54 
CTCT AE Grade for Laboratory Parameters ........................................................................... 58 
Noninvasive markers for Fibrosis ........................................................................................... 61 
Liver Function Prognostic Scores ........................................................................................... 63 
Health Related Quality of Life Score Calculation .................................................................. 64 
LIST OF TABLES 
~~e;;;l~t::n~:::,siliiii:i~dv;~~te ~!~o::i!~~.~~~·~·i·~·~~_' .. 
................ 18 
Treatment Phase Anal sis Visit Windows for Yitai Signs, 
tty 
Glucose 
cids, 
T to Platelet Ratio Index 
(APRJ), Fibrosis-4 (FIB-4), Non-alcoholic Fatty Liver Disease (NAFLD) Fibrosis 
Score (NFS), and Apolipoprotein A I ..................................................................................... 19 
. 
. . 
. 
ows for MRI-POFF, MRE, 
rocollagen LIi Amino Terminal 
etallop 
· se l[TIMP-1 , 
. 
lob· 
nd 
oglobin A I c, Cytokeratin 18 
(CK- 18) .................................................................................................................................. 19 
E · 
is Visit Rename for Chemistiy, Hematology, Coagulation Labs, 
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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APRI
AST to platelet ratio
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CLDQ
chronic liver disease questionnaire
CK
creatine kinase
CK-18
cytokeratin-18
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
FAS
Full Analysis Set
FIB-4
fibrosis-4
FU
follow-up
GGT
gamma-glutamyl transferase
HA
hyaluronic acid
HDL
high density lipoprotein
HDL-C
HDL-cholesterol
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IFG
impaired fasting glucose
INR
international normalization ratio
LDL-C
low density lipoprotein cholesterol
LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
CCI
CCI
CCI
-
• 
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MRE
magnetic resonance elastography
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
non-alcoholic fatty liver disease
NFS
NAFLD fibrosis score
PIIINP
procollagen III amino terminal peptide
PT
preferred term
Q1, Q3
first quartile, third quartile
SAP
statistical analysis plan
SD
standard deviation
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
TIMP-1
tissue inhibitor of metalloproteinase
ULN
upper limit of normal
VLDL-C
very low density lipoprotein cholesterol
WHO
World Health Organization
CCI


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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


GS-0976 
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Statistical Analysis Plan - Cohorts 10-11 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the administrative Week 12 
interim analysis and the final analysis and clinical study report (CSR) for Study 
GS-US-384-3914, Cohorts 10 and 11. This SAP is based on study protocol amendment 11 dated 
26 September 2018 and the electronic case report fonn ( eCRF). This SAP is for the analyses of 
Cohorts 10 and 11, and includes Cohorts 10 and 11 data only. Any changes made after the 
finalization of the SAP will be documented in the CSR. 
1.1. 
Study Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study drug(s) in subjects with NASH as assessed by 
magnetic resonance imaging - proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE). 
I 
I 
I 
I 
I 
I 
I 
I 
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1.2.
Study Design
This is a proof of concept, open-label study evaluating the safety, tolerability, and efficacy of 
monotherapy and combination regimens in subjects with NASH as assessed by MRI-PDFF and 
MRE.
For Cohorts 1 through 9, eligible subjects will be enrolled to receive treatment with selonsertib 
(SEL; GS-4997), GS-0976, GS-9674; the combination of SEL and GS-9674, SEL and GS-0976, 
GS-9674 and GS-0976; or SEL, GS-0976 and GS-9674 for 12 weeks. Data from Cohorts 1 
through 9 will not be analyzed in the scope of this SAP. For the design and analysis of Cohorts 1 
through 9, please refer to the SAP developed for Cohorts 1 to 9, dated 01 August 2018.
For Cohorts 10 and 11, eligible subjects will be randomized to receive pre-treatment with 
fenofibrate 48 mg or fenofibrate 145 mg from Day -14 to Day -1 and will be treated with 
GS-0976 20 mg and fenofibrate 48 mg or GS-0976 20 mg and fenofibrate 145 mg for 24 weeks 
as shown in the figure below. The data collected will be analyze separately by study phases as 
defined in Section 3.1, or for the entire study.
Approximately 30 subjects will be randomized (1:1) into either Cohort 10 or 11; randomization 
will be stratified by (1) Screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥250 mg/dL and < 500 mg/dL]), and (2) Fibrosis Stage (F3 defined by liver biopsy or 
Screening MRE with liver stiffness < 4.67 kPa, or F4 defined by liver biopsy or Screening MRE 
with liver stiffness ≥ 4.67 kPa). Approximately 60% of subjects in each Cohort should have 
cirrhosis (F4) based on Inclusion Criteria 5. Approximately 60% subjects in each cohort should 
have screening serum triglycerides ≥150 mg/dL and < 250 mg/dL as below:

Cohort 10 (GS-0976 20 mg + Fenofibrate 48 mg) will consist of 15 subjects:
Approximately 9 subjects with Screening serum triglycerides ≥ 150 mg/dL and
< 250 mg/dL
Approximately 6 subjects with Screening serum triglycerides ≥ 250 mg/dL and
< 500 mg/dL
"" 
C 
·1: 
a, 
"' 
t:; 
"' 
C 
_Q 
CohortlO 
In= 15) 
Cohortll 
In= 15) 
Pre- Treatment 
Fenofibrate 
48 m POQD 
Pre- Treatment 
Fenofibrate 
145 m PO D 
2 Weeks IDay-14 through Day-1) 
Treatment24 weeks 
GS-0976 20 mg+ Fenofibrate48 mg PO QD 
Treatment24 weeks 
GS-0976 20 mg+ Fenofibrate 145 mg PO QD 
24 Weeks I Day 1th rough Week 24) 


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
Cohort 11 (GS-0976 20 mg + Fenofibrate 145 mg) will consist of 15 subjects:
Approximately 9 subjects with Screening serum triglycerides ≥ 150 mg/dL and 
< 250 mg/dL
Approximately 6 subjects with Screening serum triglycerides ≥ 250 mg/dL and 
< 500 mg/dL
1.3.
Sample Size and Power
In Cohorts 10 and 11, it was assumed that among subjects with baseline hypertriglyceridemia 
≥150 mg/dL (60% with serum triglycerides ≥ 150 and < 250 mg/dL and 40% with serum 
triglycerides ≥ 250 and < 500 mg/dL), Grade 3 to 4 hypertriglyceridemia (> 500 mg/dL) would 
be observed in 28% of subjects following treatment with GS-0976. Assuming that the co-
administration of fenofibrate and GS-0976 will reduce the incidence of Grade 3 to 4 
hypertriglyceridemia to < 5%, a sample size of 15 subjects in each of Cohorts 10 and 11 will 
provide 82% power to detect the reduction based on a one-sided exact test at a significance level 
of 0.05.


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2.
TYPE OF PLANNED ANALYSIS
This SAP is for the analyses of Cohorts 10 and 11 and includes Cohorts 10 and 11 data only. The 
interim analyses and final analyses discussed in this section are the interim analyses and final 
analyses of Cohorts 10 and 11, and will not involve Cohorts 1 to 9.
2.1.
Interim Analyses
2.1.1.
DMC Interim Analysis
There will be no formal DMC review for Cohorts 10 and 11. Therefore, no analyses will be 
conducted for the DMC.
2.1.2.
Week 12 Interim Analysis
A Week 12 interim analysis will be conducted for administrative purposes after all subjects in 
Cohorts 10 and 11 complete Week 12 assessments or early discontinue study treatment. All 
safety and efficacy data from Cohorts 10 and 11 collected up to the time of interim analysis will 
be presented.
2.2.
Final Analysis
After all subjects in Cohorts 10 and 11 have completed the study, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the
final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable). Data collected on log forms, 
such as AEs, will be presented in chronological order within the subject. The treatment group to 
which subjects were randomized will be used in the listings. Age, sex at birth, race, and ethnicity 
will be included in the listings, as space permits.
3.1.
Study Phases
Study phases are defined according to the study drug(s) which subjects take during the study.
3.1.1.
Pre-treatment Phase
Pre-treatment Phase is the phase when subjects were only taking fenofibrate study drug. It starts 
from the date of first dose of fenofibrate to the date before the first dose of GS-0976.
3.1.2.
Treatment Phase
Treatment Phase is the phase when subjects were taking both GS-0976 and fenofibrate study 
drugs and through the follow-up visit. It starts from the date of first dose of GS-0976 to the end 
of study.
3.1.3.
Entire Study
Entire Study is the combination of the Pre-treatment Phase and the Treatment Phase.
3.2.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects included will be summarized by 
treatment group. The denominator will be the number of subjects randomized in the 
corresponding treatment group. Subjects who have been randomized but never dosed will also be 
summarized. A listing of reasons for exclusion from analysis sets will be provided by subject.


GS-0976 
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Statistical Analysis Plan - Cohorts 10-11 
3.2.1. 
All Randomized Analysis Set 
Version 1.0 
All Randomized Analysis Set includes all subjects who were randomized into cohort 10 or 1 lof 
this study. 
3.2.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were randomized into cohort 10 or 11 and 
took at least 1 dose of GS-0976. 
This is the primary analysis set for efficacy analyses. 
3.2.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who took at least 1 dose of GS-0976. 
This is the primary analysis set for safety analyses. 
-
-
3.2.6. 
Pre-treatment Safety Analysis Set 
The Pre-treatment Safety Analysis Set includes all subjects who received at least 1 dose of 
fenofibrate in the Pre-treatment Phase. 
This is the analysis set for Pre-treatment Phase safety analysis. 
3.3. 
Subject Grouping 
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were randon~
es based on the Safety Analysis Set, Pre-treatment Safety 
Analysis Set and _
, subjects will be grouped according to the actual treatment 
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received. The actual treatment received will differ from the randomized treatment only when 
their actual treatment differs from randomized treatment for the entire treatment duration.
For safety analysis of the Pre-treatment Phase, subjects in the Pre-treatment Safety Analysis Set 
will be analyzed and will be grouped into the following:
1) Fenofibrate 48 mg PO QD
2) Fenofibrate 145 mg PO QD
For analysis of the Treatment Phase or the Entire Study, subjects in the Safety Analysis Set and 
 will be analyzed and will be grouped into the following:
3) GS-0976 20 mg + Fenofibrate 48 mg PO QD
4) GS-0976 20 mg + Fenofibrate 145 mg PO QD
3.4.
Strata and Covariates
Subjects will be randomly assigned to treatment groups in a 1:1 ratio using a stratified 
randomization schedule. Stratification will be based on the following variables:

Screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or [≥ 250 mg/dL and < 
500 mg/dL])

Fibrosis stage ([F3 defined by liver biopsy or screening MRE with liver stiffness < 4.67 kPa] 
or [F4 defined by liver biopsy or screening MRE with liver stiffness ≥ 4.67 kPa])
3.5.
Examination of Subject Subgroups
Subgrouping of subjects based on fibrosis stage at randomization and Pre-treatment baseline of 
Triglycerides will be explored for subgroup analyses. Selected efficacy endpoints as defined in 
Section 6.2.3 will be summarized by treatment group and further by the following subgroups
within each treatment group.

Pre-treatment baseline triglyceride level ([ < 250 mg/dL] or [≥ 250 mg/dL])

Fibrosis stage (F3 or F4)
3.6.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
CCI


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3.7.
Missing Data and Outliers
3.7.1.
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.
3.7.2.
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.
3.8.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
In general, age collected at Day 1 (in years) which is the date of first dose of study drug GS-0976
will be used for analyses and presented in listings. If age at Day 1 is not available for a subject, 
then age derived based on the date of birth and the Day 1 visit date will be used instead. If an 
enrolled subject was not dosed with GS-0976, the randomization  date will be used instead of the 
Day 1 visit date. For screen failures, the date the first informed consent was signed will be used 
for the age derivation. Age required for longitudinal and temporal calculations and analyses (eg, 
estimates of creatinine clearance, age at date of AE) will be based on age derived from date of 
birth and the date of the measurement or event, unless otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the lower LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “x” (where x is considered the lower LOQ). For 
example, if the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will 
be used to calculate summary statistics. An exception to this rule is any value reported as < 1
or < 0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be 
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A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the fonn of"> x" (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above. 
• 
The LOQ will be used to calculate descriptive statistics if the datum is reported in the fonn of 
":S x" or"~ x" (where x is considered the LOQ). 
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3.9.
Analysis Visit Windows
3.9.1.
Definition of Study Day
3.9.1.1.
Study Day in Pre-treatment Phase
Pre-treatment study day will be calculated from the first dosing date of fenofibrate and derived as 
follows:

For postdose study days: Assessment Date First Dosing Date of Fenofibrate + 1

For days prior to the first dose: Assessment Date First Dosing Date of Fenofibrate
Therefore, pre-treatment study day 1 is the day of first dose of fenofibrate administration.
3.9.1.2.
Study Day in Treatment Phase
Study day will be calculated from the first dosing date of GS-0976 and derived as follows:

For postdose study days: Assessment Date First Dosing Date of GS-0976 + 1

For days prior to the first dose: Assessment Date First Dosing Date of GS-0976
Therefore, study day 1 is the day of first dose of GS-0976 administration.
3.9.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
For the Treatment Phase, in general, the baseline value is defined as the last available value 
collected on or prior to the first dosing date of GS-0976. Baseline values for liver tests (ALT, 
AST, total bilirubin and direct bilirubin) will be determined by averaging the values obtained 
between and including Screening and Study Day 1. Selected safety and efficacy data collected up 
to and including the last dosing date plus 30 days will be mapped according to the analysis 
windows specified Section 3.9.2.2 unless the nominal visit name is Follow-Up (FU). Quality of 
life (QoL) assessments will use nominal baseline values.
For the Pre-treatment Phase and the Entire Study, the baseline value is defined as the last 
available value collected on or prior to the first dosing date of fenofibrate. Only selected safety
analysis will be conducted for the Pre-treatment Phase and for the Entire Study. Selected safety 
lab data collected up to and including the first dosing date of GS-0976 will be mapped according 
to the analysis window specified in Section 3.9.2.1 and summarized for the Pre-treatment Phase. 
Selected safety lab data collected up to and including the last dosing date plus 30 days will be 
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The unscheduled visits and early tennination (ET) visits will be windowed, but the follow-up 
(FU) visits will be summarized as a separate visit, and labeled "Follow-up Visit". Data obtained 
after the follow-up visit or last dose date plus 30 days (whichever is later) will be excluded from 
the summaries, but will be included in the listings. 
3.9.2.1. 
Analysis Windows for Pre-treatment Phase 
Data included in the pre-treament safety analysis will include data collected from screening and 
up to and including the first dosing date of GS-0976. The analysis windows for selected safety 
data as specified in Section 7.2.1.2 are provided in Table 3-1. 
Table 3-1. 
Analysis Visit 
Pre-treatment Baseline 
Day -I I 
Day -7 
Day I 
Pre-treatment Phase Safety Ana~ndows for Chemistry, 
Hematology, Coagulation Labs,_, and Free Fatty Acids 
Nominal Pre-treatment 
Visit Window Study Day 
Study Day 
Lower Limit 
Upper Limit 
I 
(none) 
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2 
5 
8 
6 
II 
15 
12 
2: 15 if didn't take 
GS-0976 
I st dosing date of 
GS-0976 if took GS-0976 
3.9.2.2. 
Analysis Visit Window for Treatment Phase 
The analysis windows for selected efficac 
Table 3-3. 
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Table 3-2. 
Analysis Visit 
Baseline 
Week I 
Week4 
Week 8 
Week 12 
Week 16 
Week 24 
Treatment Phase Anal sis Visit Windows 
· 
· 
Che · 
· 
ree Fatty 
Glucose, Insulin, Bile Acids, Model for End-stage Liver 
Disease (MELD) Score, AST to Platelet Ratio Index (APRI), 
Fibrosis-4 (FIB-4), Non-alcoholic Fatty Liver Disease (NAFLD) 
Fibrosis Score (NFS), and Apolipoprotein Al 
Visit Window Study Day 
Nominal Study Day 
Lower Limit 
Upper Limit 
I 
(none) 
I 
8 
2 
18 
29 
19 
42 
57 
43 
70 
85 
71 
98 
113 
99 
140 
169 
141 
2: 169 
* APRJ, FIB 4 and NFS are defined in Appendix 3. 
Table 3-3. 
Analysis Visit 
Baseline 
Week 12 
Week 24 
Treatment Phase Anal sis Visit Windows for MRI-PDFF, MRE,. 
Amino Terminal Peptide(PIIIN 
Metalloproteinase 1 [TIMP-1 
Macro lobin, Haptoglobin, 
including liver stiffness and 
Procollagen ill 
r of 
Al ha-2 
C-Reactive Protein (CRP) , Hemoglobin Ale, 
Cytokeratin 18 (CK-18) 
Visit Window Study Day 
Nominal Study Day 
Lower Limit 
Upper Limit 
I 
(none) 
I 
85 
2 
126 
169 
127 
2: 169 
3.9.2.3. 
Analysis Windows for Entire Study 
For the safety analysis of the Entire Study, no separate analysis windows will be created based 
on pre-treatment study day or study day. Instead, the mapped analysis visits in both phases will 
be renamed as in Table 3-4 for entire study safety analysis. The pre-treatment baseline is to be 
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Table 3-4.
Entire Study Analysis Visit Rename for Chemistry, Hematology, 
Coagulation Labs, and 
Pre-treatment/Treatment Phase 
Analysis Visit
Entire Study 
Analysis Visit
Pre-treatment Baseline
Overall Baseline
Day -11
Overall Day 4
Day -7
Overall Week 1
Day 1
Overall Week 2
Week 1
Overall Week 3
Week 4
Overall Week 6
Week 8
Overall Week 10
Week 12
Overall Week 14
Week 16
Overall Week 18
Week 24
Overall Week 26
3.9.3.
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, measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the first dosing date of study drug in the 
corresponding phase will be selected, unless specified differently. If there are multiple 
records with the same time or no time recorded on the same day, the baseline value will be 
the average of the measurements for continuous data, or the measurement with the lowest 
severity (eg, normal will be selected over abnormal for safety electrocardiogram [ECG] 
findings) for categorical data.

Baseline values of the liver tests (ALT, AST, total bilirubin and direct bilirubin) in the 
treatment phase will be determined by averaging the values obtained from Screening to
Study Day 1.
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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, m1less 
otherwise specified. 
For serum creatinine, if both enzymatic and regular creatinine are collected from the 
same blood sample and are analyzable, regular creatinine will be picked for analysis. 
Liver stiffness by transient elastography data in each analysis visit window will be chosen based 
on the following rules: 
• 
For baseline, measurements by XL probe will be selected for analysis if available, otherwise 
measurements by M probe will be selected. 
• 
For postbaseline visits, measurements by the same probe type (XL or M) as baseline for the 
subject will be selected if available. If no measurement by the same probe type as baseline is 
available, the measurement by a different probe at postbaseline is then selected. If there are 
multiple records by the same probe type as baseline, the rules to choose postbaseline 
continuous measurements as described above will apply. 
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group and overall for each
country and investigator within a country. 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.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and study phase. This 
summary will present the number of subjects screened, the number of subjects who met all 
eligibility criteria but were not randomized with reasons subjects not randomized, the number of 
subjects randomized, and the number of subjects in each of the categories listed below :

Pre-treatment Safety Analysis Set 

Completed pre-treatment study drug

Did not complete pre-treatment study drug with reasons for premature discontinuation of pre-
treatment study drug

Safety Analysis Set

Full Analysis Set

Continuing study drug (for Week 12 Interim Analysis)

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Continuing study (for Week 12 Interim Analysis)

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 
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percentage calculation will be the total number of subjects in the All Randomized Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
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)

Subjects with different triglycerides level between screening and pre-treatment baseline
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 relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Duration of exposure to study drug will be summarized for the Pre-treatment Phase (fenofibrate 
only) by treatment group for the Pre-treatment Safety Analysis Set, and for the Entire Study 
(GS-0976 and fenofibrate) by treatment group for the Safety Analysis Set.
Total duration of exposure to fenofibrate in the Pre-treatment Phase will be defined as the last 
dosing date of fenofibrate in the pre-treatment phase or the date prior to the first dosing date of 
GS-0976, which is earlier, minus the first dosing date of fenofibrate plus 1 divided by 7, 
regardless of any temporary interruption in fenofibrate administration.
Total duration of exposure to study drug for the Entire Study will be summarized separately for 
fenofibrate and GS-0976, and will be defined as last dosing date of the corresponding study drug 
minus first dosing date of the corresponding study drug plus 1 divided by 7, regardless of any 
temporary interruptions in study drug administration.
Total duration of exposure 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 in the Pre-treatment Phase: 1 day,1 week, 2 weeks, and the following 
time periods in the Treatment Phase: 1 day, 1 week, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 
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No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total number of doses administered will be summarized using descriptive statistics.
The presumed total number of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered 
No. of Doses Dispensed
No. of Doses Returned

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











The level of prescribed 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 specified by the
protocol for a subject who completes treatment in the study.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Total Amount of Study Drug Administered
Prescribed Adherence (%) 
 x 100
Total Amount of Study Drug Specified by Protocol






Note: if calculated adherence rate is greater than 100%, the result will be set to 100%.
For subjects who complete treatment, the number of fenofibrate doses expected to be 
administered is 182 and the number of GS-0976 doses expected to be administered is 168.
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (< 75%, ≥ 75 to < 90%, ≥ 90%) will be provided 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 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 
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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 
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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. Age will be calculated in years at the date of first dosing date of GS-0976.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics will be summarized for the Treatment Phase only, which shows the
baseline information before taking study drug GS-0976. These baseline characteristics include:
 

Height (in cm)

Body mass index (BMI; in kg/m2)

BMI category (< 18.5 kg/m2, 18.5 to < 25 kg/m2, 25 to 30 kg/m2  and ≥30 kg/m2)

Screening fibrosis stage

Screening triglyceride level category ([≥ 150 mg/dL and < 250 mg/dL] or [≥250 mg/dL and 
< 500 mg/dL])

Pre-treatment triglyceride level ( < 250 mg/dL or >  250mg/dL)

Diabetes mellitus (absence or presence)

Smoking status

MRI-PDFF (%)

MRE (kPa)

Liver stiffness by transient elastography (kPa)

Liver stiffness category (< 9.9 kPa, ≥ 9.9 to < 11.4 kPa, ≥ 11.4 kPa)
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
APRI

FIB-4

NFS

NFS category (< -1.455, -1.455 to < 0.676, and ≥0.676)

MELD score

CRP (mg/dL)

CK-18 (M30 and M65) (for Final Analysis Only)

Albumin (g/dL)

International normalized ratio (INR)

Fasting insulin (uIU/mL)

Fasting glucose (mg/dL)

Hemoglobin A1c (%)

Total cholesterol (mg/dL)

High density lipoprotein -cholesterol (HDL-C) (mg/dL)
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
Calculated fasting non-HDL-C ( total cholesterol minus HDL-C) (mg/dL)

Calculated fasting very low density lipoprotein cholesterol (VLDL-C) (  triglycerides 
divided by 5) (mg/dL)

Calculated fasting low density lipoprotein cholesterol (LDL-C) (  non-HDL-C minus 
VLDL-C) (mg/dL)

Fasting total bile acids (umol/L)
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order and abnormalities in chronological order.
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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. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the protocol. 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.
Severity of adverse events will be determined by the investigator as mild, moderate, or severe. 
The severity of events for which the investigator did not record severity will be categorized as 
“missing” for tabular summaries and data listings. The missing category will be listed last in 
summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
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 Pharmacovigilence 
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) for Cohorts 10 and 11 will be summarized 
separately for the Pre-treatment Phase and the Treatment Phase, as well as summarized for the 
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TEAEs in the Pre-treatment Phase are defined as 1 or both of the following:

Any AEs with an onset date on or after the fenofibrate start date and no later than the date
before the first dosing date of GS-0976

Any AEs leading to premature discontinuation of fenofibrate in the Pre-treatment Phase.
TEAEs in the Treatment Phase are defined as 1 or both of the following:

Any AEs with an onset date on or after the GS-0976 start date and no later than 30 days after 
permanent discontinuation of both study drugs

Any AEs leading to premature discontinuation of any study drug in the Treatment Phase.
TEAEs in the Entire Study are defined as 1 or both of the following:

Any AEs with an onset date on or after the fenofibrate start date and no later than 30 days 
after permanent discontinuation of both study drugs

Any AEs leading to premature discontinuation of any study drug.
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 fenofibrate, 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 for the Pre-treatment Phase 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 
fenofibrate, and

The AE onset date is the same as or before the month and year (or year) of the date prior to 
the first dosing date of GS-0976
The event is considered treatment emergent for the Treatment Phase 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 
GS-0976, and

The AE onset date is the same as or before the month and year (or year) of the date 
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The event is considered treatment emergent for the Entire Study 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 
fenofibrate, 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 both study drugs
An AE with completely missing onset and stop dates will be considered treatment emergent in 
all phases. An AE with the onset date missing and a stop date later than the first dosing date of 
fenofibrate, will be considered to be treatment emergent in the Pre-treatment Phase and in Entire 
Study; moreover, if the stop date is later than the first dosing date of GS-0976, it will also be 
considered to be treatment emergent for the Treatment Phase. 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 fenofibrate will be considered treatment 
emergent in the Pre-treatment Phase and in Entire Study; moreover, if the incomplete stop date is 
with the same or later month and year (or year alone if month is not recorded) as the first dosing 
date of GS-0976, it will also be considered treatment emergent in the Treatment Phase.
7.1.6.
Summaries of Adverse Events and Deaths
7.1.6.1.
Summaries of Adverse Events and Deaths in The Treatment Phase
Treatment-emergent AEs in the treatment phase will be summarized based on the Safety 
Analysis Set.
A brief, high-level summary of the number and percentage of subjects who experienced at least
1 TEAEs during the Treatment Phase in the categories described below will be provided by 
treatment group. All deaths observed in the Treatment Phase will also be included in this 
summary.
The number and percentage of subjects who experienced at least 1 TEAE during the Treatment 
Phase will be provided and summarized by SOC, HLT (if applicable), PT, and treatment group. 
For other AEs described below, summaries will be provided by SOC, PT, and treatment group:

TEAEs by severity grade

TEAEs with Grade 3 or higher 

TEAEs with Grade 2 or higher

TE treatment-related AEs

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
TE treatment-related AEs with Grade 3 or higher 

TE treatment-related AEs with Grade 2 or higher

TE SAEs

TE treatment-related SAEs 

TEAEs leading to premature discontinuation of any study drug

TEAEs leading to premature discontinuation of study

TEAEs leading to dose modification or temporary interruption of any study drug

TEAEs leading to death (ie, outcome of death)
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized 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 summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study.
In addition to the above summary tables, the following tables will be summarized by PT only, in 
descending order of total frequency:

All TEAEs 

TEAEs with Grade 3 or higher 

TEAEs with Grade 2 or higher

TE treatment-related AEs

TE treatment-related AEs with Grade 3 or higher 

TE treatment-related AEs with Grade 2 or higher 

TE SAEs

TE treatment-related SAEs 
7.1.6.2.
Summaries of Adverse Events and Deaths in The Pre-Treatment Phase
Treatment-emergent AEs in the Pre-treatment Phase will be summarized based on the Pre-
treatment Safety Analysis Set.


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A brief, high-level summary of AEs as generated for the treatment phase will be provided for the 
Pre-treatment Phase AEs by treatment 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 
summary.
In addition to the above summary tables, the following tables will be summarized by PT only for 
Pre-treatment Phase AEs, in descending order of total frequency:

TEAEs with Grade 3 or higher 

TE treatment-related AEs with Grade 3 or higher 

TE SAEs

TE treatment-related SAEs 
7.1.6.3.
Summaries of Adverse Events and Deaths in The Entire Study
Treatment-emergent AEs in the Entire Study will be summarized based on the Safety Analysis 
Set.
The same set of summaries generated for Pre-treatment Phase AEs will be generated for the 
entire study AEs.
In addition, data listings for AEs in the Entire Study will be provided for the following:

All AEs, indicating whether the event is treatment emergent in each study phase

All AEs with severity of Grade 3 or higher

SAEs

All Deaths

All AEs leading to premature discontinuation of study drug 

All AEs leading to dose modifications or temporary interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the Pre-
treatment Safety Analysis Set for the Pre-treatment Phase analysis and will include data collected 
up to the first dosing date of GS-0976. Summaries of laboratory data will also be provided for 
the Safety Analysis Set for the Treatment Phase analysis and Entire Study analysis, and will 
include data collected up to the last dose of both study drugs plus 30 days for subjects who have 
permanently discontinued study drug, or all available data at the time of the database snapshot 


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for subjects who were ongoing at the time of an interim analysis. The analysis will be based on 
values reported in conventional units. When values are below the LOQ, they will be listed as 
such, and the closest imputed value will be used for the purpose of calculating summary statistics
as specified in Section 3.7. Hemolized test results will not be included in the analysis, but they 
will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and coagulation separately for the Entire 
Study. Values falling outside of the relevant reference range and/or having a severity grade of 1 
or higher on CTCAE version 4.03 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
7.2.1.1.
Summaries of Numeric Laboratory Results in the Treatment Phase
, albumin, glucose, insulin, 
 
hemoglobin A1c, and INR in the Treatment Phase will be summarized as efficacy endpoints and 
will not be repeated here.  Descriptive statistics will be provided by treatment group for 
creatinine, estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation, 
creatine kinase, white blood cells, neutrophils, lymphocytes, hemoglobin, platelets, and fasting 
free fatty acids will be summarized for the treatment phase 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 of first dose of GS-0976. 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 3.9.3.
7.2.1.2.
Summaries of Numeric Laboratory Results in the Pre-Treatment Phase and in the 
Entire Study
Descriptive statistics will be provided by treatment group for the 
, fasting free fatty 
acids, 
, albumin, creatinine, eGFR, and
creatine kinase for the pre-treatment phase and for entire study.
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A baseline laboratory value for these two periods will be defined as the last measurement 
obtained on or prior to the date of first dose of fenofibrate, and referred to as the pre-treatment
baseline. Change from pre-treatment baseline to visits afterwards will be summarized in the same 
way as in the treatment phase. Multiple values in an analysis window will be handled as in 
Section 3.9.3.
For the Pre-treatment Phase, the following visits will be presented besides pre-treatment
baseline: Day -11, Day -7, and Day 1.
For the Entire Study, the following visits will be presented besides pre-treatment baseline: Day -
11, Day -7, Day 1, Week 1, 4, 8, 12, 16, 24, and follow-up (FU).
7.2.2.
Graded Laboratory Values
The CTCAE Version 4.03 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 the baseline ALT, AST, total bilirubin and direct bilirubin in the treatment phase, the 
CTCAE version 4.03 will be used to assign toxicity grades to the derived average values. The 
reference range for each parameter will be defined as the one associated with the latest visit 
among all the values being averaged for each subject, for the purpose of determination of the 
abnormality and/or toxicity grades.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
7.2.2.1.1.
Treatment-Emergent Laboratory Abnormalities in the Treatment Phase
Treatment-emergent laboratory abnormalities in the Treatment Phase 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 both 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 for 
the Treatment Phase will be considered treatment emergent.
7.2.2.1.2.
Treatment-Emergent Laboratory Abnormalities in the Pre-Treatment Phase
Treatment-emergent laboratory abnormalities in the Pre-treatment Phase are defined as values 
that increase at least 1 toxicity grade from pre-treatment baseline at any post pre-treatment 
baseline time point, up to and including the date of first dose of GS-0976. If the relevant pre-
treatment baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above for the Pre-treatment Phase will be considered treatment 
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7.2.2.1.3.
Treatment-Emergent Laboratory Abnormalities in the Entire Study
Treatment-emergent laboratory abnormalities in the Entire Study are defined as values that 
increase at least 1 toxicity grade from pre-treatment baseline at any post pre-treatment baseline
time point, up to and including the date of last dose of both 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 for the Entire Study above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
7.2.2.2.1.
Treatment-Emergent Marked Laboratory Abnormalities in the Treatment Phase
Treatment-emergent marked laboratory abnormalities in the Treatment Phase 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 both 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 for the Treatment Phase will be considered treatment-emergent marked abnormalities.
7.2.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities in the Pre-Treatment 
Phase
Treatment-emergent marked laboratory abnormalities in the Pre-treatment Phase are defined as 
values that increase at least 3 toxicity grade from pre-treatment baseline at any post pre-treatment 
baseline time point up to and including the date of first dose of GS-0976. If the relevant pre-
treatment baseline laboratory value is missing, any Grade 3 or 4 values observed within the time 
frame specified above for the Pre-treatment Phase will be considered treatment emergent.
7.2.2.2.3.
Treatment-Emergent Laboratory Abnormalities in the Entire Study
Treatment-emergent laboratory marked abnormalities in the Entire Study are defined as values 
that increase at least 3 toxicity grade from pre-treatment baseline at any post pre-treatment 
baseline time point, up to and including the date of last dose of both 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 time 
frame specified above for the Entire Study will be considered treatment emergent.
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 for 
the Treatment Phase, and will be summarized using the number and percentage of subjects in the 


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study with the given response at pre-treatment baseline and each scheduled post pre-treatment 
baseline visit for the Pre-Treatment Phase and the Entire Study.
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 the Treatment Phase and the 
most severe post pre-treatment baseline abnormality grade for the Pre-treatment Phase and the 
Entire Study, 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 for the Treatment Phase, and with nonmissing post pre-treatment
baseline values for the Pre-treatment Phase and the Entire Study.
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 displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related laboratory results will be summarized for the Treatment Phase only.
The summary will be provided by 2 subgroups of subjects according to their baseline 
 
level in the treatment phase:

Normal

Elevated (> ULN)
Liver-related abnormalities after initial GS-0976 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 normal baseline 
:

Subjects meeting criteria for close observation
 > 3 × ULN
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
Subjects meeting criteria for study drug withheld
 > 8 × ULN
 > 5 × ULN for 2 weeks
 > 3 × ULN and total bilirubin > 2 × ULN (or direct bilirubin > 2 × baseline in 
subjects with Gilbert’s syndrome)
 > 3 × ULN and INR > 1.5 (if not on anticoagulation)
For subjects with baseline 
> ULN

Subjects meeting criteria for close observation
 > 2 × Baseline or > 300 U/L

Subjects meeting criteria for study drug withheld
 > 8 × Baseline or > 500 U/L
 > 3 × Baseline or > 300 U/L, and total bilirubin > 2 × ULN (or direct bilirubin
> 2 x Baseline in subjects with Gilbert’s syndrome)
 > 3 × Baseline and INR > 1.5 (if not on anticoagulation)
The above summary will include data from all postbaseline visits up to 30 days after the last dose 
of both study drug 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. 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 in the 
summarizing group. A listing of subjects meeting any of the criteria above will be provided.
7.2.4.
Additional Summary of Laboratory Value
Fasting triglycerides measured during the Pre-treatment Phase and at Day 1 will be summarized 
by treatment group by visit and further subgrouped by pre-treatment baseline triglycerides level 
([≥ 150 mg/dL and < 250 mg/dL] or [≥ 250 mg/dL and < 500 mg/dL]), for the Pre-treatment 
Safety Analysis Group. The following by-visit summary will be reported.

Pre-treatment baseline values

Values at each post pre-treatment baseline visit

Change from baseline at each post pre-treatment baseline visit
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Fasting triglycerides grade measured during the Pre-treatment Phase and at Day 1 will be 
summarized using the number and percentage of subjects at each toxicity grade by treatment 
group by visit, for the Pre-treatment Safety Analysis Set. A similar summary further subgrouped 
by pre-treatment baseline triglyceride level will also be generated.
7.3.
Vital Signs
Descriptive statistics will be provided by treatment group for vital signs in the Treatment Phase 
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 GS-0976. 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 3.9.3. 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.
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 dose of 
fenofibrate.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
fenofibrate will be included in the prior medication summary regardless of when the stop date is. 
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(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date of fenofibrate. Medications with a completely missing start date will be included in 
the prior medication summary, unless otherwise specified.
Summaries will be based on the Pre-Treatment 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.
Concomitant medications will be summarized separately for the Pre-treatment Phase based on 
the Pre-treatment Safety Analysis Set and for the Treatment Phase based on the Safety Analysis 
Set. 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 fenofibrate and continued to be taken after the first fenofibrate dosing date, or started after the 
first fenofibrate dosing date but prior to the first dosing date of GS-0976 will be considered 
concomitant medications in the Pre-Treatment Phase. Any medication with a start date prior to or 
on the first dosing date of GS-0976 and continued to be taken after the first GS-0976 dosing date, 
or started after the first GS-0976 dosing date but prior to the last dosing date of GS-0976 will be 
considered concomitant medication in the Treatment Phase. Medications started and stopped on 
the same day as the first dosing date or the last dosing date of fenofibrate/GS-0976 will also be 
considered concomitant in the Pre-treatment/Treatment Phase. Medications with a stop date prior 
to the date of first dosing date of fenofibrate or a start date after the first dosing date of GS-0976
will be excluded from the concomitant medication summary for the Pre-treatment Phase.
Medications with a stop date prior to the date of the first dosing date of GS-0976 or a start date 
after the last dosing date of GS-0976 will be excluded from the concomitant medication 
summary for the Treatment Phase. 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 in the corresponding phase will be excluded from the concomitant 
medication summary for that phase. 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 GS-0976 start
date will be excluded from the concomitant medication summary for the Pre-treatment Phase, 
and any medication with the month and year (if day is missing) or year (if day and month are 
missing) after the GS-0976 stop date will be excluded from the concomitant medication 
summary for the Treatment Phase. Medications with completely missing start and stop dates will 
be included in the concomitant medication summary in both phases, unless otherwise specified.
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.


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7.5.
Electrocardiogram Results
7.5.1.
Investigator Electrocardiogram Assessment
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
There are no deviations from the protocol-specified safety analyses.


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


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


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


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12.
APPENDICES
Appendix 1.
Schedule of Assessment for GS-US-384-3914 Cohorts 10 and 11
Appendix 2.
CTCTAE Grade for Laboratory Parameters
Appendix 3.
Noninvasive markers for Fibrosis
Appendix 4.
Liver Function Prognostic Scores
Appendix 5.
Health Related Quality of Life Score Calculation


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Appendix 1.
Schedule of Assessment for GS-US-384-3914 Cohorts 10 and 11
Screena
Pretreatment Period Enrollment
Treatment Period
EOT
ET
FU
Kinetic Biomarkers Cycle 1
Kinetic Biomarker Cycle 2
Kinetic Biomarker Cycle 3
D -14
D -11 
(±1d)
D -7 
(±1d)
D1b
D7 
(W1) 
(±3d)
D28 
(W4) 
(±3d)
D56 
(W8) 
(±3d)
D70 
(W10) 
(±1d)
D73 
(±1d)
D77 
(W11) 
(±3d)
D84 
(W12) 
(±3d)
D112 
(W16) 
(±3d)
D126 
(W18) 
(±3d)
D154 
(W22) 
(±1d)
D157 
(±1d)
D161 
(W23) 
(±1d)
D168 
(W24) 
(±3d)
ET
D196 
(W28) 
(±5d)
Clinical Assessment
Informed 
Consent
X
Determine 
Eligibility c
X
X
X
Medical History
X
X
X
Assess ascites 
and hepatic 
encephalopathy
X
X
X
X
X
X
X
X
X
CPT score 
X
X
X
X
X
X
X
X
X
Physical 
Examination
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Xd
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Height
X
12 lead ECG
X
X
X
X
QoLse
X
X
X
X
MRE, 
MRI PDFF
Xg
X
X
X
Adverse Events
X
X
X
X
X
X
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
X
X
X
Dispense 
fenofibrate
X
X
X
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Screena
Pretreatment Period Enrollment
Treatment Period
EOT
ET
FU
Kinetic Biomarkers Cycle 1
Kinetic Biomarker Cycle 2
Kinetic Biomarker Cycle 3
D -14
D -11 
(±1d)
D -7 
(±1d)
D1b
D7 
(W1) 
(±3d)
D28 
(W4) 
(±3d)
D56 
(W8) 
(±3d)
D70 
(W10) 
(±1d)
D73 
(±1d)
D77 
(W11) 
(±3d)
D84 
(W12) 
(±3d)
D112 
(W16) 
(±3d)
D126 
(W18) 
(±3d)
D154 
(W22) 
(±1d)
D157 
(±1d)
D161 
(W23) 
(±1d)
D168 
(W24) 
(±3d)
ET
D196 
(W28) 
(±5d)
Dispense 
GS 0976
X
X
X
X
X
X
Dispense 
Deuterated 
Water
Xk
X
X
Laboratory Assessments
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation 
Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testh
X
X
X
X
X
X
X
X
X
X
Adiponectin, 
beta
hydroxybutyrate
X
X
X
X
X
hsCRP
X
X
X
X
X
ApoA1, ApoB, 
 
NMR 
Lipoprofile
X
X
X
X
X
X
X
X
X
Lipidomics
X
X
X
X
X
X
X
X
FGF19, C4
X
X
X
X
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Screena
Pretreatment Period Enrollment
Treatment Period
EOT
ET
FU
Kinetic Biomarkers Cycle 1
Kinetic Biomarker Cycle 2
Kinetic Biomarker Cycle 3
D -14
D -11 
(±1d)
D -7 
(±1d)
D1b
D7 
(W1) 
(±3d)
D28 
(W4) 
(±3d)
D56 
(W8) 
(±3d)
D70 
(W10) 
(±1d)
D73 
(±1d)
D77 
(W11) 
(±3d)
D84 
(W12) 
(±3d)
D112 
(W16) 
(±3d)
D126 
(W18) 
(±3d)
D154 
(W22) 
(±1d)
D157 
(±1d)
D161 
(W23) 
(±1d)
D168 
(W24) 
(±3d)
ET
D196 
(W28) 
(±5d)
Hemoglobin 
A1c
X
X
X
X
X
X
Urine Drug 
Screening
X
HIV 1, HBV & 
HCV Serology
X
Genomic 
Samplej
X
Urine 
Collection for 
Kinetic 
Biomarkers
X
X
X
X
Xm
Xm
X
X
X
X
X
X
X
X
X
X
Blood 
Collection for 
Kinetic 
Biomarkers
X
X
X
X
Xm
Xm
X
X
X
X
X
X
X
X
X
X
a
Screening assessments to be completed within 6 weeks prior to Day 14 visit. The screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences.
b
Day 1 assessments must be performed prior to dosing.
c
Includes Review of historical liver biopsy obtained within the last 6 months of Screening (date of initial informed consent) for subjects with bridging fibrosis (F3) and within 
the last 12 months for subjects with cirrhosis (F4), to assess subject eligibility
d
Symptom driven physical examination.
e
For subjects with Quality of Life questionnaires available at Day 1.
CCI
CCI
CCI
CCI
--------------------------------------------------------------------------


GS-0976 
GS-US-384-3914 
Statistical Analysis Plan - Cohorts 10- 11 
r 
g 
, MRI POFF, and MRE must be perfom1ed as baseline assessments regardless of presence of historical liver biopsy. 
Version 1.0 
h 
Females o c 1 
earing potential only: Semm pregnancy testing at screening, urine pregnancy testing will occur at Day I and every 4 weeks during the dosing period and for 
30 da s followin the last dose of stud dm!!. 
r 
J 
enonuc amp e co ecte or su ~ects w o ave not opted out of sample collection. No additional blood will be drawn. 
k 
The first dose of 50 mL deuterated water will be administered under the supervision of investigative site personnel and monitored for at least 30 minutes after for any side 
effects. 
r 
Ill 
CONFIDENTIAL 
Page 57 
22 August 2019 


GS-0976 
GS-US-384-3914 
Statistical Analysis Plan - Cohorts 10-11 
Appendix 2. 
CTCTAE Grade for Laboratory Parameters 
CTCAE v4.03 
CTCAE Grade 
Corrected semm 
Corrected semm 
Corrected semm calcium 
calcium of 
calcium of 
of>ULN 
11 .5 mg/dL; 
> 11.5 12.5 mg/dL; 
> 12.5 13.5 mg/dL; 
>3. 1 3.4 mmol/L; 
1-Iypercalcemia 
>ULN 2.9mmol/L; 
>2.9 3. 1 mmol/L; 
Ionized calcium > 1.6 
Ionized calcium >ULN 
Ionized calcium > 1.5 
1.8 mmol/L; 
1.5 mmol/L 
1.6 mmol/L; 
hospitalization 
symptomatic 
indicated 
Corrected semm 
Corrected semm 
Corrected semm calcium 
calcium of 
calcium of 
of 
<8.0 7.0 mg/dL; 
<7.0 6.0 mg/dL; 
<LLN 8.0 mg/dL; 
< 1.75 
1.5 mmol/L; 
1-Iypocalcemia 
<LLN 2.0 mmol/L; 
<2.0 
1.75 mmol/L; 
Ionized calcium <0.9 
Ionized calcium < 1.0 
Ionized calcium 
0.9 mmol/L; 
0.8 mmol/L; 
<LLN 
1.0 mmol/L 
hospitalization 
symptomatic 
indicated 
eGFR (estimated 
Glomemlar Filtration 
Rate) or CrCI (creatinine 
eGFRor CrCI 
eGFR orCrCI 
Chronic kidney 
clearance) 
59 
30 ml/min/ 
29 
15 ml/min/ 
disease 
<LLN 
60 ml/min/ 
I. 73 m2 or proteinuria 
1.73 m2 
1.73 m2 
2+ present; urine 
protein/creatinine >0.5 
Creatinine 
> I 
1.5 x baseline; 
> 1.5 3.0 x baseline; 
>3.0 baseline; 
increased 
>ULN 
1.5 x ULN 
> 1.5 3.0 x ULN 
>3.0 6.0 x ULN 
CONFIDENTIAL 
Page 58 
Version 1.0 
Corrected semm 
calcium of 
> 13.5 mg/dL; 
> 3.4 mmol/L; 
Ionized calcium 
Death 
> 1.8 mmol/L; 
life threatening 
consequences 
Corrected semm 
calcium of 
<6.0 mg/dL; 
< 1.5 mmol/L; 
Ionized calcium 
Death 
<0.8 mmol/L; 
life threatening 
consequences 
eGFR orCrCI 
< 15 ml/min/ 
1.73 m2; dialysis or 
Death 
renal transplant 
indicated 
>6.0 x ULN 
22 August 2019 


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 59
22 August 2019
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
increased
Hyperglycemia
Fasting glucose value 
>ULN 160 mg/dL; 
Fasting glucose value 
>ULN 8.9 mmol/L
Fasting glucose value 
>160 250 mg/dL; 
Fasting glucose value 
>8.9 13.9 mmol/L
>250 500 mg/dL; 
>13.9 27.8 mmol/L; 
hospitalization 
indicated
>500 mg/dL; 
>27.8 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
Hemoglobin 
increased
Increase in >0 2 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN
Increase in 
>2 4 gm/dL above 
ULN or above 
baseline if baseline is 
above ULN
Increase in 
>4 gm/dL above 
ULN or above 
baseline if baseline is 
above ULN
International 
normalized ratio 
(INR) increased
>1 1.5 x ULN; 
>1 1.5 times above 
baseline if on 
anticoagulation
>1.5 2.5 x ULN; 
>1.5 2.5 times 
above baseline if on 
anticoagulation
>2.5 x ULN; 
>2.5 times above 
baseline  if on 
anticoagulation
Hyperkalemia
>ULN 5.5 mmol/L
>5.5 6.0 mmol/L
>6.0 7.0 mmol/L; 
hospitalization 
indicated
>7.0 mmol/L; 
life threatening 
consequences
Death
Hypokalemia
<LLN 3.0 mmol/L
<LLN 3.0 mmol/L; 
symptomatic; 
intervention 
Indicated 
<3.0 2.5 mmol/L; 
hospitalization 
indicated
<2.5 mmol/L; 
life threatening 
consequences
Death
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
Hyper
magnesemia
>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
Hypo
magnesemia
<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
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
Hypo
phosphatemia
<LLN 2.5 mg/dL; 
<LLN 0.8 mmol/L
<2.5 2.0 mg/dL; 
<0.8 0.6 mmol/L
<2.0 1.0 mg/dL; 
<0.6 0.3 mmol/L
<1.0 mg/dL; 
<0.3 mmol/L; 
life threatening 
consequences
Death
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
Hypernatremia
>ULN 150 mmol/L
>150 155 mmol/L
>155 160 mmol/L; 
hospitalization 
>160 mmol/L; 
life threatening 
Death


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 60
22 August 2019
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
indicated
consequences
Hyponatremia
<LLN 130 mmol/L
<130 120 mmol/L
<120 mmol/L; 
life threatening 
consequences
Death
Hyperuricemia
>ULN 10 mg/dL 
(0.59 mmol/L) without 
physiologic 
consequences
>ULN 10 mg/dL 
(0.59 mmol/L) with 
physiologic 
consequences
>10 mg/dL; 
>0.59 mmol/L; 
life threatening 
consequences
Death
White blood cell 
(WBC) 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
a.
Note: Refer to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03/CTCAE 4.03 2010 06 14 QuickReference 8.5x11.pdf


GS-0976 
GS-US-384-3914 
Statistical Analysis Plan - Cohorts 10-11 
Appendix 3. 
Noninvasive markers for Fibrosis 
I 
I 
-
-
• 
Fibrosis-4 (FIB-4) Index Calculation: 
FIB-4 Index 
rom1d ((age x AST ) / (platelet x sqrt (ALT)), 0.01); 
• 
AST to Platelet Ratio Index (APRI) Calculation: 
APRI 
round (AST/ASTULN x 100 / platelet, 0.1); 
Version 1.0 
Note: for FIB-4 index and APRI calculation, the laboratory parameters need to be measured from 
the same blood draw. Age should be the actual age at the date when laboratory values are taken. 
CONFIDENTIAL 
Page 61 
22 August 2019 


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 62
22 August 2019

NAFLD fibrosis score (NFS) Calculation:
NFS  -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG (impaired fasting
glucose) / pre-diabetes or diabetes (yes 1,no 0) + 0.99 × AST / ALT ratio - 0.013 × platelet 
(×109/L) - 0.66 × albumin (g/dL).  Keep 3 decimal places.
The laboratory parameters need to be measured from the same blood draw.  The last non-missing
BMI on or prior to laboratory date should be used. Age should be the actual age at the date when 
laboratory values are taken.  Status of pre-diabetes/diabetes should also be decided on the 
laboratory date.  If a subject had pre-diabetes/diabetes at baseline, the pre-diabetes/diabetic status 
will be yes for all the postbaseline visits.  If the subject does not have pre-diabetes/diabetes at 
baseline, the pre-diabetic/diabetic status will be determined based on the start date AEs of pre-
diabetes and diabetes, and the collection date when fasting glucose is greater than 100 (IFG). If 
the AE start date or the fasting glucose collection date is on or prior to the laboratory date of a 
specific visit, then the pre-diabetic/diabetic status will be yes for that visit and later visits. If the 
day of the AE start date is missing, it will be imputed using the 1st day of the month. 
The categories of NFS to be presented will be < -1.455, -1.455 to < 0.676, and >  0.676.


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 63
22 August 2019
Appendix 4.
Liver Function Prognostic Scores

MELD Score Calculation
MELD score 
3.78 [Ln total bilirubin (mg/dL)] + 11.2 [Ln INR] + 9.57 [Ln serum creatinine 
(mg/dL)] + 6.43. If the serum creatinine, the total bilirubin or the INR value is < 1.00 mg/dL, the 
calculation will use 1.00 as the test value. If the serum creatinine is > 4.00 mg/dL or subjects on 
dialysis, the calculation will use 4.00 as the serum creatinine value.


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 64
22 August 2019
Appendix 5.
Health Related Quality of Life Score Calculation

SF-36
Scoring of the SF-36 scales will be performed as described in Chapter 6 of the SF-36 Health 
Survey Manual and Interpretation Guide, Version 2.  Summary will be done for 8 domains of the 
SF-36 (physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health), and for the physical component score and 
mental component summary.

CLDQ-NAFLD
CLDQ-NAFLD scores are calculated using subject responses to 36 questions in the 
questionnaire. If Ri is the score for the patient’s response to the item i, for i 1, 2, …., 36 then the 
6 domain scores are calculated as follows:
Abdominal  Mean of {R1, R5, R17}
Fatigue  Mean of {R2, R4, R8, R11, R13, R35}
Systemic  Mean of {R3, R6, R21, R23, R27, R36}
Activity  Mean of {R7, R9, R14, R30, R31}
Emotion  Mean of {R10, R12, R15, R16, R19, R20, R24, R26, R34}
Worry  Mean of {R18, R22, R25, R28, R29, R32, R33}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is calculated 
only if at least half of corresponding items are not missing. Otherwise, the score will be missing.
Overall CLDQ score is calculated by taking the mean of 6 domain scores {abdominal, fatigue, 
systemic, activity, emotion, worry}. Overall CLDQ score will be summarized.

WPAI: NASH
The response to Question 1 of this questionnaire provides the binary endpoint whether or not the 
subject had been in a paid employment during the week prior to assessment.
If the subject had been in a paid employment (Response to Q1 is “Yes”) at the visit when 
questionnaire was given, then following three scores are derived:
Percent work time missed (Absenteeism)  100 × Q2 / (Q2 + Q4)
Percent impairment while working (Presenteeism)  100 × Q5 / 10


GS-0976
GS-US-384-3914
Statistical Analysis Plan – Cohorts 10-11
Version 1.0
CONFIDENTIAL
Page 65
22 August 2019
Percent work productivity loss  
Question 6 is applicable to all subjects:
Percent activity impairment  100 × Q6 / 10.
Percent work productivity loss and percent activity impairment will be summarized.

















10
5
)
4
2
2
1
)
4
2
(
2
100
Q
Q
Q
Q
Q
Q
Q


GS-US-384-3914 Cohort 10-11 SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 27-Aug-2019
16:00:34
Biostatistics eSigned
27-Aug-2019
18:25:36
PPD
PPD--

SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Regimens in Subjects with 
Nonalcoholic Steatohepatitis (NASH)
Name of Test Drug:
CILO (cilofexor, GS-9674); FIR (firsocostat, GS-0976) 
Study Number:
GS-US-384-3914
Protocol Version (Date):
Amendment 12: 11 September 2019
Analysis Type:
Final Analysis, Cohorts 12-13
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
27 January, 2021
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
[r) GILEAU 


CILO+FIR
GS-US-384-3914
Statistical Analysis Plan – Cohorts 12-13
Version 1.0
CONFIDENTIAL
Page 2
27 January 2021
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF TABLES..........................................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Interim Analyses........................................................................................................................................9
2.1.1.
DMC Interim Analysis ............................................................................................................9
2.1.2.
Interim Analysis ......................................................................................................................9
2.2.
Final Analysis............................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Study Phases............................................................................................................................................10
3.1.1.
Pretreatment Phase ................................................................................................................10
3.1.2.
Treatment Phase ....................................................................................................................10
3.1.3.
Entire Study...........................................................................................................................10
3.2.
Analysis Sets ...........................................................................................................................................10
3.2.1.
All Randomized Analysis Set................................................................................................11
3.2.2.
Full Analysis Set....................................................................................................................11
3.2.3.
Safety Analysis Set................................................................................................................11
3.2.5.
Pretreatment Safety Analysis Set ..........................................................................................11
3.3.
Subject Grouping.....................................................................................................................................11
3.4.
Strata and Covariates...............................................................................................................................12
3.5.
Examination of Subject Subgroups .........................................................................................................12
3.6.
Multiple Comparisons .............................................................................................................................12
3.7.
Missing Data and Outliers.......................................................................................................................12
3.7.1.
Missing Data..........................................................................................................................12
3.7.2.
Outliers ..................................................................................................................................13
3.8.
Data Handling Conventions and Transformations ..................................................................................13
3.9.
Analysis Visit Windows..........................................................................................................................14
3.9.1.
Definition of Study Day ........................................................................................................14
3.9.1.1.
Study Day in Pretreatment Phase ....................................................................14
3.9.1.2.
Study Day in Treatment Phase ........................................................................15
3.9.2.
Analysis Visit Windows........................................................................................................15
3.9.2.1.
Analysis Windows for Pretreatment Phase......................................................15
3.9.2.2.
Analysis Visit Window for Treatment Phase ..................................................16
3.9.2.3.
Analysis Windows for Entire Study ................................................................16
3.9.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................17
4.
SUBJECT DISPOSITION ...................................................................................................................................18
4.1.
Subject Enrollment and Disposition........................................................................................................18
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................19
4.2.1.
Duration of Exposure to Study Drug.....................................................................................19
4.2.2.
Adherence to Study Drug ......................................................................................................20
4.3.
Protocol Deviations .................................................................................................................................20
CCI-


CILO+FIR 
GS-US-384-3914 
Statistical Analysis Plan - Coho1ts 12-13 
Version 1.0 
4.4. 
AssessinentofCOVID-19 Impact ........................................................................................................... 21 
4.4.1 
Study Thug or Study Discontinuation Due to COVID-19 ..................................................... 21 
4.4.2 
Protocol Deviations Due to COVID-19 ................................................................................ 21 
4.4.3. 
Missed and Viitual Visits due to COVID-19 ........................................................................ 21 
5. 
BASELINE CHARACTERISTICS ..................................................................................................................... 22 
5 .1. 
De1nographics .......................................................................................................................................... 22 
5.2. 
Other Baseline Characteristics ................................................................................................................ 22 
5.3. 
Medical Histo1y ....................................................................................................................................... 24 
I 
7. 
SAFETY ANALYSES ......................................................................................................................................... 28 
7 .1. 
Adverse Events and Deaths ..................................................................................................................... 28 
7.1.1. 
Adverse Event Dictiona1y ..................................................................................................... 28 
7.1.2. 
Adverse Event Severity ......................................................................................................... 28 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 28 
7.1.4. 
Serious Adverse Events ......................................................................................................... 28 
7.1.5. 
Treatinent-Emergent Adverse Events .................................................................................... 28 
7 .1.5.1. 
Definition of Treatinent-Emergent Adverse Events ........................................ 28 
7.1.5.2. 
Inco1npleteDates ............................................................................................. 29 
7.1.6. 
Summaries of Adverse Events and Deaths ............................................................................ 30 
7.1.6.1. 
Summaries of Adverse Events and Deaths in The Treatinent 
Phase ................................................................................................................ 30 
7.1.6.2. 
Summaries of Adverse Events and Deaths in The 
Pretreatinent Phase ........................................................................................... 32 
7.1.6.3. 
Summaries of Adverse Events and Deaths in The Entii'e 
Study ................................................................................................................ 32 
7.2. 
Laborato1y Evaluations ........................................................................................................................... 32 
7.2.1. 
Summaries of Numeric Laborat01y Results .......................................................................... 33 
7.2.1.1. 
Summaries of Numeric Laborato1y Results in the Treatment 
Phase ................................................................................................................ 33 
7.2.1.2. 
Summaries of Numeric Laborato1y Results in the 
Pretreatinent Phase and in the Entii'e Study ..................................................... 33 
7.2.2. 
Graded Laborato1y Values .................................................................................................... 34 
7 .2.2.1. 
Treatinent-Emergent Laborat01y Abnonnalities ............................................. 34 
7.2.2.2. 
Treatinent-Emergent Marked Laborat01y Abnormalities ................................ 35 
7.2.2.3. 
Summaries ofLaborat01 Abnonnalities ........................................................ 35 
-
7.2.4. 
Additional Summa1y ofLaborato1y Value ............................................................................ 37 
7.3. 
Sensitivity Analysis ................................................................................................................................. 38 
7.4. 
Vital Signs ............................................................................................................................................... 38 
7.5. 
Prior and Concolllitant Medications ........................................................................................................ 38 
7.5.1. 
Prior Medications .................................................................................................................. 39 
7.5.2. 
Conco1nitant Medications ...................................................................................................... 39 
7.6. 
Electrocardiogra1n Results ...................................................................................................................... .40 
7. 6 .1. 
Investigator Electi·ocardiogram Assessment ........................................................................ .40 
7. 7. 
Other Safety Measures ........................................................................................................................... .40 
7.8. 
Changes From Protocol-Specified Safety Analyses ............................................................................... .40 
CONFIDENTIAL 
Page3 
27 Janua1y 2021 


CILO+FIR 
GS-US-384-3914 
Statistical Analysis Plan - Coho1ts 12-13 
Version 1.0 
I 
9. 
REFERENCES .................................................................................................................................................... .42 
10. SOFTWARE ........................................................................................................................................................ .43 
11. SAP REVISION ................................................................................................................................................... 44 
12. APPENDICES ..................................................................................................................................................... .45 
Appendix 1. --
Appendix 4. 
Appendix 5. 
Table 3-1. 
Table 3-2. 
Table 3-3. 
CONFIDENTIAL 
Schedule of Assessment for GS-US-384-3914 Coho1ts 12 and 13 ........................................ .46 
CTCAE Grade for Laborato1 Parameters ............................................................................. .48 
Liver Function Prognostic Scores ............................................................................................ 53 
Dete1ming Missing and Vitmal Visits due to COVID-19 ....................................................... 54 
LIST OF TABLES 
~l::~~~:~::t i:i:,e!~iiiiii~~~~~. 
~~~.l~~~:.'. 
.................. 16 
Treatment Phase Analysis V1S1t Wmdows for Vital Signs,. 
Chemistiy, 
Hematology, Coagulation Panel, .... 
, Model for En -stage Liver Disease 
(MELD) Score, AST to Platelet ~
APRI), Fibrosis-4 (FIB-4), Non-
alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS), and Apolipoprotein 
Al and ApoB ........................................................................................................................... 16 
;;~i---~~~~. 
.. 
........... 17 
Page4 
27 Janua1y 2021 


CILO+FIR
GS-US-384-3914
Statistical Analysis Plan – Cohorts 12-13
Version 1.0
CONFIDENTIAL
Page 5
27 January 2021
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APRI
AST to platelet ratio
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CAP
controlled attenuation parameter
CI
confidence interval
CLDQ
chronic liver disease questionnaire
CILO
Cilofexor (GS-9674)
CK
creatine kinase
CK-18
cytokeratin-18
COVID-19
corona virus disease 2019
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
ELF
enhanced liver fibrosis
ET
early termination
FAS
Full Analysis Set
FENO
fenofibrate
FIB-4
fibrosis-4
FIR
Firsocostat (GS-0976)
FU
follow-up
GGT
gamma-glutamyl transferase
HA
hyaluronic acid
HDL
high density lipoprotein
HDL-C
HDL-cholesterol
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IFG
impaired fasting glucose
INR
international normalization ratio
LDL-C
low density lipoprotein cholesterol
CCI-


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Statistical Analysis Plan – Cohorts 12-13
Version 1.0
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LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
non-alcoholic fatty liver disease
NFS
NAFLD fibrosis score
PIIINP
procollagen III amino terminal peptide
PK
pharmacokinetics
PT
preferred term
Q1, Q3
first quartile, third quartile
SAP
statistical analysis plan
SD
standard deviation
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
TIMP-1
tissue inhibitor of metalloproteinase
ULN
upper limit of normal
VLDL-C
very low density lipoprotein cholesterol
WHO
World Health Organization
CCI-


CILO+FIR 
GS-US-384-3914 
Statistical Analysis Plan - Coho1ts 12-13 
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 final analysis for the clinical 
study repo1i (CSR) for Study GS-US-384-3914, Coho1is 12 and 13. This SAP is based on study 
protocol amendment 12 dated 11 September 2019 and the electronic case repo1i f01m (eCRF). 
This SAP is for the analyses of Coho1is 12 and 13, and includes Coho1is 12 and 13 data only. 
Any changes made after the finalization of the SAP will be documented in the CSR. 
1.1. 
Study Objectives 
The primaiy objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study dmg(s) in subjects with NAFLD/NASH. 
I 
I 
I 
I 
1.2. 
Study Design 
For Cohorts 12 and 13, eligible subjects will be randoinized to receive pretreatment with 
Vascepa 2 g twice daily or fenofibrate 145 mg once daily from Day-14 to Day -1 and will be 
treated with CILO 30 mg once daily, FIR 20 mg once daily, and Vascepa® 2 g twice daily; or 
CILO 30 mg once daily, FIR 20 mg once daily, and fenofibrate 145 mg once daily for 6 weeks as 
shown in the figure below. 
Treatment with Vascepa or fenofibrate will be initiated 2 weeks prior to dosing with CILO and 
FIR with the goal of lowering pretreatment triglyceride concentrations in order to Initigate 
possible increases in triglycerides that result from combination treatment with CILO and FIR . 
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Statistical Analysis Plan – Cohorts 12-13
Version 1.0
CONFIDENTIAL
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27 January 2021
* GS-0976 = FIR;  GS-9674 = CILO.
Approximately 60 subjects will be randomized (1:1) into either Cohort 12 or 13. Randomization 
will be stratified by screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥ 250 mg/dL and < 500 mg/dL]).

Cohort 12 (CILO 30 mg once daily + FIR 20 mg once daily+ Vascepa 2 g twice daily) will 
consist of 30 subjects

Cohort 13 (CILO 30 mg once daily + FIR 20 mg once daily + fenofibrate 145 mg once daily) 
will consist of 30 subjects
1.3.
Sample Size and Power
For Cohorts 12 and 13, it was assumed that among subjects with baseline hypertriglyceridemia 
(serum triglycerides ≥ 150 mg/dL and < 500 mg/dL), treatment with CILO+FIR once daily will 
lead to a mean increase in serum triglycerides of 60 mg/dL from baseline after 6 weeks of 
treatment. Assuming that the coadministration of Vascepa or fenofibrate with CILO+FIR will 
mitigate this increase in serum triglycerides and that the standard deviation for serum 
triglycerides after 6 weeks of treatment is 120 mg/dL, a sample size of 30 subjects in each cohort 
will provide 85% power to detect any increase based on a one-sided t-test at a significance level 
of 0.05.
.. ·= 
C: 
QJ 
QJ 
.x 
Cohort 12 
(n = 30) 
Cohort 13 
(n = 30) 
Pretreatment 
Vascepa 
2 
PO BID 
Pretreatment 
Fenofi brate 
145 m PO D 
2 Weeks (Day-14 t hrough Day-1) 
Treatment 6 weeks 
GS-0976 20 mg PO QD + GS-9674 30mg PO QD + 
Vascepa 2 g PO BID 
Treatment 6 weeks 
GS-0976 20 mg PO QD + GS-9674 30 mg PO QD + 
Fenofibrate 145 mg PO QD 
6 Weeks (Day 1 through Week 6) 
.... 
0 


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Statistical Analysis Plan – Cohorts 12-13
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2.
TYPE OF PLANNED ANALYSIS
This SAP is for the analyses of Cohorts 12 and 13 data only. 
2.1.
Interim Analyses
2.1.1.
DMC Interim Analysis
There will be no formal DMC review for Cohorts 12 and 13. Therefore, no analyses will be 
conducted for the DMC.
2.1.2.
Interim Analysis
No formal interim analysis was planned from protocol.
2.2.
Final Analysis
After all subjects in Cohorts 12 and 13 have completed the study, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the 
final analysis of the data will be performed.


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Statistical Analysis Plan – Cohorts 12-13
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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable). Data collected on log forms, 
such as AEs, will be presented in chronological order within the subject. The treatment group to 
which subjects were randomized will be used in the listings. Age, sex at birth, race, and ethnicity 
will be included in the listings, as space permits.
3.1.
Study Phases
Study phases are defined according to the study drug(s) which subjects take during the study.
3.1.1.
Pretreatment Phase
Pretreatment Phase is the phase when subjects take only Vascepa or fenofibrate study drug. It 
starts from the date of first dose of Vascepa or fenofibrate to the date before the first dose of 
CILO and FIR.
3.1.2.
Treatment Phase
Treatment Phase is the phase when subjects take CILO+FIR study drugs and through the follow-
up visit. It starts from the date of first dose of CILO+FIR to the end of study.
3.1.3.
Entire Study
Entire Study is the combination of the Pretreatment Phase and the Treatment Phase.
3.2.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects included will be summarized by 
treatment group. The denominator will be the number of subjects randomized in the 
corresponding treatment group. Subjects who have been randomized but never dosed will also be 
summarized. 
A listing of reasons for exclusion from analysis sets will be provided by subject.


CILO+FIR 
GS-US-384-3914 
Statistical Analysis Plan - Coho1ts 12-13 
3.2.1. 
All Randomized Analysis Set 
Version 1.0 
The All Randomized Analysis Set includes all subjects who were randomized into Coho1i 12 or 
13 of this study. 
3.2.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were randomized into either Coho1i 12 or 
13 and took at least 1 dose of CILO+FIR. 
This is the primaiy analysis set for efficacy analyses. 
3.2.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who took at least 1 dose of CILO+FIR. 
This is the primaiy analysis set for safety analyses. This analysis set will be used for safety 
analysis for Treatment Phase and Entire Study. 
-
3.2.5. 
Pretreatment Safety Analysis Set 
The Pretreatment Safety Analysis Set includes all subjects who received at least 1 dose of 
Vascepa or fenofibrate in the Pretreatment Phase. 
This is the analysis set for Pretreatment Phase safety analysis. 
3.3. 
Subject Grouping 
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were randomi~es based on the Safety Analysis Set, Pretreatment Safety 
Analysis Set, and_, subjects will be grouped according to the actual treatment 
received. The actual treatment received will differ from the randomized treatment only when 
their actual treatment differs from randomized treatment for the entire treatment dmation. 
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Statistical Analysis Plan – Cohorts 12-13
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For safety analysis of the Pretreatment Phase, subjects in the Pretreatment Safety Analysis Set 
will be analyzed and will be grouped into the following:
1) Vascepa 2 g PO BID
2) Fenofibrate 145 mg PO QD
For analysis of the Treatment Phase or the Entire Study, subjects in the Safety Analysis Set and 
 will be analyzed and will be grouped into the following:
3) CILO 30 mg PO QD + FIR 20 mg PO QD + Vascepa 2 g PO BID
4) CILO 30 mg PO QD + FIR 20 mg PO QD + Fenofibrate 145 mg PO QD
3.4.
Strata and Covariates
Subjects will be randomly assigned to treatment groups in a 1:1 ratio using a stratified 
randomization schedule. Stratification will be based on the following variables:

Screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or [≥ 250 mg/dL and
< 500 mg/dL])
3.5.
Examination of Subject Subgroups
Subgrouping of subjects based on pretreatment baseline triglyceride levels will be explored for 
subgroup analyses. Selected efficacy endpoints as defined in Section 6.2.3 will be summarized 
by treatment group and further by the following subgroups within each treatment group.

Pretreatment baseline triglyceride level ([ < 250 mg/dL] or [≥ 250 mg/dL])
3.6.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.7.
Missing Data and Outliers
3.7.1.
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 7.5.
CCI


CILO+FIR 
GS-US-384-3914 
Statistical Analysis Plan - Coho1ts 12-13 
3.7.2. 
Outliers 
Version 1.0 
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. 
3.8. 
Data Handling Conventions and Transformations 
The following conventions will be used for the imputation of date of bi1i h when it is pa1iially 
missing or not collected: 
• If only month and year of bi1i h is collected, then "15" will be imputed as the day of bi1ih 
• If only year of bi1i h is collected, then "01 July" will be imputed as the day and month of bi1i h 
• If year of biith is missing, then date ofbiith will not be imputed 
In general, age collected at Day 1 (in years) which is the date of first dose of study diug 
CILO+FIR will be used for analyses and presented in listings. If age at Day 1 is not available for 
a subject, then age derived based on the date of bi1i h and the Day 1 visit date will be used 
instead. If an enrolled subject was not dosed with CILO+FIR, the randomization date will be 
used instead of the Day 1 visit date. For screen failures, the date the first info1med consent was 
signed will be used for the age derivation. Age requii·ed 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 othe1w ise 
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 lower LOQ will be used to calculate descriptive statistics if 
the datum is repo1ied in the fonn of "< x" (where x is considered the lower LOQ). For 
example, if the values are repo1ied 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 summa1y statistics. 
• 
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is repo1ied in the fonn of"> x" (where xis considered the upper 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). 
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CILO+FIR 
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Statistical Analysis Plan - Coho1ts 12-13 
I 
I 
I 
I 
I 
3.9. 
3.9.1. 
3.9.1.1. 
Analysis Visit Windows 
Definition of Study Day 
Study Day in Pretreatment Phase 
Version 1.0 
Pretreatment study day will be calculated from the first dosing date of Vascepa or fenofibrate 
and derived as follows: 
• 
For postdose study days: Assessment Date -First Dosing Date of Vascepa/Fenofibrate + 1 
• 
For days prior to the first dose: Assessment Date - First Dosing Date ofVascepa/Fenofibrate 
Therefore, Pretreatment study day 1 is the day of first dose ofVascepa or fenofibrate 
administration. 
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CILO+FIR 
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Statistical Analysis Plan - Coho1ts 12-13 
Version 1.0 
3.9.1.2. 
Study Day in Treatment Phase 
Study day will be calculated from the first dosing date of CILO+FIRand derived as follows: 
• 
For postdose study days: Assessment Date - First Dosing Date of CILO+FIR + 1 
• 
For days prior to the first dose: Assessment Date - First Dosing Date of CILO+FIR 
Therefore, study day 1 is the day of first dose of CILO+FIR administration. 
3.9.2. 
Analysis Visit Windows 
Subject visits might not occm on protocol-specified days. Therefore, for the pmpose of analysis, 
observations will be assigned to analysis windows. 
For the Treatment Phase, in general, the baseline value is defined as the last available value 
• 
! 
• 
• 
• 
to and including the last dosing date plus 30 days will be mapped according to the analysis 
windows specified in Section 3.9.2.2 unless the nominal visit name is Follow-Up (FU). 
up 
For the Pretreatment Phase and the Entire Study, the baseline value is defined as the last 
available value collected on or prior to the first dosing date ofVascepa or fenofibrate. Only 
selected safety analysis will be conducted for the Pretreatment Phase and for the Entire Study. 
Selected safety lab data collected up to and including the first dosing date of CILO + FIR will be 
mapped according to the analysis window specified in Section 3 .9 .2.1 and summarized for the 
Pretreatment Phase. Selected safety lab data collected up to and including the last dosing date 
plus 30 days will be mapped according to the analysis window specified in Section 3.9.2.3 and 
summarized for the Entire Study. 
The unscheduled visits and early tennination (ET) visits will be windowed, but the follow-up 
(FU) visits will be summarized as a separate visit, and labeled "Follow-up Visit". Data obtained 
after the follow-up visit or last dose date plus 30 days (whichever is later) will be excluded from 
the summaries, but will be included in the listings. 
3.9.2.1. 
Analysis Windows for Pretreatment Phase 
Data included in the pre-treament safety analysis will include data collected from screening and 
up to and including the first dosing date of CILO+FIR. The analysis windows for selected safety 
data as specified in Section 7.2.1.2 are provided in Table 3-1. 
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CILO+FIR 
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Statistical Analysis Plan - Coho1t s 12-13 
Version 1.0 
Table 3-1. 
Pretreatment Phase Safety Analysis Visit Windows for Chemistry, 
Hematology, Coagulation Labs, and 
Nominal Pretreatment 
Visit Window Study Day 
Analysis Visit 
Study Day 
Lower Limit 
Upper Limit 
Pretreatment Baseline 
1 
(none) 
1 
Day 1 
15 
2 
2:: 15 if didn't take 
CILO+FIR 
1st dosing date of 
CILO+FIR if took 
CILO+FIR 
3.9.2.2. 
Analysis Visit Window for Treatment Phase 
Table 3-2. 
Analysis Visit 
Baseline 
Week4 
Week6 
Treatment Phase Analysis Visit Windows fo~-
Chemistry, Hematology, Coagulation Panel,_
, Model for 
End-stage Liver Disease (MELD) Score, AST to Platelet Ratio Index 
(APRI), Fibrosis-4 (FIB-4), Non-alcoholic Fatty Liver Disease 
(NAFLD) Fibrosis Score (NFS), and Apolipoprotein Al and ApoB 
Visit Window Study Day 
Nominal Study Day 
Lower Limit 
Upper Limit 
1 
(none) 
1 
29 
2 
35 
43 
36 
2:: 43 
* MELD, APRI, FIB-4 and NFS are defined in Appendix 3 and Appendix 4. 
3.9.2.3. 
Analysis Windows for Entire Study 
For the safety analysis of the Entire Study, no separate analysis windows will be created based 
on pretreatment study day or study day. Instead, the mapped analysis visits in both phases will be 
renamed as in Table 3-3 for entire study safety analysis. The pretreatment baseline is to be 
mapped to overall baseline. 
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CILO+FIR 
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Statistical Analysis Plan - Coho1ts 12-13 
Version 1.0 
Table 3-3. 
Entire Study Analysis Visit Rename for Chemistry, Hematology, 
Coagulation Labs, and 
Pretreatment/Treatment Phase 
Analysis Visit 
Pretreatment Baseline 
Day l 
Week 4 
Week 6 
Entire Study 
Analysis Visit 
Overall Baseline 
Overall Week 2 
Overall Week 6 
Overall Week 8 
3.9.3. 
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, measurements exist in an analysis window, records will be chosen 
based on the following mies if a single value is needed: 
• 
For baseline, the last nonmissing value on or prior to the first dosing date of study chug in the 
con esponding phase 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 abno1m al for safety electrocardiogram [ECG] 
findings) for categorical data. 
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 picked for analysis. 
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Statistical Analysis Plan – Cohorts 12-13
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group and overall for each 
country and investigator within a country. 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.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and study phase. This 
summary will present the number of subjects screened, the number of subjects who met all 
eligibility criteria but were not randomized with reasons subjects not randomized, the number of 
subjects randomized, and the number of subjects in each of the categories listed below:

Pretreatment Safety Analysis Set 

Completed pretreatment study drug

Did not complete pretreatment study drug with reasons for premature discontinuation of 
pretreatment study drug

Safety Analysis Set

Full Analysis Set

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study 

Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the All Randomized Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
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Statistical Analysis Plan – Cohorts 12-13
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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)

Subjects with different triglyceride levels (< 250 mg/dL vs ≥ 250 mg/dL) at between 
screening and at pretreatment baseline
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 relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Duration of exposure to study drug will be summarized for the Pretreatment Phase (Vascepa or 
fenofibrate only) by treatment group for the Pretreatment Safety Analysis Set, and for the Entire 
Study (CILO+FIR and Vascepa or fenofibrate) by treatment group for the Safety Analysis Set.
Total duration of exposure to Vascepa or fenofibrate in the Pretreatment Phase will be defined as 
the last dosing date of Vascepa or fenofibrate in the pretreatment phase or the date prior to the 
first dosing date of CILO+FIR, whichever is earlier, minus the first dosing date of Vascepa or 
fenofibrate plus 1 divided by 7, regardless of any temporary interruption in Vascepa or 
fenofibrate administration.
Total duration of exposure to study drug for the Entire Study will be summarized separately for 
Vascepa or fenofibrate, CILO, and FIR, and will be defined as last dosing date of the 
corresponding study drug minus first dosing date of the corresponding study drug plus 1 divided 
by 7, regardless of any temporary interruptions in study drug administration.
Total duration of exposure 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 in the Pretreatment Phase: 1 day, 1 week, 2 weeks, and the following time 
periods in the Treatment Phase: 1 day, 1 week, 4 weeks and 6 weeks.
No formal statistical testing is planned.


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4.2.2.
Adherence to Study Drug
The total number of doses administered will be summarized using descriptive statistics.
The presumed total number of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
The level of prescribed 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 specified by the 
protocol for a subject who completes treatment in the study.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Note: if calculated adherence rate is greater than 100%, the result will be set to 100%.
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (< 75%, ≥ 75 to < 90%, ≥ 90%) will be provided 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 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 an important protocol deviation.
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol








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4.4.
Assessment of COVID-19 Impact 
This study was ongoing during the novel coronavirus (2019 nCOV [COVID-19]) pandemic 
which has caused a disruption in the regular visit schedules for this study. Some subjects were 
unable to attend onsite visits due to shelter in place guidelines, site closures, or other reasons. 
This section provides how to handle special situations due to COVID-19 in the analysis.
4.4.1
Study Drug or Study Discontinuation Due to COVID-19
A similar summary as described in subject enrollment and disposition section of reasons for 
discontinuing study drug or study due to COVID-19 will be provided by treatment group and 
overall.
A by-subject listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be created.
4.4.2
Protocol Deviations Due to COVID-19
Similar summary as described in protocol deviations section will be performed for important 
protocol deviations due to COVID-19. The number and percentage of subjects with non-
important protocol deviations related to COVID-19 by number of deviations (e.g., at least 1, with 
1, 2, 3 or more deviations) will be summarized by treatment group.
A by-subject listing will be provided for subjects with important protocol deviation related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviation related to COVID-19.
4.4.3.
Missed and Virtual Visits due to COVID-19
A summary of subjects affected by the COVID-19 pandemic will be provided for each scheduled 
study visit by treatment group and overall. For each visit the summary will present the number 
and percentage of subjects who missed the visit due to COVID-19 or had a virtual visit due to 
COVID-19. For each column, the denominator for the percentage calculation will be the total 
number of subjects in the safety population for that column.
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order .
Information regarding missed or virtual visits due to COVID-19 was collected as free text in the 
CRF comment fields. The determination of missing or virtual visits due to COVID-19 was done 
using Natural Language Processing (NLP) to search the CRF comment fields.  A detailed 
explanation of the algorithm is given in Appendix 5.


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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. Age will be calculated in years at the date of first dosing date of CILO+FIR.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics will be summarized for the Treatment Phase only, which shows the 
baseline information before taking study drug CILO+FIR. These baseline characteristics include: 
 

Height (in cm)

Body mass index (BMI; in kg/m2) 

BMI category  (< 18.5 kg/m2, 18.5 to < 25 kg/m2, 25 to 30 kg/m2,  and ≥ 30 kg/m2)

Diabetes mellitus (absence or presence)

Smoking status

Screening triglyceride level category ([≥ 150 mg/dL and < 250 mg/dL] or [≥ 250 mg/dL and 
< 500 mg/dL])

Pretreatment triglyceride level ( < 250 mg/dL or ≥ 250mg/dL)

Pretreatment baseline (Day -14) triglycerides (mg/dL) 

Fasting triglycerides (mg/dL)

Total cholesterol (mg/dL)

High density lipoprotein -cholesterol (HDL-C) (mg/dL)

Calculated fasting non-HDL-C (equal to total cholesterol minus HDL-C) (mg/dL)
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
Calculated fasting very low density lipoprotein cholesterol (VLDL-C) (mg/dL) (equal to 
triglycerides divided by 5. If the triglyceride level is greater than 400 mg/dl, VLDL will not 
be calculated.) 

Calculated fasting low density lipoprotein cholesterol (LDL-C) (equal to non-HDL-C minus 
VLDL-C) (mg/dL)

APRI

FIB-4

NFS 

NFS category (< -1.455, -1.455 to < 0.676, and ≥ 0.676)

MELD score

Albumin (g/dL)

International normalized ratio (INR)

Fasting glucose (mg/dL)

Hemoglobin A1c (%)
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
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5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order and abnormalities in chronological order.


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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. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. 
The severity grade of events for which the investigator did not record severity will be 
categorized as “missing” for tabular summaries and data listings. The missing category will be 
listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
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 Global Patient Safety  
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) for Cohorts 12 and 13 will be summarized 
separately for the Pretreatment Phase and the Treatment Phase, as well as summarized for the 
Entire Study.
TEAEs in the Pretreatment Phase are defined as 1 or both of the following:

Any AEs with an onset date on or after the Vascepa or fenofibrate start date and no later than 
the date before the first dosing date of CILO+FIR

Any AEs leading to premature discontinuation of Vascepa or fenofibrate in the Pretreatment 
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TEAEs in the Treatment Phase are defined as 1 or both of the following:

Any AEs with an onset date on or after the CILO+FIR start date and no later than 30 days 
after permanent discontinuation of any study drugs

Any AEs leading to premature discontinuation of any study drug in the Treatment Phase.
TEAEs in the Entire Study are defined as 1 or both of the following:

Any AEs with an onset date on or after the Vascepa or fenofibrate start date and no later than 
30 days after permanent discontinuation of any study drugs

Any AEs leading to premature discontinuation of any study drug.
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 Vascepa or fenofibrate, 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 for the Pretreatment Phase 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 
Vascepa or fenofibrate, and

The AE onset date is the same as or before the month and year (or year) of the date prior to 
the first dosing date of CILO+FIR
The event is considered treatment emergent for the Treatment Phase 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 
CILO+FIR, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of any study drugs
The event is considered treatment emergent for the Entire Study 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 
Vascepa or fenofibrate, and

The AE onset date is the same as or before the month and year (or year) of the date 
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An AE with completely missing onset and stop dates will be considered treatment emergent in 
all phases. An AE with the onset date missing and a stop date later than the first dosing date of 
Vascepa or fenofibrate, will be considered to be treatment emergent in the Pretreatment Phase 
and in Entire Study; moreover, if the stop date is later than the first dosing date of CILO+FIR, it 
will also be considered to be treatment emergent for the Treatment Phase. 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 Vascepa or fenofibrate will be 
considered treatment emergent in the Pretreatment Phase and in Entire Study; moreover, if the 
incomplete stop date is with the same or later month and year (or year alone if month is not 
recorded) as the first dosing date of CILO+FIR, it will also be considered treatment emergent in 
the Treatment Phase.
7.1.6.
Summaries of Adverse Events and Deaths
The AEs will be summarized separately for the following phases. The Treatment Phase will 
include the most detailed summaries, while only selected summaries will be generated for either 
the Pretreatment Phase or Entire Study. Refer to detailed information in section 7.1.6.1-7.1.6.3.  

Treatment Phase (in Safety Analysis Set)

Pretreatment Phase (in Pretreatment Safety Analysis Set)

Entire Study (Safety Analysis Set)
7.1.6.1.
Summaries of Adverse Events and Deaths in The Treatment Phase
Treatment-emergent AEs in the Treatment Phase will be summarized based on the Safety 
Analysis Set.
A brief, high-level summary of the number and percentage of subjects who experienced at least 
1 TEAE during the Treatment Phase in the categories described below will be provided by 
treatment group. All deaths observed in the Treatment Phase will also be included in this 
summary.
The number and percentage of subjects who experienced at least 1 TEAE during the Treatment 
Phase will be provided and summarized by SOC, HLT (if applicable), PT, and treatment group. 
For other AEs described below, summaries will be provided by SOC, PT, and treatment group:

TEAEs by severity grade

TEAEs with Grade 3 or higher 

TEAEs with Grade 2 or higher

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
All TE treatment-related AEs by severity grade

TE treatment-related AEs with Grade 3 or higher 

TE treatment-related AEs with Grade 2 or higher

TE SAEs

TE treatment-related SAEs 

TEAEs leading to premature discontinuation of any study drug

TEAEs leading to premature discontinuation of study

TEAEs leading to dose modification or temporary interruption of any study drug

TEAEs leading to death (ie, outcome of death)
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized 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 summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study.
In addition to the above summary tables, the following tables will be summarized by PT only, in 
descending order of total frequency:

All TEAEs 

TEAEs with Grade 3 or higher 

TEAEs with Grade 2 or higher

TE treatment-related AEs

TE treatment-related AEs with Grade 3 or higher 

TE treatment-related AEs with Grade 2 or higher 

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7.1.6.2.
Summaries of Adverse Events and Deaths in The Pretreatment Phase
Treatment-emergent AEs in the Pretreatment Phase will be summarized based on the 
Pretreatment Safety Analysis Set.
A brief, high-level summary of AEs as generated for the treatment phase will be provided for the 
Pretreatment Phase AEs by treatment 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 
summary.
In addition to the above summary tables, the following tables will be summarized by PT only for 
Pretreatment Phase AEs, in descending order of total frequency:

TEAEs with Grade 3 or higher 

TE treatment-related AEs with Grade 3 or higher 

TE SAEs

TE treatment-related SAEs 
7.1.6.3.
Summaries of Adverse Events and Deaths in The Entire Study
Treatment-emergent AEs in the Entire Study will be summarized based on the Safety Analysis 
Set.
The same set of summaries generated for Pretreatment Phase AEs will be generated for the entire 
study AEs.
In addition, data listings for AEs in the Entire Study will be provided for the following:

All AEs, indicating whether the event is treatment emergent in each study phase

All AEs with severity of Grade 3 or higher

SAEs

All Deaths

All AEs leading to premature discontinuation of study drug 

All AEs leading to dose modifications or temporary interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Pretreatment Safety Analysis Set for the Pretreatment Phase analysis and will include data 
collected up to the first dosing date of CILO+FIR. Summaries of laboratory data will also be 
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and will include data collected up to the last dose of any study chugs plus 30 days for subjects 
who have pennanently discontinued study ch11g, 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 repo1i ed 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 sUllllnaiy 
statistics as specified in Section 3.7. Hemolized test results will not be included in the analysis, 
but they will be listed in by-subject laborato1y listings. 
A by-subject listing for laborato1y test results will be provided by subject ID number and visit in 
chronological order for hematology, sernm chemistiy, and coagulation separately for Treatinent 
Phase and the Entire Study. Values falling outside of the relevant reference range and/or having a 
severity grade of 1 or higher on CTCAE version 5.0 severity grade will be flagged in the data 
listings, as appropriate. 
No fonnal statistical testing is planned. 
7.2.1. 
7.2.1.1. 
Summaries of Numeric Laboratory Results 
Summaries of Numeric Laborato1y Results in the Treatinent Phase 
Descriptive statistics will be provided by tl'eatment group for creatinine, creatinine cleai·ance 
using the Cockcroft-Gault equation, white blood cells, neuti·ophils, lymphocytes, hemoglobin, 
and platelets, and will be sUllllnarized for the Treatment Phase as follows: 
• 
Baseline values 
• 
Values at each postbaseline visit 
• 
Change from baseline at each postbaseline visit 
A baseline laborato1y value will be defined as the last measurement obtained on or prior to the 
date of first dose of CILO+FIR. Change from baseline to a postbaseline visit will be defined as 
the visit value minus the baseline value. The mean, median, Ql, Q3, minimum, and maximum 
values will be displayed to the repo1ied number of digits; SD values will be displayed to the 
repo1i ed 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 3.9.3. 
7.2.1.2. 
Smnmai·ies of Numeric Laborato1y Results in the Preti·eatinent Phase and in the 
Entire Study 
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A baseline laborato1y value for these 2 periods will be defined as the last measurement obtained 
on or prior to the date of first dose of Vascepa or fenofibrate, and refe1Ted to as the pretreatment 
baseline. Change from pretreatment baseline to visits afte1wards will be summarized in the same 
way as in the treatment phase. Multiple values in an analysis window will be handled as in 
Section 3.9.3. 
7.2.2. 
Graded Laboratory Values 
The CTCAE Version 5.0 will be used to assign toxicity grades (0 to 4) to laborato1y results for 
analysis. Grade O includes all values that do not meet the criteria for an abno1mality of at least 
Grade 1. For laborato1y tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1. 
7.2.2.1.1. 
Treatment-Emergent Laborato1y Abno1malities 
Treatment-Emergent Laborato1y Abno1malities in the Treatment Phase 
Treatment-emergent laborato1y abno1malities in the Treatment Phase 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 any study diug plus 30 days for subjects who pennanently 
discontinued study diug, 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 laborato1y value is 
missing, any abno1mality of at least Grade 1 observed within the time frame specified above for 
the Treatment Phase will be considered treatment emergent. 
7.2.2.1.2. 
Treatment-Emergent Laborato1y Abno1malities in the Pretreatment Phase 
Treatment-emergent laborato1y abno1malities in the Pretreatment Phase are defined as values 
that increase at least 1 toxicity grade from pretreatment baseline at any post pretreatment 
baseline time point, up to and including the date of first dose of CILO+FIR. If the relevant 
pretreatment baseline laborato1y value is missing, any abnonnality of at least Grade 1 observed 
within the time frame specified above for the Pretreatment Phase will be considered treatment 
emergent. 
7.2.2.1.3. 
Treatment-Emergent Laborato1y Abno1malities in the Entire Study 
Treatment-emergent laborato1y abno1malities in the Entire Study are defined as values that 
increase at least 1 toxicity grade from pretreatment baseline at any post pretreatment baseline 
time point, up to and including the date of last dose of any study di11g plus 30 days for subjects 
who pe1manently discontinued study diug, or the last available date in the database snapshot for 
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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 for the Entire Study above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
7.2.2.2.1.
Treatment-Emergent Marked Laboratory Abnormalities in the Treatment Phase
Treatment-emergent marked laboratory abnormalities in the Treatment Phase 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 any 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 for the Treatment Phase will be considered treatment-emergent marked abnormalities.
7.2.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities in the Pretreatment Phase
Treatment-emergent marked laboratory abnormalities in the Pretreatment Phase are defined as 
values that increase at least 3 toxicity grade from pretreatment baseline at any post pretreatment 
baseline time point up to and including the date of first dose of CILO+FIR. If the relevant 
pretreatment baseline laboratory value is missing, any Grade 3 or 4 values observed within the 
time frame specified above for the Pretreatment Phase will be considered treatment emergent.
7.2.2.2.3.
Treatment-Emergent Laboratory Abnormalities in the Entire Study
Treatment-emergent laboratory marked abnormalities in the Entire Study are defined as values 
that increase at least 3 toxicity grade from pretreatment baseline at any post pretreatment 
baseline time point, up to and including the date of last dose of any 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 time 
frame specified above for the Entire Study will be considered treatment emergent.
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 for 
the Treatment Phase, and will be summarized using the number and percentage of subjects in the 
study with the given response at pretreatment baseline and each scheduled post pretreatment 
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The following summaries (number and percentage of subjects) for treatment-emergent laborato1y 
abnonnalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abno1mality grade for the Treatment Phase and the 
most severe post pretreatment baseline abno1mality grade for the Pretreatment Phase and the 
Entire Study, for a given lab test: 
• 
Graded laborato1y abno1m alities 
• 
Grade 3 or 4 laborato1y abno1m alities 
• 
Marked laborato1y abno1m alities 
For all summaries of laborato1y abno1malities, the denominator is the number of subjects with 
nonmissing postbaseline values for the Treatment Phase, and with nonmissing post pretreatment 
baseline values for the Pretreatment Phase and the Entire Study. 
By-subject listings of treatment-emergent Grade 3 or 4 and marked laborato1y abno1malities will 
be provided by subject ID number, and postbaseline visit in chronological for Treatment Phase, 
and post pretreatment baseline visit for Entire Study. The listings will include all test results that 
were collected throughout the study for the lab test of interest, with all applicable severity grades 
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Fasting triglycerides measured during the Pretreatment Phase and at Day 1 will be summarized 
by treatment group by visit and fmi her subgrouped by pretreatment baseline triglycerides level 
catego1y ([~ 150 mg/d.L and < 250 mg/d.L] or[~ 250 mg/d.L and < 500 mg/d.L]), for the 
Pretreatment Safety Analysis Group. The following by-visit sUilllnaiy will be reported. 
• 
Pretreatment baseline values 
• 
Values at each post pretreatment baseline visit 
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Change from baseline at each post pretreatment baseline visit 
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Fasting triglycerides grade measured during the Pretreatment Phase and at Day 1 will be 
summarized using the number and percentage of subjects at each toxicity grade by treatment 
group by visit, for the Pretreatment Safety Analysis Set. A similar summary further subgrouped 
by pretreatment baseline triglyceride level will also be generated.
7.3.
Sensitivity Analysis
Local laboratory test results were collected during the study due to COVID-19 for a few patients. 
Primary analysis will only include cenral laboratory results collected through Covance without 
additional specifying.  Sensitivity analysis will be performed as summary for selected laboratory 
parameters by including both central and local laboratory results.  
In laboratory parameters listings, all available central and local labs will be listed.
7.4.
Vital Signs
Descriptive statistics will be provided by treatment group for vital signs in the Treatment Phase 
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 CILO+FIR. 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 3.9.3. 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.
7.5.
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.


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7.5.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first dose of 
Vascepa or fenofibrate.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
Vascepa or fenofibrate 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 of Vascepa or fenofibrate. Medications with a completely missing start 
date will be included in the prior medication summary, unless otherwise specified.
Summaries will be based on the Pretreatment Safety Analysis Set. No formal statistical testing is 
planned.
7.5.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. 
Concomitant medications will be summarized separately for the Pretreatment Phase based on the 
Pretreatment Safety Analysis Set and for the Treatment Phase based on the Safety Analysis Set. 
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 Vascepa or fenofibrate and continued to be taken after the first Vascepa or fenofibrate dosing 
date, or started after the first Vascepa or fenofibrate dosing date but prior to the first dosing date 
of CILO+FIR will be considered concomitant medications in the Pretreatment Phase. Any 
medication with a start date prior to or on the first dosing date of CILO+FIR and continued to be 
taken after the first CILO+FIR dosing date, or started after the first CILO+FIR dosing date but 
prior to the last dosing date of CILO+FIR will be considered concomitant medication in the 
Treatment Phase. Medications started and stopped on the same day as the first dosing date or the 
last dosing date of Vascepa or fenofibrate/CILO+FIR will also be considered concomitant in the 
Pretreatment/Treatment Phase. Medications with a stop date prior to the date of first dosing date 
of Vascepa or fenofibrate or a start date after the first dosing date of CILO+FIR will be excluded 
from the concomitant medication summary for the Pretreatment Phase. Medications with a stop 
date prior to the date of the first dosing date of CILO+FIR or a start date after the last dosing date 


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of CILO+FIR will be excluded from the concomitant medication summary for the Treatment 
Phase. 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 in the corresponding phase will be excluded from the concomitant medication 
summary for that phase. 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 CILO+FIR start date will be 
excluded from the concomitant medication summary for the Pretreatment Phase, and any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
after the CILO+FIR stop date will be excluded from the concomitant medication summary for 
the Treatment Phase. Medications with completely missing start and stop dates will be included 
in the concomitant medication summary in both phases, unless otherwise specified. 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.
7.6.
Electrocardiogram Results
7.6.1.
Investigator Electrocardiogram Assessment
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.7.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.8.
Changes From Protocol-Specified Safety Analyses
CTCAE version 4.03 will be used for the severity garde of AEs. While CTCAE 5.0 will be used 
for the severity grade of lab abnormalities.


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


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


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


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12.
APPENDICES
Appendix 1.
Schedule of Assessment for GS-US-384-3914 Cohorts 12 and 13
Appendix 2.
CTCAE Grade for Laboratory Parameters
Appendix 4.
Liver Function Prognostic Scores
Appendix 5.
Determing Missing and Vitrual Visits due to COVID-19
CCI-


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Appendix 1.
Schedule of Assessment for GS-US-384-3914 Cohorts 12 and 13
Pretreatment 
Period/ 
Enrollment
TreatmentPeriod
End of 
Treatment
ET
Phone 
Follow-Up
ET Phone 
Follow-Up
Screena
D-14
D1b
D28(W4)(±3d)
D42 (W6) 
(±3d)
ET
D56 (W8) 
(±5d)
2 Weeks 
After Last 
Dose
ClinicalAssessment
Informed Consent
X
Determine Eligibilityc
X
X
Medical History
X
X
Assess Ascites and Hepatic 
Encephalopathy
X
CPTScore
X
Physical Examination
X
Xd
Xd
Xd
Xd
Xd
Vital Signs
X
X
X
X
X
X
Height
X
12-leadECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Dispense Vascepa® 
(Cohort12)
X
X
Dispense Fenofibrate 
(Cohort13)
X
Dispense FIR and CILO
X
X
Review of Study Drug 
Dosing Compliance (Pill 
Count)
Xe
X
X
CCI


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a 
b 
C 
d 
e 
f 
Chemistry 
Hematology 
Coagulation Panel 
Pregnancy Testf 
Hemoglobin Ale 
Urine Dmg Screening 
HIV-1, HBV &HCV 
Serology 
Genomic Sample i 
Screen• 
X 
X 
X 
X 
X 
X 
X 
Pretreatment 
Pe1iod/ 
Enrollment 
D-14 
X 
X 
X 
X 
Dlb 
X 
X 
X 
X 
X 
X 
TreatmentPeriod 
D28(W4)(±3d) 
X 
X 
X 
X 
End of 
Phone 
ET Phone 
Treatment 
ET 
Follow-Up 
Follow-Up 
2 Weeks 
D42 (W6) 
D56 (WS) 
After Last 
(±3d) 
ET 
(±Sd) 
Dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening assessments to be completed within 4 weeks prior to Day -14 visit. The screening period also may be extended under special circumstances with the explicit approval 
of Gilead Sciences. 
Day I assessments must be performed prior to dosing. 
Includes review of historical liver biopsy obtained within 6 months of the Screening Visit for subjects without compensated cinhosis (F4) or within 12 months of the 
Screening Visit for subjects with compensated cin-hosis (F4); or review of historical MRE or historical FibroScan® obtained within 6 months of the Screening Visit. 
Symptom driven physical examination. 
Vascepa®(Coho,t 12) or fenofibrate (Coho,t 13) only 
Females of childbearing potential only: Semm pregnancy testing at screening, urine pregnancy testing will occur at D-14, DI, D28, D42, and 2 weeks after last dose of study 
drug. Home urine regnanc test for Phone Follow-U will be rovided at the D42 Visit or ET Visit. 
or su 1ects who have not opted out of sample collection. No additional blood will be drawn. 
CONFIDENTIAL 
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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
 -
 -
 -
 -
Blood bilirubin 
increased
>ULN - 1.5 x ULN if 
baseline was normal; > 1.0 - 
1.5 x baseline if baseline 
was abnormal
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline if 
baseline was abnormal
>3.0 - 10.0 x ULN if baseline 
was normal; >3.0 - 10.0 x 
baseline if baseline was 
abnormal
>10.0 x ULN if baseline was 
normal; >10.0 x baseline if 
baseline was abnormal
 -
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
 -
CCI
CCI


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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 
Corrected serum 
calcium of >11.5 - 12.5 
mg/dL; >2.9 - 3.1 
mmol/L; Ionized 
Corrected serum calcium of 
>12.5 - 13.5 mg/dL; >3.1 - 
3.4 mmol/L; Ionized calcium 
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L; 
Death
CCI


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
calcium >ULN - 1.5 
mmol/L
calcium >1.5 - 1.6 
mmol/L; symptomatic
>1.6 - 1.8 mmol/L; 
hospitalization indicated
Ionized calcium >1.8 mmol/L; 
life-threatening consequences
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


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
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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Appendix 4.
Liver Function Prognostic Scores

MELD Score Calculation
MELD score = 3.78 [Ln total bilirubin (mg/dL)] + 11.2 [Ln INR] + 9.57 [Ln serum creatinine 
(mg/dL)] + 6.43. If the serum creatinine, the total bilirubin or the INR value is < 1.00 mg/dL, the 
calculation will use 1.00 as the test value. If the serum creatinine is > 4.00 mg/dL or subjects on 
dialysis, the calculation will use 4.00 as the serum creatinine value.


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Appendix 5.
Determing Missing and Vitrual Visits due to COVID-19
This appendix describes the site collection of COVID-19 data as pertains to missed/virtual visits 
and the data processing algorithm used to determine which visits were missing and which visits 
were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic.  If a visit was missed, sites should enter “Visit 
missed due to COVID-19.”  If an in-person visit was conducted virtually, sites should enter 
“Virtual visit due to COVID-19.”  
Determination of Missed and Virtual visits
Natural Language Processing (NLP) was used to search the CRF comment fields to identify 
instances of “COVID-19” (or synonyms, see Appendix Table 1) and “Virtual” (or synonyms, 
see Appendix Table 1).  The search terms are maintained in a global lookup table and can be 
modified to tune the NLP model.  For any comments with COVID-19 search terms, assign 
“Missed visit” or “Virtual visit as follows:
i)
If COVID-19 terms are identified through NLP and the visit date is missing, then result is 
”Missed Visit”
ii) If COVID-19 and Virtual terms are identified through NLP for a visit, then result is “Virtual 
Visit”. When there are multiple records for the same subject and the same visit, NLP will be 
based on multiple records to ensure 1 unique category per subject per visit
iii) Otherwise result is missing
Appendix Table 1.
Examples of search terms for “COVID-19” and “Virtual” used to 
identify missed and virtual visits.
Search terms for “COVID-19”
Search terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-384-3914 Cohort 12-13 SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 01-Feb-2021
22:35:11
Biostatistics eSigned
02-Feb-2021
06:54:28
PPD
PPD-

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Regimens in Subjects with Nonalcoholic 
Steatohepatitis (NASH)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404 
IND Number:
Clinical Trials.gov 
Identifier:
141683
NCT02781584
Indication:
Nonalcoholic steatohepatitis (NASH)
Protocol ID:
GS-US-384-3914
Contact Information:
The medical monitor name and contact information will be provided 
on the Key Study Team Contact List.  
Protocol Version/Date:
Original:
13 April 2016
Amendment 1:
19 May 2016
Amendment 2:
14 July 2016
Amendment 3:
07 October 2016
Amendment 4:
22 December 2016
Amendment 5:
22 February 2017
Amendment 6:
28 April 2017
Amendment 7: 
05 June 2017
Amendment 8:
03 November 2017
Amendment 9:
14 June 2018
Amendment 10:
13 July 2018
Amendment 11:
26 September 2018
Amendment 12:
11 September 2019
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
GILEAU 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................................ 2 
LIST OF IN-TEXT FIGURES ........................................................................................................................................ 6 
PROTOCOL SYNOPSIS ................................................................................................................................................ 7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 25 
1. 
INTRODUCTION ................................................................................................................................................ 31 
1.1. 
Background .............................................................................................................................................. 31 
1.2. 
General Infonnation for Selonseit ib ........................................................................................................ 32 
1.2.1. 
Selonse11ib ............................................................................................................................. 32 
1.2.2. 
Preclinical Phannacology and Toxicology ............................................................................ 33 
1.2.3. 
Clinical Trials ofSelonseitib ................................................................................................. 33 
1.3. 
General Infonnation for GS-0976 ........................................................................................................... 33 
1.3.1. 
GS-0976 ................................................................................................................................. 33 
1.3.2. 
Nonclinical Pha1macology .................................................................................................... 33 
1.3 .3. 
Nonclinical Toxicology ......................................................................................................... 34 
1.3.4. 
Nonclinical Pha1macokinetics ............................................................................................... 35 
1.3.5. 
Clinical Trials of GS-0976 .................................................................................................... 36 
1.4. 
General Infonnation for GS-9674 ........................................................................................................... 44 
1.4.1. 
GS-9674 ................................................................................................................................. 44 
1.4.2. 
Nonclinical Pha1macology, Phannacokinetics, Drng Metabolism, and 
Toxicology ............................................................................................................................. 44 
1.4.3. 
Clinical Trials of GS-9674 ................................................................................................... .45 
1.5. 
Combination Studies ofSelonse11ib, GS-9674, and GS-0976 ................................................................ 49 
1.5.1. 
Nonclinical Pha1macology, Phannacokinetics, Drng Metabolism, and 
Toxicology ............................................................................................................................ .49 
1.5.2. 
Clinical Trials ........................................................................................................................ 51 
1.6. 
Info1mation about Fenofibrate ................................................................................................................. 57 
1.7. 
Info1mation about Vascepa® .................................................................................................................... 58 
1.8. 
Rationale for This Study .......................................................................................................................... 58 
1.8.1. 
Rationale for Dose Selection of Selonseit ib .......................................................................... 61 
1.8.2. 
Rationale for Dose Selection of GS-0976 ............................................................................. 61 
1.8.3. 
Rationale for Dose Selection of GS-9674 ............................................................................. 62 
1.8.4. 
Rationale for Dose Selection of Selonse1t ib, GS-9674, and/or GS-0976 in 
Combination .......................................................................................................................... 62 
1.8.5. 
Rationale for Dose Selection of GS-0976 + Fenofibrate in Combination ............................. 62 
1.8.6. 
Rationale for Dose Selection ofGS-0976 + GS-9674 + Vascepa® in 
Combination .......................................................................................................................... 63 
1.8.7. 
Rationale for Dose Selection ofGS-0976 + GS-9674 + Fenofibrate in 
Combination .......................................................................................................................... 63 
1.8.8. 
Rationale for Study Population ............................................................................................. 63 
1.9. 
Coinpliance .............................................................................................................................................. 64 
2. 
OBJECTIVES ....................................................................................................................................................... 65 
3. 
STUDY DESIGN ................................................................................................................................................. 66 
3.1. 
3.2. 
Study Design ........................................................................................................................................... 66 
Treattnent Plan and Re ·1nen .................................................................................................................. 66 
CONFIDENTIAL 
Page2 
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Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
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4.
SUBJECT POPULATION...................................................................................................................................72
4.1.
Number of Subjects and Subject Selection .............................................................................................72
4.2.
Inclusion Criteria.....................................................................................................................................72
4.3.
Exclusion Criteria....................................................................................................................................75
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................78
5.1.
Randomization.........................................................................................................................................78
5.2.
Description and Handling of Selonsertib ................................................................................................78
5.2.1.
Formulations..........................................................................................................................78
5.2.2.
Packaging and Labeling ........................................................................................................78
5.2.3.
Storage and Handling ............................................................................................................78
5.3.
Description and Handling of GS-0976....................................................................................................79
5.3.1.
Formulations..........................................................................................................................79
5.3.2.
Packaging and Labeling ........................................................................................................79
5.3.3.
Storage and Handling ............................................................................................................80
5.4.
Description and Handling of GS-9674....................................................................................................80
5.4.1.
Formulation ...........................................................................................................................80
5.4.2.
Packaging and Labeling ........................................................................................................80
5.4.3.
Storage and Handling ............................................................................................................81
5.5.
Description and Handling of Fenofibrate................................................................................................81
5.5.1.
Formulation ...........................................................................................................................81
5.5.2.
Packaging and Labeling ........................................................................................................81
5.5.3.
Storage and Handling ............................................................................................................81
5.6.
Description and Handling of Vascepa®...................................................................................................82
5.6.1.
Formulation ...........................................................................................................................82
5.6.2.
Packaging and Labeling ........................................................................................................82
5.6.3.
Storage and Handling ............................................................................................................82
5.7.
Dosage and Administration .....................................................................................................................82
5.7.1.
Selonsertib .............................................................................................................................82
5.7.2.
GS-0976.................................................................................................................................82
5.7.3.
GS-9674.................................................................................................................................83
5.7.4.
Selonsertib + GS-9674 ..........................................................................................................83
5.7.5.
Selonsertib + GS-0976 ..........................................................................................................83
5.7.6.
GS-0976 + GS-9674..............................................................................................................83
5.7.7.
SEL + GS-0976 + GS-9674...................................................................................................83
5.7.8.
GS-0976 + Fenofibrate..........................................................................................................84
5.7.9.
GS-0976 + GS-9674 + Vascepa® ..........................................................................................84
5.7.10.
GS-0976 + GS-9674 + Fenofibrate .......................................................................................84
5.8.
Prior and Concomitant Medications........................................................................................................84
5.8.1.
Prohibited Medications for Use with Administration of Selonsertib ....................................85
5.8.2.
Prohibited Medications for Use with Administration of GS-0976........................................86
5.8.3.
Prohibited Medications for Use with Administration of GS-9674........................................87
5.8.4.
Medications to Be Used with Caution with Fenofibrate .......................................................87
5.8.5.
Medications to Be Used with Caution with Vascepa® ..........................................................88
5.9.
Study Drug Accountability......................................................................................................................88
5.9.1.
Investigational Medicinal Product Return or Disposal .........................................................89
6.
STUDY PROCEDURES......................................................................................................................................90
6.1.
Subject Enrollment and Treatment Assignment......................................................................................90
6.2.
Screening Assessments for Cohorts 1-11................................................................................................90
6.2.1.
Screening Visit (Cohorts 1-11)..............................................................................................90
6.3.
Pretreatment Assessments for Cohorts 1-11............................................................................................92
6.3.1.
Day -14 Visit (Cohorts 1-11).................................................................................................92


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
6.3.2. 
Day -11 and Day -7 Visits(± 1 Day) (Cohorts l-11) ............................................................ 94 
6.4. 
Treatinent Assessments for Cohorts 1-11 ................................................................................................ 94 
6.4.1. 
Day I Visit(Coho11s l -11) .................................................................................................... 94 
6.4.2. 
Day 7 (Week I) Visit(± 3 days) (Coho11s l-11) ................................................................... 96 
6.4.3. 
Day 14 (Week 2) Visit (±1 day) (Coho1ts 1-9) ..................................................................... 97 
6.4.4. 
Day 17 (± 1 day) and Day 21 (Week 3) Visits(± 1 day) (Coho1ts l -9) ................................ 98 
6.4.5. 
Day 28 (Week 4) Visit(± 3 days) (Coho11s l-11) ................................................................. 98 
6.4.6. 
Day 35 (Week 5) Visit(± 3 days) (Coho11s 1-3) ................................................................. 100 
6.4.7. 
Day 56 (Week 8) Visit(± 3 days) (Coho11s l-1 l) ............................................................... 100 
6.4.8. 
Day 70 (Week 10) Visit(± I Day) (Coh01ts 1-11) ............................................................. 101 
6.4.9. 
Day73 and Day 77 (Week II) Visits(± I day) (Coho1ts 1-11) ......................................... 101 
6.4.10. 
Day 84 (Week 12) Visit (±3 days) / End of Treatment (Coh01ts 1-9) ................................ 102 
6.4.11. 
Day 84 (Week 12) Visit (±3 days) (Cohorts 10-l 1) ............................................................ 103 
6.4.12. 
Day 91 (Week 13) Visit(± 3 days) (Coho11s 1-3) ............................................................... 105 
6.4.13. 
Day 112 (Week 16) Follow up Visit(± 5 days) (Coh01ts 1-9) ........................................... 105 
6.4.14. 
Day 112 (Week 16) Visit(± 3 days) (Coho11s 10-11) ......................................................... 106 
6.4.15. 
Day 126 Visit (Week 18) (± 3 days) (Coho11s 10-11) ......................................................... 106 
6.4.16. 
Day 154 (Week 22) Visit(± I day) (Coho1ts 10-11) .......................................................... 107 
6.4.17. 
Day 157 (± 1 day) and Day 161 Visits(± 1 day) (Week 23) 
(Coho1ts 10-11) ................................................................................................................... 108 
6.4.18. 
Day 168 (Week 24) Visit (±3 days) / End of Treatment (Coho1ts 10-11) .......................... 108 
6.4.19. 
Day 196 (Week 28) Follow up Visit(± 5 days) (Coh01ts 10-11) ....................................... 110 
6.4.20. 
Early Termination (ET) Visit (Coho1ts 10 - 11) .................................................................. l 10 
6.4.21. 
UnscheduledVisits .............................................................................................................. 112 
6.5. 
STUDY PROCEDURES FOR COHORTS 12-13 ................................................................................ 112 
6.5.1. 
Screening Assessments for Cohorts 12-13 .......................................................................... 112 
6.5.2. 
Preti·eatment Assessments for Cohorts 12-13 ...................................................................... l 13 
6.5.3. 
TreatmentAssessment.sforCohorts 12-13 .......................................................................... 114 
6.5.4. 
Post.treatment Assessments for Cohorts 12-13 .................................................................... 118 
6.6. 
Assessments for Premature Discontinuation from Study ...................................................................... 119 
6. 7. 
Criteria for Discontinuation of Study Treatment.. ................................................................................. 119 
6.8. 
Description of Assessinents ................................................................................................................... 120 
6.8.1. 
Clinical Laborato1y Analytes .............................................................................................. 120 
6.8.2. 
Electrocardio -a1n ............................................................................................................... 120 
6.8.5. 
6.8.6. 
6.8.7. 
6.8.8. 
6.8.9. 
6.8.10. 
6.8.11. 
1111 
Medical Histo1y ................................................................................................................... 121 
Physical Examination .......................................................................................................... 121 
Vital Signs ........................................................................................................................... 121 
Pregnancy Testing ............................................................................................................... 122 
Quality of Life (QoL) Measures .......................................................................................... 122 
Child-Pugh-Tw·cotte Score .................................................................................................. 122 
Creatinine Clearance ........................................................................................................... 123 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT .............................................................................. 124 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ............................... 124 
7 .1.1. 
Adverse Events .................................................................................................................... 124 
7 .1. 2. 
Serious Adverse Events ....................................................................................................... 125 
7 .1.3. 
Clinical Laborato1y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ........................................................................ 126 
7.2. 
Assessment. of Adverse Events and Serious Adverse Events ................................................................ 126 
7.2.1. 
Assessment. of Causality for Study Thugs and Procedw-es ................................................. 126 
7.2.2. 
Assess1nent. of Severity ........................................................................................................ 127 
CONFIDENTIAL 
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II September 2019 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
7.3. 
Investigator Repo1ting Requirements and Instrnctions for Adverse Events and Serious 
Adverse Events to Gilead ...................................................................................................................... 127 
7.4. 
Gilead Repo1ting Requirements ............................................................................................................ 129 
7.5. 
Toxicity Manageinent ............................................................................................................................ 129 
7.5.1. 
Observation for Drng Induced Liver Injwy (DILi): (Coho1ts 1-9) ..................................... 129 
7.5.2. 
Observation for Drng Induced Liver Injwy (DILi) (Coho1ts 10-13) .................................. 131 
7.5.3. 
CPT Score (Coho11s 10-11) ................................................................................................. 134 
7 .5 .4. 
Hype11riglyceridelllia ........................................................................................................... 134 
7.6. 
Special Situations Repoits ..................................................................................................................... 136 
7 .6.1. 
Definitions of Special Situations ......................................................................................... 136 
7.6.2. 
Instrnctions for Reporting Special Situations ...................................................................... 137 
8. 
STATISTICAL CONSIDERATIONS ............................................................................................................... 139 
8.1. 
Analysis Objectives and Endpoints ....................................................................................................... 139 
8.1.1. 
Analysis Objectives ............................................................................................................. 139 
8.1.2. 
Pri1nru End oint. ................................................................................................................ 139 
-
8.2. 
Analysis Conventions ............................................................................................................................ 140 
8.2.1. 
Analysis Sets ....................................................................................................................... 140 
8.2.2. 
Interi1n Analysis .................................................................................................................. 141 
8.3. 
Data Handling Conventions .................................................................................................................. 142 
8.4. 
Demographic Data and Baseline Characteristics .................................................................................. 142 
8.5. 
Efficacy Anal sis ................................................................................................................................... 142 
-
8.6. 
Safety Analysis ...................................................................................................................................... 143 
8.6.1. 
Extent ofExposw·e .............................................................................................................. 143 
8.6.2. 
Adverse Events .................................................................................................................... 143 
8.6.3. 
Laborato1y Evaluations ....................................................................................................... 143 
Other Safe Evaluations ..................................................................................................... 143 
8.8. 
8.8.1. -
8.9. 
Sample Size ........................................................................................................................................... 144 
8.10. 
Data Monitoring Co1nmittee .................................................................................................................. 145 
9. 
RESPONSIBILITIES ......................................................................................................................................... 146 
9. I. 
Investigator Responsibilities ................................................................................................................. 146 
9 .1.1. 
Good Clinical Practice ......................................................................................................... 146 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Comlllittee (IEC) 
Review and Approval .......................................................................................................... 146 
9.1.3. 
Info1med Consent ................................................................................................................ 147 
9.1.4. 
Confidentiality ..................................................................................................................... 147 
9.1.5. 
Study Files and Retention of Records ................................................................................. 147 
9 .1. 6. 
Electronic Case Repo1t F onns ............................................................................................. 14 9 
9.1.7. 
Investigational Medicinal Product Accountability and Retwn ........................................... 149 
9.1.8. 
Inspections ........................................................................................................................... 149 
9.1.9. 
Protocol Compliance ........................................................................................................... 149 
9.2. 
Sponsor Responsibilities ....................................................................................................................... 150 
9.2.1. 
Protocol Modifications ........................................................................................................ 150 
9.2.2. 
Study Report and Publications ............................................................................................ 150 
9.3. 
Joint Investigator/Sponsor Responsibilities .......................................................................................... 150 
9 .3 .1. 
Payment Repo1ting .............................................................................................................. 150 
9.3.2. 
Access to Infonnation for Monitoring ................................................................................. 151 
CONFIDENTIAL 
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II September 2019 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
9 .3 .3. 
Monitoring and Oversight of Biomarker Specimens ........................................................... 151 
9 .3 .4. 
Access to Infonnation for Auditing or Inspections ............................................................. 151 
9 .3 .5. 
Study Discontinuation ......................................................................................................... 151 
10. REFERENCES ................................................................................................................................................... 152 
11. APPENDICES .................................................................................................................................................... 156 
Appendix 1. 
Appendix 2. 
Appendix 3. 
Appendix 4. 
Investigator Signature Page ................................................................................................... 157 
Study Procedures Tables for GS-US-384-3914 ..................................................................... 158 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements .................................................................................................. 166 
Child-Pugh-Turcotte Classification of the Severity of Cinhosis .......................................... 170 
LIST OF APPENDIX TABLES 
Appendix Table 1. 
Appendix Table 2. 
Appendix Table 3. 
(Coho1ts l-9) .................................................................................................. 158 
(Coho1ts 10-l 1) .............................................................................................. 161 
(Coho1ts 12-13) .............................................................................................. 164 
Table 1-1. 
Table 1-2. 
Table 1-3. 
Table 1-4. 
Table 1-5. 
Table 1-6. -
Table 5-1. 
Table 5-2. 
Table 5-3. 
Table 5-4. 
Table 5-5. 
Filllil'e 1-1. 
Figure 7-3. 
Figure 7-4. 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Prelirnina1y Phannacokinetic Results from Study GS-US-426-4074 Evaluating 
DDis with GS-0976 (20 mg or 50 mg) .................................................................................... 38 
GS-US-426-3988: Prelimina1y GS-0976 and GS-834773 PK Parameters Following 
a Single Dose of GS-0976 20 mg in Subjects with Mild or Moderate Hepatic 
Impaiiment or Nonnal Hepatic Function ............................................................................... .40 
GS-US-402-3885: Prelimina1y GS-9674, GS-716070, and GS-1056756 PK 
Parameters Following a Single Dose ofGS-9674 30 mg or 10 mg in Subjects with 
Hepatic Impaiiment or Nonnal Hepatic Function .................................................................. .48 
GS-US-402-2101: Changes in prima1y 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 .................................... 53 
GS-US-384-3914: Safety Summa1y ........................................................................................ 56 
GS-US-384-3914: Treatrnent-Emeroent Grade 3 and 4 Lab Abnonnali Summar ............. 57 
List of Medications Prohibited and to Be Used with Caution ................................................. 86 
List of Disallowed Medications ............................................................................................... 86 
List of Medications Prohibited and to Be Used with Caution ................................................. 87 
List of Medications to Be Used with Caution ......................................................................... 88 
List of Medications to Be Used with Caution ......................................................................... 88 
LIST OF IN-TEXT FIGURES 
Algorithm for Monitoring and Treatment of Hypert1·iglycerideinia for Coho1ts 12-13 ........ 136 
Page6 
11 September 2019 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Number of Subjects 
Planned: 
Target Population: 
Duration of 
Treatment: 
Duration of Study: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Dr. 
Foster City, CA 94404 USA 
Final 
Amendment 12 
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Regimens in Subjects with 
Nonalcoholic Steatohepatitis (NASH) 
141683 
NCT02781584 
Approximately 10 centers in the United States and New Zealand 
Approximately 230 Subjects 
Males and non-pregnant, non-lactating females between 18-75 years 
(Cohorts 1-9) and ::::18 years (Coho1is 10-13) of age with 
NAFLD/NASH. 
Up to 24 weeks 
Pa1i icipation in the study can last up to 36 weeks, which includes up 
to a 6-week screening period, a 2-week pretreatment assessment 
period, up to a 24-week treatment period, and up to a 4-week 
follow-up period 
The primaiy objective of this study is as follows: 
To evaluate the safety and tolerability of study drng(s) in subjects 
with NAFLD/NASH. 
Page7 
11 September 2019 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
I 
I 
I 
I 
I 
I 
Final 
Amendment 12 
This is a proof of concept, open-label study evaluating the safety, 
tolerability, and efficacy of monotherapy and combination regimens 
in subjects with NAFLD/NASH. 
For Coho1is 1 through 9, eligible subjects will be enrolled to receive 
treatment with selonsertib (SEL; GS-4997), GS-0976, GS-9674; the 
combination of SEL and GS-9674, SEL and GS-0976, GS-9674 and 
GS-0976; or SEL, GS-0976 and GS-9674 for 12 weeks as shown in 
the figure below. 
Non-dnhotit 
Cohort L 
SEL 18 Mgl>O QO(l'I • tOt 
GS•OWI) 20 l"'l.g POOO(": 101 
Cohort J 
GS-9074 30mg POQJ)(n: lO) 
Cohort 4 
S£Llt In& • GS-967.t )0 m11 POQO (nS20) 
Coh01'1:S 
SELUm ;, GS-C97020 
PO OP nilO) 
Cohon6 
G.S.9674 30mg•GS.o976 :0 mg POQO (!'\S lO) 
Cirrhotic 
Cohort 7 
20 m11 PO QO Ins 10t 
Cohort I 
GS-9674 301'!'11 POQO(nslO) 
12Y.'cdc 
Page8 
11 September 2019 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 9
11 September 2019
Approximately 230 subjects total will be enrolled into one of 
13 cohorts:
Cohort 1 (SEL) will consist of 10 enrolled subjects
Cohort 2 (GS-0976) will consist of 10 enrolled subjects
Cohort 3 (GS-9674) will consist of 10 enrolled subjects
Cohort 4 (SEL + GS-9674) will consist of up to 20 enrolled subjects
Cohort 5 (SEL + GS-0976) will consist of up to 20 enrolled subjects
Cohort 6 (GS-9674 + GS-0976) will consist of up to 20 enrolled 
subjects
Cohort 7 (GS-0976) will consist of up to 10 enrolled subjects with 
Child-Pugh-Turcotte Class A (CPT A) cirrhosis
Cohort 8 (GS-9674) will consist of up to 10 enrolled subjects with 
CPT A cirrhosis
Cohort 9 (SEL + GS-0976 + GS-9674) will consist of approximately 
10 enrolled subjects.
For Cohorts 10 and 11, eligible subjects will be randomized to 
receive pretreatment with fenofibrate 48 mg or fenofibrate 145 mg 
from Day -14 to Day -1 and will be treated with GS-0976 20 mg and 
fenofibrate 48 mg or GS-0976 20 mg and fenofibrate 145 mg for 24 
weeks as shown in the figure below.
Approximately 30 subjects will be randomized (1:1) into either 
Cohorts 10 or 11. Randomization will be stratified by (1) screening 
serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or [≥ 
250 mg/dL and < 500 mg/dL]), and (2) fibrosis stage [F3 defined by 
liver biopsy or screening MRE with liver stiffness < 4.67 kPa or F4 
defined by liver biopsy or screening MRE with liver stiffness 
≥ 4.67 kPa. Approximately 60% of subjects in each cohort should 
have cirrhosis (F4) based on Inclusion Criteria 5. Approximately 
60% subjects in each cohort should have screening serum 
triglycerides ≥ 150 mg/dL and < 250 mg/dL as below:

Cohort 10 (GS-0976 20 mg + fenofibrate 48 mg) will consist of 
15 subjects:
o
Approximately 9 subjects with Screening serum triglycerides 
≥ 150 mg/dL and < 250 mg/dL
o
Approximately 6 subjects with Screening serum triglycerides 
≥ 250 mg/dL and < 500 mg/dL
6Weeks 
CohortlO 
(n= 15) 
Co ho rt11 
(n: 15) 
Treatment 24 w eeks 
GS-0976 20 mg+ fenofibrate48 mg PO QD 
Treatment 24 weeks 
GS-0976 20 mg+ Fenoflbrate145 mg POQD 
24 weeks(Dayl throughWeek24} 
4Weeks 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 10
11 September 2019

Cohort 11 (GS-0976 20 mg + fenofibrate 145 mg) will consist of 
15 subjects:
o
Approximately 9 subjects with Screening serum triglycerides 
≥ 150 mg/dL and < 250 mg/dL
o
Approximately 6 subjects with Screening serum triglycerides 
≥ 250 mg/dL and < 500 mg/dL
For Cohorts 12 and 13, eligible subjects will be randomized to 
receive pretreatment with Vascepa® 2 g twice daily or fenofibrate 
145 mg once daily from Day -14 to Day -1 and will be treated with 
GS-0976 20 mg once daily, GS-9674 30 mg once daily, and 
Vascepa® 2 g twice daily; or GS-0976 20 mg once daily, GS-9674 30 
mg once daily, and fenofibrate 145 mg once daily for 6 weeks as 
shown in the figure below. 
Approximately 60 subjects will be randomized (1:1) into either 
Cohorts 12 or 13. Randomization will be stratified by screening 
serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥ 250 mg/dL and < 500 mg/dL]).

Cohort 12 (GS-0976 20 mg once daily + GS-9674 30 mg once 
daily + Vascepa® 2 g twice daily) will consist of 30 subjects

Cohort 13 (GS-0976 20 mg once daily + GS-9674 30 mg once 
daily + fenofibrate 145 mg once daily) will consist of 30 subjects
Diagnosis and Main 
Eligibility Criteria:
Key Inclusion Criteria:
1. Males and females between 18-75 years (Cohorts 1-9) and 
≥ 18 years (Cohorts 10-13) of age; inclusive based on the date of 
the Screening Visit;
2. Willing and able to provide informed consent prior to any study 
specific procedures being performed;
3. For Cohorts 1 through 6 and 9, subjects must meet all of the 
following conditions (a-d OR e&f):
a) Clinical diagnosis of nonalcoholic fatty liver disease 
(NAFLD),
Cohort 12 
(n • 30) 
Cohort 13 
(n =30) 
2 Weeks {Day -14 through Oay-1) 
Treatment 6 weeks 
GS-0976 20 mg PO QD + GS-9674 30mg PO QD + 
Vascepa 2 g PO BIO 
Treatment 6 weeks 
GS-0976 20 mg PO QD + GS-9674 30 mg PO QD + 
Fenofibrate 145 mg PO QD 
6 Weeks (Day 1 through Week 6) 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 11
11 September 2019
b) Screening FibroTest® < 0.75, unless a historical liver biopsy 
within 12 months of Screening does not reveal cirrhosis. In 
subjects with Gilbert’s syndrome or hemolysis, FibroTest® 
will be calculated using direct bilirubin instead of total 
bilirubin,
c) Screening MRI-PDFF with ≥ 10% steatosis,
d) Screening MRE with liver stiffness ≥ 2.88 kPa,
OR
e) A historical liver biopsy within 12 months of Screening 
consistent with NASH (defined as the presence of steatosis, 
inflammation, and ballooning) with stage 2-3 fibrosis 
according to the NASH Clinical Research Network (CRN) 
classification (or equivalent),
AND
f)
No documented weight loss > 5% between the date of the 
liver biopsy and Screening;
4. For Cohorts 7 and 8, subjects must have a clinical diagnosis of 
NAFLD and have at least one of the following criteria (a-d):
a) Screening MRE with liver stiffness ≥ 4.67 kPa,
b) A historical FibroScan® ≥ 14 kPa within 6 months of 
Screening,
c) Screening FibroTest® ≥ 0.75,
d) A historical liver biopsy consistent with stage 4 fibrosis 
according to the NASH CRN classification (or equivalent);
5. For Cohorts 10 and 11, subjects must have a clinical diagnosis of 
NAFLD and the following criteria:
a) At least two criteria for metabolic syndrome modified from 
the NCEP ATP III 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,
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,


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 12
11 September 2019
AND one of the following criteria:
b) A historical liver biopsy within 6 months of Screening 
consistent with NASH and bridging fibrosis (F3) or within 
12 months of Screening consistent with NASH and 
compensated cirrhosis (F4) in the opinion of the investigator,
c) Screening liver stiffness by MRE ≥ 3.64 kPa,
d) Screening liver stiffness by FibroScan® ≥ 9.9 kPa;
6. For Cohorts 12 and 13, subjects must have a clinical diagnosis of 
NAFLD/NASH and the following criteria:
a) At least two criteria for metabolic syndrome modified from 
the NCEP ATP III 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,
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,
OR one of the following criteria:
b) A historical liver biopsy within 6 months of Screening 
consistent with NASH for subjects without compensated 
cirrhosis (F4); or within 12 months of Screening consistent 
with NASH for subjects with compensated cirrhosis (F4) in 
the opinion of the investigator,
c)  A historical MRE with liver stiffness ≥ 2.88 kPa within 6 
months of Screening,
d)  A historical FibroScan® with liver stiffness ≥ 9.9 kPa within 
6 months of Screening,
AND
e) No documented weight loss > 5% between the date of the 
historical liver biopsy, historical MRE, or historical 
FibroScan® and Screening;
7. Platelet count ≥ 100,000/µL;
8. Serum creatinine < 2 mg/dL (Cohorts 1-9) at Screening;
9. Estimated glomerular filtration rate (eGFR) ≥ 80 mL/min 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 13
11 September 2019
(Cohorts 10-11) or ≥ 60 mL/min (Cohorts 12-13), as calculated by 
the Cockcroft-Gault equation at Screening;
10. For Cohorts 10-13, serum triglyceride level ≥ 150 mg/dL at 
Screening.
Key Exclusion Criteria:
1. Pregnant or lactating females;
2. Other causes of liver disease including autoimmune, viral, and 
alcoholic liver disease;
3. Any history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding;
4. For Cohorts 7-8 and 10-13, Child-Pugh-Turcotte (CPT) score > 6 
(Appendix 4) at Screening, unless due to an alternative etiology 
such as Gilbert’s syndrome or therapeutic anticoagulation;
5. History of liver transplantation;
6. History of hepatocellular carcinoma;
7. Weight reduction surgery in the past 2 years or planned during the 
study;
8. Documented weight loss > 5% between the date of the historical 
liver biopsy and Screening, if applicable;
9. Body Mass Index (BMI) < 18 kg/m2;
10. ALT > 5 x ULN at Screening;
11. For Cohorts 10-13, HbA1c ≥ 9.5% (or serum fructosamine 
≥ 381 µmol if HbA1c is unable to be resulted) at Screening;
12. For Cohorts 10-13, hemoglobin ≤ 10.6 g/dL at Screening;
13. INR > 1.2 (Cohorts 1-9) or INR > 1.4 (Cohorts 10-13) at 
Screening, unless on anticoagulation therapy;
14. Total bilirubin > 1x ULN (Cohorts 1 through 6 and 9), >1.5 x 
ULN (Cohorts 7 and 8), or >1.3 x ULN (Cohorts 10-13) except in 
confirmed cases of Gilbert’s syndrome; 
15.  Triglycerides ≥ 500 mg/dL (Cohorts 5-8 and 10-13) or 
≥ 250 mg/dL (Cohort 9) at Screening;
16. Model for End-Stage Liver Disease (MELD) score > 12 at 
Screening (Cohorts 10 -13), unless due to an alternate etiology 
such as therapeutic anticoagulation;
17. Chronic hepatitis B (HBsAg positive);
18. Chronic hepatitis C (HCV RNA positive). Subjects cured of HCV 
infection less than 2 years prior to the Screening visit are not 
eligible (Cohorts 10-13);


SEL, GS-0976, GS-9674
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Gilead Sciences, Inc.
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19. HIV Ab positive;
20. Presence of gallstones within 6 months of Screening 
(Cohorts 10-13);
21. Alcohol consumption greater than 21 oz/week for males or 
14 oz/week for females (1oz/30 mL of alcohol is present in 
1 12oz/360 mL beer, 1 4oz/120 mL glass of wine, and a 
1 oz/30 mL measure of 40% proof alcohol);
22. Positive urine screen for amphetamines, cocaine or opiates 
(i.e., 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 
opioid-based medication are eligible if the prescription and 
diagnosis are reviewed and approved by the investigator;
23. Unstable cardiovascular disease;
24. History of intestinal resection of the extent that would result in 
malabsorption;
25. Use of any prohibited concomitant medications as described in 
Section 5.8;
26. 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.
Study Procedures/
Frequency:
After signing the informed consent form, subjects will complete a 
Screening Visit which will include the following assessments: 
complete medical history with review of historical liver biopsy 
obtained within the last 12 months of Screening (date of initial 
informed consent) for noncirrhotics and at any time for cirrhotics, to 
assess subject eligibility for Cohorts 1-9. For Cohorts 10-11, review 
of the historical liver biopsy obtained within the last 6 months of 
Screening (date of initial informed consent) for subjects with 
bridging fibrosis (F3) and within the last 12 months for subjects with 
cirrhosis (F4), to assess subject eligibility (if applicable). For 
Cohorts 12-13, review of historical liver biopsy within 6 months of 
Screening (date of initial informed consent) consistent with NASH 
for subjects without compensated cirrhosis (F4); or within 12 months 
of Screening consistent with NASH for subjects with compensated 
cirrhosis (F4), or review of historical MRE and/or FibroScan® 
obtained within the last 6 months of Screening (date of initial 
informed consent), to assess subject eligibility (if applicable). Other 
assessments include complete physical examination (PE) including 
height, 
, and vital signs; laboratory assessments; serum 
CCI-


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
CONFIDENTIAL 
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ctrocardiogram 
verse events 
edications; and 
Subjects determined to be eligible for the study based on the 
inclusion/exclusion criteria will then begin Cvcle 1 of the Kinetic 
Biomarkers (Coho1ts 1-11 ). 
or o 01ts - su ~ects w1 comp ete two additional 
eye es o 
etic Biomarkers from Day 14 through Day 20 (Cycle 2) 
and Day 70 through Day 76 (Cycle 3). For Coho1ts 10-11, subjects 
will complete two additional cycles of Kinetic Biomarkers from 
Day 70 through Day 76 (Cycle 2) and Day 154 through Day 160 
(Cycle 3). 
All Coho1t 1-11 subjects enrolled in the study will complete the 
Kinetic Biomarker studies. The first dose of 50 mL deuterated water 
will be administered under the supervision of investigative site 
personnel and monitored for at least 30 minutes after for any side 
effects. 
For Coho1ts 1 through 9, eligible subjects will be enrolled to receive 
treatment with SEL, GS-0976, GS-9674; the combination of SEL and 
GS-9674, SEL and GS-0976, GS-9674 and GS-0976; or SEL, 
GS-0976 and GS-9674 for 12 weeks. For Coho1ts 10-11, eligible 
subjects will be randomized to receive pretreatment with fenofibrate 
from Day -14 to Day -1 and receive treatment with GS-097 6 and 
fenofibrate from Day 1 through 24 weeks. 
For Coho1ts 12-13, eligible subjects will be randomized to receive 
pretreatment with Vascepa® or fenofibrate from Day -14 to Day -1 
and receive treatment with GS-097 6 and GS-967 4 and Vascepa® or 
fenofibrate from Day 1 through Week 6. 
Pretreatment and Treatment study assessments will include: 
• 
Confnmation of eligibility at Day -14 
• 
Medical histo1y at Day -14 (Coho1ts 10-13) and Day 1 
(Coho1ts 1-11) 
• 
Symptom driven PE, vital signs, and weight at 
o 
Day 1 and Weeks 1, 4, 8, 12 (Coho1ts 1-9) 
o 
Days -14, 1 and Weeks 1, 4, 8, 12, 16, 24 (Coho1ts 10-11) 
o 
Days -14, 1 and Weeks 4, 6 (Coho1ts 12-13) 
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11 September 2019 


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Gilead Sciences, Inc.
Amendment 12
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11 September 2019
 
 
 

Standard 12-lead ECG at 
o
Week 12 (Cohorts 1-9) 
o
Weeks 12, 24 (Cohorts 10-11) 
o
Week 6 (Cohorts 12-13)

Chemistry, hematology, and coagulation panel at 
o
Day 1 and at Weeks 1, 4, 8, 12 (Cohorts 1-9)
o
Days -14, -11, -7, 1 and Weeks 1, 4, 8, 12, 16, 24, 28 
(Cohorts 10-11)  
o
Days -14, 1 and Weeks 4, 6 (Cohorts 12-13)

Pregnancy testing (females of childbearing potential only) at 
o
Day 1 and at Weeks 4, 8, 12 (Cohorts 1-9)
o
Day 1 and Weeks 4, 8, 12, 16, 22, and 24 (Cohorts 10-11)
o
Days -14, 1 and Weeks 4, 6 (Cohorts 12-13)

Biomarker Testing
 
 
 
 
 
 
 
 
CCI
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SEL, GS-0976, GS-9674 
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Gilead Sciences, Inc. 
CONFIDENTIAL 
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Final 
Amendment 12 
• 
Apolipoprotein Al (ApoAl), apolipoprotein B (ApoB), and 
NMR Lipoprofile collection at 
o Day 1 and at Weeks 1, 4, 8, 12 (Coho1is 1-9) 
o Days -14, 1 and Weeks 1, 4, 8, 12, 16, 24 (Coho1is 10-11) 
o Days -14, 1 and Weeks 4, 6 (Coho1is 12-13) 
• 
Total bile acids at 
o Day 1 and at Weeks 1, 4, 8, 12 (Coho1is 1-9) 
o Days -14, 1 and Weeks 1, 4, 8, 12, 16, 24 (Coho1is 10-11) 
• 
Beta-hydroxybutyrate and adiponectin collection at 
o Day 1 and Weeks 4, 12 (Coho1is 1-9) 
o Days -14, 1 and Weeks 12, 24 (Coho1is 10-11) 
• 
hsCRP at 
o Days -14, 1 and Weeks12, 24 (Coho1is 10-11) 
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Genomic sample collection at Day 1 (Coho1is 1-13) 
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Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 18
11 September 2019

Hemoglobin A1c (HbA1c) at 
o
Day 1 and Week 12 (Cohort 1-9) 
o
Day -14, 1 and Weeks 12, 24 (Cohorts 10-11)
o
Day 1 (Cohorts 12-13)

Quality of Life (QoL) questionnaires at 
o
Day 1 and Week 12 (Cohorts 1-9) 
o
Day 1 and Week 12, 24 (Cohorts 10-11)
Kinetic Biomarker Assessments (Cohorts 1-11)
Cycle 1
Subjects will drink 50 ml of deuterated water three times per day 
starting on Day -14 through Day -8.
Plasma Collection
Blood will be collected at Day -14, Day -11, Day -7, Day 1 and 
Day 7 (Cohorts 1-11).
Urine Collection
Urine will be collected on Day -14, Day -11, Day -7, Day 1 
(Cohorts 1-11) and Day 7 (Cohorts 4-11).
Saliva Collection
Saliva will be collected on Day 7(Cohorts 1-3).
Cycle 2
Subjects will drink 50 ml of deuterated water three times per day 
starting on Day 14 through Day 20 (Cohorts 1-9) and on Day 70 
through Day 76 (Cohorts 10-11).
Plasma Collection
Blood will be collected at Day 14, Day 17, Day 21, and Day 28 
(Cohorts 1-9) and Day 56, Day 70, Day 73, Day 77 , Day 84 and 
Day 126 (Cohorts 10-11).
Urine Collection
Urine will be collected on Day 14, Day 17, Day 21, and Day 28 for 
(Cohorts 1-9) and  Day 56, Day 70, Day 73, Day 77, Day 84 and 
Day 126 for (Cohorts 10-11).
Saliva Collection
Saliva will be collected on Day 35 for (Cohorts 1-3).


SEL, GS-0976, GS-9674
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Final
Gilead Sciences, Inc.
Amendment 12
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Page 19
11 September 2019
Cycle 3
Subjects will drink 50 ml of deuterated water three times per day 
starting on Day 70 through Day 76 (Cohorts 1-9) and on Day 154 
through Day 160 (Cohorts 10-11).
Plasma Collection
Blood will be collected at Day 70, Day 73, Day 77, and Day 84 
(Cohorts 1-9) Day 154, Day 157, Day 161 and Day 168 
(Cohorts 10-11).
Urine Collection
Urine to be collected on Day 70, Day 73, Day 77, and Day 84 
(Cohorts 1-9) and Day 154, Day 157, Day 161, and Day 168 
(Cohorts 10-11).
Saliva Collection
Saliva will be collected on Day 91 (Cohorts 1-3).
Subjects will return for their final visit 4 weeks after the Week 12 
visit (Week 16) (Cohorts 1-9), or 4 weeks after the Week 24 visit 
(Week 28) (Cohorts 10-11). At this visit, subjects will have a 
symptom driven PE, vital signs, 
, review of concomitant 
medications and AEs, and blood will be drawn for hematology, blood 
chemistry, and a coagulation panel. A urine pregnancy test will be 
performed for females of childbearing potential only.
For Cohorts 12 and 13, subjects will have a Follow-up Phone Visit 
two weeks after last dose of study drug. At this visit, a review of 
concomitant medications and AEs will be completed, and a urine 
pregnancy test will be performed for females of childbearing 
potential only. 
Test Product:
For Cohorts 1, 4, 5 and 9, SEL will be supplied as round, plain-faced, 
white film-coated tablets containing 18 mg of SEL. In addition to the 
active ingredient, SEL tablets contain the following inactive 
ingredients: lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, polyethylene glycol 3350, titanium 
dioxide and talc.
For Cohort 2, GS-0976 will be supplied as white opaque size 0 hard 
gelatin capsules containing 10 mg of GS-0976. In addition to the 
active ingredient, GS-0976 capsules contain the following inactive 
ingredients: lactose monohydrate, stearoyl polyoxylglycerides and 
croscarmellose sodium, which are common pharmaceutical 
excipients.
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Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
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11 September 2019
For Cohorts 5-7 and 9-13, GS-0976 will be supplied as 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.
For Cohort 3, GS-9674 will be supplied as round, plain-faced, 
film-coated orange tablets containing 10 mg (as free form equivalent) 
of GS-9674. In addition to the active ingredient, GS-9674 tablets 
contain the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, 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.
For Cohorts 4, 6, 8 and 9, GS-9674 will be supplied as round, 
plain-faced, film-coated orange tablets containing 30 mg (as free 
form equivalent) of GS-9674. In addition to the active ingredient, 
GS-9674 tablets contain the following 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.
For Cohorts 12 and 13, GS-9674 will be supplied as round, 
film-coated green tablets, debossed with “GSI” on one side of the 
tablet and “30” on the other side of the tablet, and containing 30 mg 
(as free form equivalent) of GS-9674. In addition to the active 
ingredient, GS-9674 tablets contain the following inactive 
ingredients: microcrystalline cellulose, mannitol, crospovidone, 
magnesium stearate and film-coating material composed of polyvinyl 
alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron 
oxide, and ferrosoferric oxide. 
For Cohorts 10 and 11, fenofibrate will be supplied in 48 mg and 
145 mg tablets. Commercially available fenofibrate will be used for 
the study. Information regarding the formulation of commercially 
available fenofibrate can be found in the prescribing information.
For Cohort 12, Vascepa® will be supplied in 1 g capsules, with two 
capsules to be taken two times daily. Commercially available 
Vascepa® will be used for the study. Information regarding the 
formulation of commercially available Vascepa® can be found in the 
prescribing information.


SEL, GS-0976, GS-9674
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Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
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11 September 2019
For Cohort 13, fenofibrate will be supplied in 145 mg tablets.  
Commercially available fenofibrate will be used for the study. 
Information regarding the formulation of commercially available 
fenofibrate can be found in the prescribing information.
Dose, and Mode of 
Administration:
Cohort 1: SEL 18 mg (1 x 18 mg tablet) administered orally 
once daily
Cohort 2: GS-0976 20 mg (2 x 10 mg capsules) administered orally 
once daily
Cohort 3: GS-9674 30 mg (3 x 10 mg tablets) administered orally 
once daily
Cohort 4: SEL 18 mg (1 x 18 mg tablet) + GS-9674 30 mg 
(1 x 30 mg tablet) administered orally once daily
Cohort 5: SEL 18 mg (1 x 18 mg tablet) + GS-0976 20 mg 
(1 x 20 mg tablet) administered orally once daily
Cohort 6: GS-9674 30 mg (1 x 30 mg tablet) + GS-0976 20 mg 
(1 x 20 mg tablet) administered orally once daily
Cohort 7: GS-0976 20 mg (1 x 20 mg tablet) administered orally 
once daily
Cohort 8: GS-9674 30 mg (1 x 30 mg tablet) administered orally 
once daily
Cohort 9: SEL 18 mg (1 x 18 mg tablet) + GS-0976 20 mg (1 x 
20 mg tablet) + GS-9674 30 mg (1 x 30 mg tablet) 
administered orally once daily
Cohort 10: GS-0976 20 mg (1 x 20 mg tablet) + fenofibrate 48 mg 
(1 x 48 mg tablet) administered orally once daily
Cohort 11: GS-0976 20 mg (1 x 20 mg tablet) + fenofibrate 145 mg 
(1 x 145 mg tablet) administered orally once daily
Cohort 12: GS-0976 20 mg (1x 20 mg tablet) + GS-9674 (1x 30 mg 
tablet) administered orally once daily + Vascepa® 4 g 
(2 x 1 g capsule) administered orally two times daily 
Cohort 13: GS-0976 20 mg (1x 20 mg tablet) + GS-9674 (1 x 30 mg 
tablet) + fenofibrate 145mg (1 x 145 mg tablet) 
administered orally once daily


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Criteria for 
Evaluation: 
Safety: 
Statistical Methods: 
Primaiy Endpoint: 
CONFIDENTIAL 
Final 
Amendment 12 
Safety will be assessed during the study through the repo1i ing of 
AEs, and by clinical laborato1y tests and vital sign assessments at 
various time points during the study. Concomitant medication usage 
will also be assessed throughout the study. 
The primaiy endpoint is the safety of study dmg(s) in subjects with 
NAFLD/NASH. 
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SEL, GS-0976, GS-9674 
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Gilead Sciences, Inc. 
Efficacy Analysis: 
Safety Analysis: 
Phannacokinetic 
Analysis: 
Kinetic Biomarker 
Analysis: 
Sample Size: 
CONFIDENTIAL 
Final 
Amendment 12 
The biological and histological activity of study drng(s) will be 
evaluated using radiologic endpoints and biomarker variables. 
Because efficacy endpoints will be evaluated for explorato1y 
pmpose, fonnal statistical comparisons will not be made for these 
endpoints. Descriptive statistics (n, mean, standard deviation [SD], 
median, 1st quartile [Ql ], }rd quartile [Q3], minimum, and maximum) 
will be provided by treatment group. 
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnonnalities for categorical values or 
descriptive statistics (n, mean, SD, median, Ql, Q3, minimum, and 
maximum) for continuous values by treatment group. 
The kinetic biomarkers will be analyzed to evaluate the 
phaimacodynainic (PD) effects of study drng( s). The assessment will 
involve the analysis of DNL values; specifically, the change 
(absolute and relative) from baseline between the post-dose and 
pre-dose deuterated water loading periods. 
For Coho1is 1 to 9, due to the explorato1y natme of this study, no 
fonnal power calculations were used to detennine sample size. The 
number of subjects was chosen based on clinical experience with 
other siinilar proof of concept studies. 
For Coho1is 10 to 11, we assumed that among subjects with baseline 
hype1iriglycerideinia ~150 mg/dL (60% with senun triglycerides 
150 mg/dL and < 250 mg/dL and 40% with sernm triglycerides 
250 mg/dL and < 500 mg/dL), Grade 3-4 hype1iriglycerideinia 
(>500 mg/dL) would be observed in 28% following treatment with 
GS-0976. Assmning that the co-adininistration of fenofibrate and 
GS-0976 will reduce the incidence of Grade 3-4 hype1iriglycerideinia 
to <5%, a sample size of 15 in each of Cohorts 10 and 11 will 
provide 82% power to detect the reduction based on a one-sided 
exact test at a significance level of 0.05. 
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Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 24
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For Cohorts 12 and 13, we assumed that among subjects with 
baseline hypertriglyceridemia (serum triglycerides ≥ 150 mg/dL and 
< 500 mg/dL), GS-0976 20 mg + GS-9764 30 mg once daily 
treatment will lead to a mean increase in serum triglycerides of 
60 mg/dL from baseline after 6 weeks of treatment. Assuming that 
the co-administration of Vascepa® or fenofibrate with GS-0976 
20 mg + GS-9764 30 mg will mitigate this increase in serum 
triglycerides and that the standard deviation for serum triglycerides 
after 6 weeks of treatment is 120 mg/dL, a sample size of 30 subjects 
in each cohort will provide 85% power to detect any increase based 
on a one-sided t-test at a significance level of 0.05. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 


SEL, GS-0976, GS-9674
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Gilead Sciences, Inc.
Amendment 12
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
 C 
degrees Celsius
 F
degrees Fahrenheit
%GMR
percent geometric mean ratio
ACC
acetyl-coA carboxylases
ADR
adverse drug reaction
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ApoA1
apolipoprotein A1
ApoB
apolipoprotein B
ASK1
apoptosis signal-regulating kinase 1
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration 
versus time curve
AUROC
area under the receiver operating characteristic curve
-hCG
beta human chorionic gonadotropin
BAP
Biomarker Analysis Plan
BCL-2
B-cell lymphoma 2
BCRP
breast cancer resistance protein
BID
twice daily
BMI
body mass index
BSEP
bile salt export pump
BUN
blood urea nitrogen
C4
7alpha-hydroxy-4-cholesten-3-one
CBC
complete blood count
Cc
cubic centimeter
CDHFD
choline-deficient, high-fat diet
CFR
Code of Federal Regulations
CI
confidence interval
c-Jun
c-Jun protein
CK18
cytokeratin 18
Clast 
last observed quantifiable plasma/serum concentration of the drug
CLDQ
Chronic Liver Disease Questionnaire
CLrenal
renal clearance
CLss
steady state clearance
Cmax
maximum observed plasma/serum concentration of drug
CCI-


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
COLlAl 
CPT 
CPTA 
CRF 
CRN 
CRO 
CsA 
CSR 
CTCAE 
½ough 
CXCLl 
CYP 
CYP1A2 
CYP2B6 
CYP2Cl9 
CYP2C8 
CYP2D26 
CYP3A 
CYP3A4 
DAB 
DDI 
DHA 
DILi 
DKD 
dL 
DMC 
DNA 
DNL 
DRSP 
PVE 
EC 
ECG 
eCRF 
EDC 
eGFR 
Eg -
EPA 
EU 
FAS 
CONFIDENTIAL 
collagen type I alpha 1 chain 
Child-Pugh-Turcotte 
Child-Pugh-Turcotte Class A 
case report form 
Clinical Research Netv.•ork 
contract research organization 
Cyclosporine 
clinical study report 
Common Terminology Criteria for Adverse Events 
Final 
Amendment 12 
lowest concentration at which a medication is present in the body 
chemokine (C-X-C motif) ligand 1 
cytochrome P450 
cytochrome P450 1A2 
cytochrome P450 2B6 
cytochrome P450 2C19 
cytochrome P450 2C8 
cytochrome P450 2D6 
cytochrome P450 3A 
cytochrome P450 3A4 
Dabigatran 
drug-drug interaction 
docosahexaenoic acid 
Drug Induced Liver Injury 
Diabetic Kidney Disease 
Deciliter 
Data Monitoring Committee 
deoxyribonucleic acid 
de novo lipogenesis 
Drospirenone 
Pharmacovigilance and Epidemiology 
ethics cormnittee 
Electrocardiogram 
electronic case report form 
electronic data capture 
estimated glomernlar filtration rate 
Example 
eicosapentaenoic acid 
European Union 
Full Analysis Set 
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Gilead Sciences, Inc.
Amendment 12
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FDA
(United States) Food and Drug Administration
FGF19
FSH
fibroblast growth factor 19
follicle stimulating hormone
FXR
Farnesoid X Receptor
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
gastrointestinal 
GMP
Good Manufacturing Practice
GMR
geometric mean ratio
HA
hyaluronic acid
Hb
Hemoglobin
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
Hct
Hematocrit
HCV
hepatitis C virus
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLT
high-level term
HLGT
high-level group term
HPAH
heritable pulmonary arterial hypertension
Hr
Hour
Hz
Hertz
IB
investigator’s brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IL-1β
interleukin-1 beta
IL-6
interleukin-6
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio
IPAH
idiopathic pulmonary arterial hypertension
IRB
institutional review board
IRS1
insulin receptor substrate 1
IUD
intrauterine device
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Gilead Sciences, Inc.
Amendment 12
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IV
Intravenous
IWRS
interactive web response system
JNK
c-Jun N-terminal kinase
Kg
Kilogram
kPa
Kilopascal
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LLT
lower-level term
LPL
lipoprotein lipase
LSM
least squares mean
LXR
liver X receptor
g
Microgram
MAPK
mitogen-activated protein kinase
MATE1
multidrug and toxin extrusion protein 1
MCP-1
monocyte chemoattractant protein-1
MCV
mean corpuscular volume
MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
Min
Minute
mL
Milliliter
Mm
Millimeter
mmHg
millimeter of mercury
MRP2
multidrug resistance-associated protein 2
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
mRNA
messenger ribonucleic acid
NAFLD
nonalcoholic fatty liver disease
NaNO2
sodium nitrite
NAS
NAFLD Activity Score
NASH
nonalcoholic steatohepatitis
Ng
Nanogram
ng*h
nanogram*Planck’s constant
NMR
nuclear magnetic resonance
NOAEL
no observed adverse event level
NOEL
no-observed-effect level
NTCP
sodium-taurocholate cotransporting polypeptide
OATP
organic anion-transporting polypeptide


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OATP1B1
organic anion transporting polypeptide 1B1
OATP1B3
organic anion transporting polypeptide 1B3
OATP2B1
organic anion transporting polypeptide 2B1
OCT1
organic cation transporter 1
OCT2
organic cation transporter 2
OSTα
organic solute transporter alpha
OSTβ
organic solute transporter beta
Oz
Ounce
p38
mitogen-activated protein kinase
PAH
pulmonary arterial hypertension
PAH-CTD
pulmonary arterial hypertension associated with connective tissue disease
PAI-1
plasminogen activator inhibitor type 1
PBC
primary biliary cirrhosis
PBMC
peripheral blood mononuclear cells
PD
Pharmacodynamics
PDGF
platelet-derived growth factor
PE
physical exam
P-gp
P-glycoprotein
pH
measure of the acidity
PIIINP
N-Terminal Propeptide of Type III Collagen
 
PO
by mouth
p-p38
phospho-p38
PRA
Pravastatin
PSC
primary sclerosing cholangitis
PSR
picrosirius red
PT
preferred term
PT
prothrombin time
PTT
partial prothrombin time
PVR
pulmonary vascular resistance
Q1
1st quartile
Q3
3rd quartile
QD
Once daily
QoL
Quality of Life
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
ΔΔQTcF
time matched, baseline adjusted, placebo-corrected QTcF
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula
CCI


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RHC
right heart catheterization
RIF
Rifampin
RNA
ribonucleic acid
ROS
reactive oxygen species
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEL
selonsertib (formerly known as GS-4997)
SF-36
Short Form (36) Health Survey
SIM
Simtuzumab
SMA
α-smooth muscle actin
SOC
System Organ Class
SOP
standard operating procedure
SREBP-1c
sterol regulatory element-binding transcription factor 1c
SUSAR
Suspected Unexpected Serious Adverse Reaction
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)
TEAEs
treatment emergent adverse events
TESAE
treatment-emergent SAE
TIMP 1
tissue inhibitor of metalloprotease 1
TGF-β
transforming growth factor beta
Tlast 
last measured concentration
Tmax 
time (observed time point) of Cmax
TNF-α
tumor necrosis factor alpha
TQT
thorough QT
TXNIP
thioredoxin interacting protein
UDP
uridine 5’-diphospho
UGT1A1
UDP glucuronosyltransferase family 1 member A1
ULN
upper limit of the normal range
US
United States
USPI
United States Product Inserts
VAS
visual analogue scale
VORI
Voriconazole
VLDL
very-large density lipoprotein
WBC
white blood cell
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 
nonalcoholic fatty liver disease (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 hepatocellular 
carcinoma (HCC) and other complications of end-stage liver disease, including jaundice, fluid 
retention (edema and ascites), portal hypertension and variceal hemorrhage, impaired 
coagulation, and hepatic encephalopathy. 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. 
General Information for Selonsertib 
1.2.1. 
Selonsertib 
Final 
Amendment 12 
SEL is a potent and selective small molecule inhibitor of apoptosis signal-regulating kinase 1 
(ASKl). ASKl is a ubiquitously expressed serine/threonine kinase that is primarily activated by 
pathological oxidative sti·ess {Makie 2007, Takeda 2008, Tobiume 2002}. ASKl in tum 
phospho1ylates and activates mitogen-activated protein kinase (p38) and c-Jun N-tenninal (JNK) 
kinases. p38 and JNK mediate metabolic, pro-inflammato1y , and pro-fibrotic changes in the 
liver, which are centi·al to disease progression in NASH. By inhibiting ASKl signaling in 
patients with NASH, SEL is expected to halt progressive liver fibrosis and reverse existing 
fibrosis, thus preventing the development of cinhosis-related complications. The mechanism of 
ASKl signaling in NASH is presented graphically in Figure 1-1. 
Figure 1-1. 
ASK1 Signaling in NASH 
Oxidative Stress 
j Reactive oxygen species 
i Insulin resistance 
i Lipogenesis 
i Apoptosis, Necrosis 
i Cytokines 
i Chemokines 
Fibroblast 
T Activation 
T Fibrotic genes 
For further infonnation on SEL, refer to the Investigator's Brochure (IB). 
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1.2.2.
Preclinical 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 in 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 Selonsertib
As of 17 July 2019, 10 Phase 1, 6 Phase 2, and 3 Phase 3 clinical studies have been 
conducted/are ongoing in which 390 healthy subjects, 248 subjects with DKD, an estimated 40 
subjects with CKD, 1473 subjects with NASH, 50 subjects with AH, and 145 subjects with PAH 
have been dosed with SEL.
Information on the ongoing or completed Phase 1 and 2 clinical studies can be found in the IB.
1.3.
General Information for GS-0976
1.3.1.
GS-0976
GS-0976 is a small molecule allosteric inhibitor that acts at the protein-protein homodimer 
interface of acetyl coenzyme A (acetyl-CoA) carboxylases (ACC) ACC1 and ACC2 to prevent 
dimerization. ACC1 and ACC2 are important regulators of fatty acid metabolism. ACC1 
catalyzes the first step of de novo lipogenesis (DNL) by converting acetyl-CoA to malonyl-CoA 
while ACC2 regulates the entry of fatty acids into the mitochondria where beta oxidation can 
occur. Therefore, inhibition of ACC1 and ACC2 will reduce DNL and increase fatty acid beta 
oxidation. GS-0976 is being developed for the treatment of nonalcoholic steatohepatitis (NASH) 
under IND 124915.
For further information on GS-0976, refer to the current IB for GS-0976.
1.3.2.
Nonclinical Pharmacology
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.


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The results of these pharmacodynamic (PD) studies indicate that GS-0976 can reduce the DNL, 
hepatic steatosis, insulin resistance, and fibrosis produced in nonclinical models of metabolic 
disease and fibrosis without affecting food consumption or markers of liver function.
As described in the IB, GS-834356, a liver-targeted ACC inhibitor and analogue of GS-0976, 
reduced steatosis in a murine model of NASH induced by a diet enriched in fat, cholesterol, and 
fructose (Fast food diet, FFD). ACC inhibition by GS-834356 dose-dependently reduced hepatic 
steatosis, liver triglycerides and cholesterol, plasma ALT and AST, and markers of hepatic 
fibrosis, but also dose-dependently increased plasma triglycerides in this model. GS-834356 also 
decreased hepatic triglycerides and increased plasma triglycerides in a rat high fat, high sucrose 
model of hepatic steatosis. These findings are consistent with a recent report that pharmacologic 
or genetic inhibition of ACC in the liver decreases hepatic triglyceride levels and increases 
plasma triglyceride levels {Goedeke 2018, Hertz 1995, Kim 2017}.
In high fat, high sucrose fed rats, GS-834356-induced increased plasma triglycerides were found 
to be due to increased very-large density lipoprotein (VLDL) secretion and decreased clearance 
of triglyceride-rich VLDL and chylomicrons2. The increase in plasma triglycerides by ACC 
inhibition was accompanied by an increase in plasma ApoC3 protein, which inhibits lipoprotein 
lipase activity and suppresses VLDL and chylomicron clearance. ApoC3 transcription in 
hepatocytes is repressed by the nuclear hormone receptor PPAR. Evaluation of gene 
transcription profiles of FFD-fed mice treated with the ACC inhibitor GS-834356 revealed a 
reduction in PPAR target gene signatures2.These findings suggest that ACC inhibition in the 
liver leads to a reduction in hepatic PPAR activity and associated increases in VLDL and 
ApoC3 production, and reduced VLDL/chylomicron clearance. Indeed, the combination of ACC 
inhibition with PPARα agonism using fenofibrate blocked the ACC-induced plasma TG 
increases in the mouse NASH model. Importantly, the combination of the ACC inhibitor and 
fenofibrate caused a similar reduction in hepatic triglycerides compared to ACC inhibitor 
treatment alone. In addition, the combination caused a greater increase in plasma ketone bodies 
(a marker of fatty acid beta-oxidation) and a greater reduction of hepatic cholesterol levels 
relative to ACC inhibition alone2. These findings demonstrate that the addition of fenofibrate 
overcomes triglyceride elevations induced by ACC inhibition and further increases fatty acid 
oxidation and cholesterol metabolism.
In total, these studies confirm the potential for GS-0976 to impact important metabolic endpoints 
associated with NASH, and for the addition of PPAR agonists to reverse increases in plasma 
triglycerides.
Please refer to the GS-0976 IB for additional details.
1.3.3.
Nonclinical Toxicology
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.


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GS-0976 was well tolerated up to 13 weeks in the mouse, 26 weeks in the rat, and 39 weeks in 
the dog. The primary target organ toxicity was the presence of cataracts and/or lens degeneration 
in the mouse and dog after 2 and 13 weeks, respectively. In the 2-week mouse study, while 1 of 
10 female mice at the lowest dose (5 mg/kg/day) had lens degeneration, none of the male mice at 
the same dose, whereas they did at 3 times higher mean 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.
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 of the lens degeneration observed in the mouse to humans 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 AUC (88 ng•h/mL), the margins of 
exposure at the NOAELs are 8, 206 and 48 in the mouse, rat and dog, respectively. Thus, data 
from the nonclinical studies support the continued clinical evaluation of 20 mg GS-0976.
Please refer to the GS-0976 IB for additional details.
1.3.4.
Nonclinical Pharmacokinetics
GS-0976 is highly protein bound in plasma, and the volume of distribution of GS-0976 across 
nonclinical species is greater than total body water (0.7 L/kg), suggesting that GS-0976 is well 
distributed. A significant fraction of the absorbed parent compound is extracted by the liver 
indicating that GS-0976 is available to the target site (ie, the liver).
The metabolism of GS-0976 has been evaluated in in vitro incubations of rat, dog, Cynomolgus 
monkey, and human hepatocytes. No metabolites unique to the human were detected. In vivo 
metabolite identification studies in Sprague-Dawley rat and Beagle dog have demonstrated that 
the primary metabolite of GS-0976 is the glucuronide conjugate, NDI-011535, renamed as 
GS-834773.
Neither GS-0976 nor GS-834773 inhibits the cytochrome P450 (CYP) enzymes involved in drug 
metabolism. GS-0976 is not an inducer of CYP1A2 or CYP2B6 isozymes and is a mild inducer 
of CYP3A4 in human hepatocytes in vitro.


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A single nonclinical study to evaluate elimination of GS-0976 and the metabolite GS-834773 
was performed in bile duct cannulated Sprague-Dawley rats to profile concentrations over time 
in plasma, urine, and bile. Overall, the pharmacokinetic (PK) profile in plasma and bile indicate 
that GS-0976 is rapidly cleared from the plasma compartment, and the primary route of 
elimination is via the bile.
Please refer to the GS-0976 IB for additional details.
1.3.5.
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, with 
studies not yet included in the IB briefly described below.
1.3.5.1.
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.
1.3.5.1.1.
Subject Disposition
As of 1 November 2017, a total of 90 subjects were dosed; 88 subjects had completed study 
treatment. Two subjects discontinued early. One subject withdrew on Study Day 23 due to 
personal reasons, and the second subject withdrew on Study Day 8 following a positive 
pregnancy test.
1.3.5.1.2.
Preliminary Safety Results
Forty-eight out of 90 subjects (53.3%) experienced an AE. Of these subjects, 10 subjects 
experienced AE(s) that were deemed related to the study drug. The most common AE was 
headache (20%). All of these AEs were Grade 1 or 2, and no subject discontinued the study due 
to an AE.
Fourteen subjects (15.6%) experienced a Grade 3 lab abnormality. Thirteen of these subjects had 
asymptomatic hematuria (3+) on their urine dipstick, and all were menstruating females. One 
subject had a Grade 3 asymptomatic elevation of their total and low-density lipoprotein (LDL) 
cholesterol, and one subject had a transient Grade 3 decrease in hemoglobin. There were no 
Grade 4 lab abnormalities.


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1.3.5.1.3.
Preliminary PK Results
Preliminary PK results from the following cohorts are presented below and in Table 1-1.
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 
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.


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Table 1-1.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 
Evaluating DDIs with GS-0976 (20 mg or 50 mg)
GS-0976
%GMR (90% CIs)
GS-834773
%GMR (90% CIs)
Inhibitor/Inducer 
Drug
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
1.3.5.2.
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 


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(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.
1.3.5.2.1.
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.
1.3.5.2.2.
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 was no Grade 3 or 4 AEs in either cohort. No AEs led to 
dose modification, interruption, or premature discontinuation of study drug. There were no 
SAEs, pregnancies, or deaths.
In the mild hepatic impairment cohort, 4 subjects had Grade 3 lab abnormalities. Elevations in 
GGT (2 subjects) and LDL cholesterol (2 subjects) were the most common, and all Grade 3 lab 
abnormalities of GGT and LDL were present at Screening. In the healthy matched controls, 
2 subjects also had Grade 3 LDL cholesterol lab abnormalities that were present at Day 1. In the 
moderate hepatic impairment cohort, 3 subjects had Grade 3 lab abnormalities 
(decreased lymphocytes, hypomagnesemia, and hyponatremia). There were no Grade 4 lab 
abnormalities.
1.3.5.2.3.
Preliminary PK Results
Preliminary PK results from Cohorts 1 and 2 are presented below and in:

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 in subjects with mild hepatic impairment, exposure margins 


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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 once daily, 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.
Table 1-2.
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)
Moderate Hepatic 
Impairment (N=10)
%GMR
(90% CI)
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)
GS-0976
Cmax (ng/mL)
25.4 
(80.6)
50.9 
(90.3)
169 
(87.5, 325)
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)
1
(Mild HI)
GS-834773
Cmax (ng/mL)
2.29 
(91.8)
12.9 
(125)
391 
(164, 935)
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)
GS-0976
Cmax (ng/mL)
20.1 
(60.2)
198 
(60.0)
905
(539, 1520)
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)
2
(Moderate HI)
GS-834773
Cmax (ng/mL)
1.4
 (81.2)
77.3 
(72.5)
4470
(2190, 9130)
Data presented to 3 significant figures


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
Based on the preliminaiy PK data from this study as well as the overall safety profile of 
GS-0976, dose adjustments ai·e not considered necessaiy in subjects with mild hepatic 
impai1ment. 
1.3.5.3. 
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 paiiicipate, subjects were required to have a clinical diagnosis of 
NAFLD with imaging or a liver biopsy documenting fatty liver within 2 yeai·s 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. 
1.3.5.3.1. 
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 drng (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 drng 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. 
1.3.5.3.2. 
Safety Results 
Treatment with GS-0976 20 or 5 mg was generally well tolerated. The most collllllon AEs in 
each treatment group were nausea, abdominal pain, and diaiThea (GS-0976 20 mg); diaiThea, 
headache, and hype1iriglyceridemia (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. These AEs included abdominal pain, back pain, HE, 
hyperglycemia, hype1iriglyceridemia, sepsis, transient ischemic attack, and dive1iiculitis. None 
of the Grade 3 AEs were repo1ied in > 1 subject, and all but 1 was considered unrelated to study 
diug. One Grade 4 AE, which was not considered treatment-related, was repo1ied. SAEs were 
repo1ied for 4 subjects and included transient ischemic attack, sepsis, pyrexia, abdominal pain, 
CONFIDENTIAL 
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Amendment 12
CONFIDENTIAL
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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.
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.
1.3.5.3.3.
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]).


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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.
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.


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1.4.
General Information for GS-9674
1.4.1.
GS-9674
GS-9674 is a potent and selective agonist of the Farnesoid X Receptor (FXR) whose activity in 
intestinal epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is 
an endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Thus GS-9674, by agonizing FXR, is 
expected to improve NASH. Please refer to the Investigator’s Brochure (IB) for additional 
information on GS-9674, 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, Pharmacokinetics, Drug Metabolism, 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 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, OSTα, and 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 choline-deficient high fat diet /NaNO2 rat model of liver fibrosis that utilizes 
“2 hits” to mimic the metabolic and oxidative stress components of NASH in humans, 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.
GS-9674 has low oral bioavailability, volume of distribution and clearance with very high 
plasma protein binding (>99.6%) across species. Elimination of GS-9674 is primarily through 
the fecal route. GS-9674 undergoes oxidative metabolism in human hepatocytes via CYP2C8, 
CYP3A4, and CYP2C19. Potent inhibitors of these CYPs therefore may affect metabolism of 
GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, CYP2B6, CYP2C19 
or CYP2D6. Whereas CYP2C8, CYP2C9, and CYP3A were moderately inhibited, GS-9674 was 
not a mechanism-based inhibitor of these enzymes. GS-9674 showed moderate inhibition of 
human UGT1A1, sodium-taurocholate cotransporting polypeptide (NTCP), and bile salt export 


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pump (BSEP) and strongly inhibited human OATP1B1, OATP1B3, and OATP2B1. GS-9674 
has the potential to affect hepatic/intestinal uptake of OATP substrates or metabolism of 
CYP2C8, CYP2C9, or CYP3A4 substrates. However, low solubility, high protein binding and 
low systemic levels may reduce the potential for GS-9674 to cause drug-drug interactions at 
clinically relevant exposures via inhibition of metabolic enzymes and transporters. GS-9674 is a 
substrate for efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP), as 
well as the hepatic uptake transporters OATP1B1, 1B3, and 2B1, and NTCP. Inhibitors or 
genetic polymorphisms affecting the activity of these transporters may affect GS-9674 intestinal 
absorption and hepatic uptake.
Based on nonclinical assays, GS-1056756 (the R-enantiomer of M13), an inactive, major 
circulating metabolite of GS-9674 has shown low potential to inhibit CYP enzymes (IC50 values 
of 3.49 for CYP2C8 and >25 uM for CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6) and 
UGT (IC50 value of 13.9 for UGT1A1) in vivo. GS-1056756 did not inhibit P-gp, BCRP, OCT2, 
MATE1, MATE2K, and showed low probability to be clinically relevant inhibitor of OAT1, 
OCT1, OATP1B1, OATP1B3 or OATP2B1. No clinical DDI liability of GS-1056756 on 
enzymes and transporters was predicted from in vitro characterizations.
GS-1056756 has been identified in nonclinical assays as a substrate of OATP1B1/1B3. In vitro, 
GS-1056756 is formed by oxidative metabolism by CYP3A4 and CYP2C8 with additional 
conversion to enantiomers by dehydrogenases (eg, ALDH), and is subsequently metabolized by 
CYP3A and CYP2C8 and UGTs. Together with available clinical data described in Section 
1.4.3, the potential clinical DDI liability of GS-1056756 is low.
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 once daily 
with food.
Refer to the GS-9674 IB for additional details.
1.4.3.
Clinical Trials of GS-9674
As of 07 January 2019, 4 Phase 1 and 1 Phase 2 clinical studies have been completed and 8 
Phase 1 or 2 studies are ongoing Approximately 1161 subjects have been dosed with GS-9674: 
approximately 462 subjects in Phase 1 studies, approximately 577 subjects in Phase 2 NASH 
studies, 70 subjects in 1 Phase 2 PBC study, and 52 subjects in 1 Phase 2 PSC study. 
Information about ongoing and completed clinical studies can be found in the current GS-9674 
IB, with studies not yet included in the IB briefly described below.


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1.4.3.1.
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. 
A brief summary of preliminary results that are not included in the IB from ongoing study 
GS-US-402-3885 is presented below. Preliminary clinical PK data for the newly identified major 
circulating GS-9674 metabolite GS-1056756 (the R-enantiomer of M13) is described in 
Section 1.4.3.1.3. Briefly, GS-1056756 exhibits a plasma half-life of approximately 175 h. 
Preliminary steady-state plasma concentrations of GS-1056756 in PSC patients administered 100 
mg GS-9674 are as expected based on the preliminary single dose PK data for GS-1056756 from 
the ADME study (GS-US-402-4287). Additionally, plasma exposures of GS-1056756 are 
minimally altered in subjects with mild or moderate hepatic impairment compared to subjects 
with normal hepatic function. These data, taken together with the adequate safety margins from 
nonclinical safety studies and the nonclinical understanding of the metabolic formation (CYP3A 
and CYP2C8) and clearance (CYP3A, CYP2C8, and UGTs) mechanisms of GS-1056756 
support the concomitant medication restrictions in Section 5.8.
1.4.3.1.1.
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.
1.4.3.1.2.
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 


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Amendment 12
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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.
1.4.3.1.3.
Preliminary PK Results
Preliminary PK results are presented below and in Table 1-4:

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). Overall exposure for GS-1056756 was modestly 
higher (AUCinf was increased 28% and Cmax increased 7%) in subjects with mild hepatic 
impairment compared with subjects with normal hepatic function. GS-9674 and GS-716070 
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 100 mg once daily in subjects 
with mild hepatic impairment, exposure margins relative to preclinical NOAEL exposures for 
both parent and metabolites 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. GS-1056756 AUCinf was increased 16% and Cmax was 30% lower in subjects with 
moderate hepatic impairment compared with subjects with normal hepatic function. Plasma 
unbound fraction (fu) of 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.

Cohort 3 (severe hepatic impairment; CP C): GS-9674 exposure (AUCinf and Cmax) was 
higher in subjects with severe hepatic impairment (approximately 6.2- and 2.5-fold, 
respectively) as compared to subjects with normal hepatic function. Exposure (AUCinf) of the 
metabolite GS-716070 was also higher (approximately 3-fold) with Cmax reduced by 33%. 
GS-1056756 AUCinf was approximately 2.6-fold higher and Cmax approximately 39% lower 
in subjects with severe hepatic impairment compared with subjects with normal hepatic 
function. 


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Table 1-3.
GS-US-402-3885: Preliminary GS-9674, GS-716070, and GS-1056756 
PK Parameters Following a Single Dose of GS-9674 30 mg or 10 mg in 
Subjects with Hepatic Impairment or Normal Hepatic Function
Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched 
Healthy 
Control (N=10)
Hepatic 
Impairment 
(N=10)
%GMR
(90% CI)
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)
GS-9674
Cmax (ng/mL)
604 
(45.6)
994 
(53.7)
157
(108, 229)
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)
GS-716070
Cmax (ng/mL)
179 
(42.6)
234 
(50.8)
125
(85.0, 188)
AUCinf (hr ng/mL)
2040 
(57.7)
2850 
(69.5)
128
(80.1, 204)
AUClast (hr ng/mL)
850 
(45.6)
1030 
(70.0)
109
(73.0, 163)
1
(Mild HI, 
GS-9674 30 mg)
GS-1056756
Cmax (ng/mL)
13.0 
(44.4)
15.5 
(70.1)
107
(70.4, 161)
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)
GS-9674
Cmax (ng/mL)
496 
(40.2)
909 
(52.5)
164 
(115, 233)
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)
GS-716070
Cmax (ng/mL)
168 
(51.6)
181 
(61.5)
89.5 
(54.3, 147)
AUCinf (hr ng/mL)
1620 
(41.6)
1900 
(41.2)
116
(83.5, 161)
AUClast (hr ng/mL)
734 
(40.7)
586 
(34.0)
79.4
(58.3, 108)
2
(Moderate HI, 
GS-9674 30 mg)
GS-1056756
Cmax (ng/mL)
11.6 
(39.7)
8.25 
(37.6)
70.0
(50.2, 97.6)


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Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched 
Healthy 
Control (N=10)
Hepatic 
Impairment 
(N=10)
%GMR
(90% CI)
AUCinf (hr ng/mL)
989 
(36.4)
6710 
(60.3)
623
(430, 905)
AUClast (hr ng/mL)
963 
(37.2)
6535
(58.0)
631
(437, 913)
GS-9674
Cmax (ng/mL)
182 
(47.5)
427 
(32.0)
254
(177, 365)
AUCinf (hr ng/mL)
2450 
(77.5)
688 
(50.1)
303
(173, 528)
AUClast (hr ng/mL)
2070 
(71.2)
653 
(52.9)
280
(166, 473)
GS-716070
Cmax (ng/mL)
47.9 
(45.6)
77.2 
(55.7)
67.0
(44.3, 101)
AUCinf (hr ng/mL)
520 
(38.8)
3360 
(181)
262
(118, 581)
AUClast (hr ng/mL)
241 
(39.2)
181 
(45.8)
73
(51.0, 104)
3
(Severe HI,
GS-9674 10 mg)
GS-1056756
Cmax (ng/mL)
3.67 
(37.0)
2.35 
(50.2)
60.7
(41.9, 88.0)
Data reported to 3 significant figures

Preliminary PD results for Cohort 1 are also available for change from baseline (Day -1) in 
plasma FGF19 and serum 7-alpha-hydroxy-4-cholesten-3-one (C4) levels following a single 
30-mg dose of 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.
For further information on GS-9674, refer to the current IB.
1.5.
Combination Studies of Selonsertib, GS-9674, and GS-0976
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 with 
GS-9674 and GS-0976 will provide greater benefit to reduce or reverse NASH progression.


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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 
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 -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 (COL1A1, TIMP1, and 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. These 
data suggest that a triple combination therapy of SEL, GS-0976 and GS-9674 may be even more 
efficacious to reverse fibrosis than double combination therapies.


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In a 13-week repeat dose combination toxicity monkey study, 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 and 
activated partial thromboplastin time, 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, 
respectively, than the clinical exposures.
In a 13-week repeat dose combination toxicity mouse study, GS-0976 and 
GS-9674 (FXR agonist) 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 exposures.
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, 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 
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/GS-0976 exposure 
margins of 1/6 times above the clinical exposures.
There were no new or additive toxicities observed in the dual combination toxicity studies that 
would be considered relevant to human. The triple combination of SEL, GS-0976 and GS-9674 
is not expected to change the current toxicity profile of the individual agents. Thus, the 
nonclinical safety data support the clinical evaluation of the triple combination.
1.5.2.
Clinical Trials
1.5.2.1.
GS-US-402-2101
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). Study conduct is complete. Cohorts 1 and 2, designed to 
evaluate potential combination DDIs using a lower dose of GS-9674, and Cohort 6, designed to 


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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
As of 18 January 2017, a total of 108 subjects were enrolled; 104 subjects had completed study 
treatment. 4 subject prematurely discontinued study treatment, with 1 subject prematurely 
discontinuing due to an AE. 2 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, serious adverse events (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.
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. 7of 108 subjects (6.5%) had a Grade 3 laboratory abnormality: 
increased low-density lipoprotein (LDL) cholesterol (5 subjects), increased creatine 
phosphokinase (1 subject), and occult blood (1 subject). All subjects who had a Grade 3 
increased LDL cholesterol had Grade 1 or 2 increased 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 


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7 days are summarized in the Table 1-4. None of modest changes observed were considered 
clinically significant, and no dose modifications were needed upon coadministration of SEL, 
GS-9674, and/or GS-0976.
Table 1-4.
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%.
GS-0976 and GS-834773 exposures following 20 mg once-daily dosing of the tablet formulation 
under fasting conditions (Cohort 3) were similar to those previously observed following 20 mg 
once-daily dosing of the capsule formulation under fasting conditions (Study GS-US-426-3987).
1.5.2.2.
GS-US-384-3914
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, GS-0976, and GS-9674 alone and in 
combination in subjects with NASH and stage 2 to 3 fibrosis (by NASHCRN criteria) as 
evaluated by a MRE ≥ 2.88 kPa and an MRI-PDFF ≥ 10% or a historical biopsy within 
12 months of Screening. Cohorts 1 through 3 are monotherapy cohorts, and Cohorts 4 through 6 
are combination cohorts. All Cohorts were designed to receive study drug for 12 weeks duration 
Preliminary results from Cohorts 1-3 and 4-6 are provided below.


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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 September 29, 2017, a total of 30 were enrolled (n=10 for each Cohort) and all had 
completed study treatment. There were no subjects who prematurely discontinued study drug. No 
subjects withdrew consent, and no subjects were lost to follow-up.
1.5.2.2.2.
Preliminary Safety Results
Overall, 50% (5/10) of subjects had a TEAE in each of Cohorts 1 and 3, and 60% (6/10) of 
subjects had TEAE in Cohort 2. There were no Grade 3 or 4 adverse events, and no serious 
adverse events. In Cohort 1 and Cohort 2, the most common adverse events occurred in the 
system organ class of GI disorders, with 20% (2/10) of subjects in each Cohort experiencing this 
type of adverse event. In Cohort 3, the system organ class of infections and infestations included 
the most common adverse events 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. They were asymptomatic, and they 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 subjects 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 or Grade 3 or above lab 
abnormalities 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 aTEAE, 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 TEAE, 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 
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 


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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 (i.e., Cohorts 7 and 8) in terms of AEs or 
Grade 3 or above lab abnormalities dosed with either GS-0976 or GS-9674.
Table 1-5.
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 1-6.
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.
Information about Fenofibrate
Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid which is a PPARα 
activator. Fenofibrate is indicated as an adjunct to diet to reduce elevated LDL-C, Total-C, 
triglyceride and ApoB, and to increase HDL-C in adult patients with primary 
hypercholesterolemia and for treatment of adult patients with severe hypertriglyceridemia. 
Fenofibrate is available as 48 or 145 mg tablets for once daily oral administration without regard 
to meals. For treatment of severe hypertriglyceridemia the recommended initial dose of 
fenofibrate is 48 to 145 mg once daily and should be individualized according to patient response 
and adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals with the 
maximum dose of 145 mg daily. In patients with mild to moderately impaired renal function 
fenofibrate should be initiated at a dose of 48 mg once daily and increased only after evaluation 
of the effects on renal function and lipid levels at this dose. The use of fenofibrate has not been 
evaluated in formal hepatic impairment studies; as such fenofibrate usage is contraindicated in 
subjects with active liver disease. However, use of fibrates (including fenofibrate) has been 
described in subjects with liver disease, including those with cirrhosis, due to primary biliary 
cholangitis. In these studies, the safety of fibrate therapy has been consistent with data in 
subjects without pre-existing liver disease {Corpechot 2018}. Myopathy and rhabdomyolysis 
have been reported in patients taking fenofibrate (>2% and at least 1% greater than placebo). The 
risk for myopathy and rhabdomyolysis are increased when fibrates are co-administered with a 
statin, particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism. 


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Fenofibrate can increase serum transaminases and reversibly increase serum creatinine (>2% and 
at least 1% greater than placebo). Liver tests including ALT should be monitored periodically 
during therapy. Renal function should be monitored periodically in patients with renal 
impairment. Fenofibrate increases cholesterol excretion into the bile, which may lead to 
cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Concomitant oral 
coumarin anticoagulants should be used with caution with fenofibrate. Dose of coumarin 
anticoagulants should be adjusted to maintain prothrombin time/INR at the desired level to 
prevent bleeding complications.
1.7.
Information about Vascepa®
Vascepa® (Icosapent ethyl) contains ethyl esters of an omega-3 fatty acid, eicosapentaenoic acid 
(EPA), obtained from fish oil. It contains ≥96% EPA and does not contain docosahexaenoic acid 
(DHA). Historically, mixtures containing both EPA and DHA have increased LDL cholesterol in 
patients with severe hypertriglyceridemia. However, studies have suggested that icosapent ethyl 
has not caused significant increases in LDL cholesterol while significantly decreasing 
triglyceride levels. In a placebo-controlled, double-blind clinical trial that enrolled patients with 
high fasting triglyceride levels (135 to 499 mg/dL) and established cardiovascular disease or 
diabetes and other risk factors, it was found that patients who received 2 grams of Vascepa® 
twice daily had significantly lower risk of ischemic events compared to placebo{Bhatt 2019}.
1.8.
Rationale for This Study
NASH involves as 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, 
reactive oxygen species, growth factors, and ultimately hepatocyte cell death {Neuschwander-
Tetri 2010}. These metabolic stress signals directly promote the activation and differentiation of 
hepatic stellate cells into myofibroblasts, the primary source of collagen and extracellular matrix 
that causes fibrosis. In addition, hepatocyte lipotoxicity promotes an immune response by 
resident macrophages, which produce ROS, growth factors and cytokines such as transforming 
growth factor beta (TGF and platelet-derived growth factor (PDGF), that further increase 
myofibroblast activation, migration, proliferation and survival and 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. 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 in rats fed a choline-deficient, 
high-fat diet. In a recently-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 


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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. Reduction of DNL by GS-0976 is therefore expected to improve steatosis and 
fibrosis in subjects with NASH. FXR agonism has been shown to reduce hepatic lipid and bile 
acid synthesis due to down regulation of SREBP-1c and CYP7A1, respectively, as well as reduce 
insulin resistance and hepatic gluconeogenesis {Zhang 2006}. Thus, GS-9674 is postulated to 
halt these instigating triggers for NASH {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. 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. Triple combination therapy of SEL, GS-9674 and 
GS-0976 has potential to further increase efficacy by targeting three distinct pathways that 
independently contribute to NASH pathogenesis. 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 hepatocellular carcinoma. 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 – liver biopsy – is invasive, prone to complications, and is not 
appropriate for use as an endpoint in a study of 12 weeks duration. As such, this study will 
incorporate noninvasive endpoints for the assessment of fibrosis including serum markers 
(eg, ELF™ test), imaging (eg, MRE), and deuterated water labeling. Deuterated water labeling 
allows for a rate-based assessment of disease activity including fibrogenesis {Decaris 2015} and 
also evaluation of changes in the rate of other metabolic processes relevant to NASH (eg, DNL, 
cytokine production, etc.) {Allister 2015}.
Previous clinical studies with GS-0976 20 mg have demonstrated that some patients experience 
hypertriglyceridemia with ACC inhibition. In the Phase 2 study (GS-US-426-3989, 
Section 1.3.5.3) described above, 7 out of 49 subjects (14%) with F1 to F3 fibrosis due to NASH 
experienced asymptomatic, treatment-emergent Grade 3-4 hypertriglyceridemia (>500 mg/dL) 
while being treated with GS-0976 20 mg daily for 12 weeks. In study GS-US-426-3989, the 
median relative increase from baseline in serum triglycerides was 11% in GS-0976 20 mg treated 
subjects. In this study, GS-US-384-3914 (Section 1.5.2.2), subjects with F2 to F4 fibrosis due to 
NASH have been treated with GS-0976 20 mg alone and in combination with other compounds. 
In each of these GS-0976-containing Cohorts described above (Cohorts 2, 5, 6, and 7) 10% of 
subjects have experienced asymptomatic, treatment-emergent Grade 3-4 hypertriglyceridemia.
Preclinical studies described above (Section 1.3.2) suggest there are two mechanisms 
contributing to hypertriglyceridemia with ACC inhibition: 1) increased production and secretion 
of TG-rich VLDL particles from the liver and 2) decreased clearance of TG-rich lipoproteins 
(i.e. chylomicrons and VLDL particles) from the circulation. Data from these preclinical models 


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of NASH suggest that transrepression of PPAR-α and subsequent inhibition of lipoprotein lipase 
(LPL) through an increase in ApoC3 both contribute to the hypertriglyceridemia.
In the Phase 2 study (GS-US-426-3989) and in this study (GS-US-384-3914), all 13 of the 
subjects with Grade 3-4 hypertriglyceridemia had elevated triglycerides (>150 mg/dL) at 
baseline. In the Phase 2 study, the most important predictor of Grade 3-4 treatment-emergent 
hypertriglyceridemia was the presence of triglycerides >250 mg/dL. Whereas 
treatment-emergent triglycerides >500 mg/dL were observed in 17% of subjects with baseline 
triglycerides between 150 and 250 mg/dL, 43% of patients with baseline triglycerides 
>250 mg/dL developed Grade-3-4 hypertriglyceridemia.
In studies including GS-0976 20 mg, a subset of patients with Grade 3-4 hypertriglyceridemia 
were treated with PPAR-α agonists (e.g. fibrates or fish oil), and all these patients had reductions 
in their triglycerides towards their baseline levels without any discontinuations in GS-0976 
treatment. In GS-US-426-3989, 1 subject was treated with fenofibrate for Grade 3 
hypertriglyceridemia; and this subject was noted to have decrease in the triglycerides, ApoB48, 
VLDL particles, and ApoC3 to their baseline levels despite continued treatment with GS-0976 
20 mg were noted.
In previous studies, there are a total of 11 patients who have received GS-0976 20 mg and were 
already receiving a PPAR-α medication (3/11 on a fibrate, 8/11 on fish oil) prior to starting 
GS-0976. These patients had a median decrease in their triglycerides of -0.9 mg/dL, and none of 
these subjects experienced treatment-emergent Grade 3-4 hypertriglyceridemia. This subset of 
patients also demonstrated greater improvements in liver biochemistry, serum markers of 
fibrosis, imaging parameters for hepatic steatosis and fibrosis (MRI-PDFF, MRE, and 
FibroScan®) compared to subjects treated with GS-0976 20 mg without a PPAR-α agonist. This 
preliminary data suggests the combination of GS-0976 and PPARα agonists are safe and that 
there may be a synergistic benefit in terms of increased beta-oxidation and treatment for NASH 
with ACC inhibition from GS-0976 and a PPAR-α agonist, as indicated in the preclinical studies 
described previously. 
Among subjects with baseline hypertriglyceridemia (serum triglycerides ≥ 150 mg/dL and 
< 500 mg/dL), data from study GS-US-384-3914 Cohorts 2, 5, 6, and 7, which treated subjects 
with either GS-0976 (20 mg), or GS-0976 (20 mg) + GS-9674 (30 mg), as well as data 
from study GS-US-426-3989 Treatment Group B, which treated subjects with GS-0976 (20 mg), 
showed a mean increase in triglycerides of 80 mg/dL from baseline at 4 weeks of treatment and a 
mean increase of 87 mg/dL from baseline at 8 weeks of treatment. While on treatment, a total of 
9 out of 63 subjects experienced treatment-emergent Grade 3 hypertriglyceridemia, and a total 
of 4 subjects experienced treatment-emergent Grade 4 hypertriglyceridemia. Data from study 
GS-US-384-3914 Cohort 10, which treated subjects with GS-0976 (20 mg) + fenofibrate 
(48 mg), showed a mean increase in triglycerides of 47 mg/dL from baseline at 4 weeks of 
treatment and a mean increase of 42 mg/dL from baseline at 8 weeks of treatment. While on 
treatment, 1 subject experienced treatment-emergent Grade 3 hypertriglyceridemia. However, in 
study GS-US-384-3914 Cohort 11, subjects who were treated with the high-dose fenofibrate 
(145 mg daily) co-administered with GS-0976 (20 mg) showed no increase in triglycerides from 


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baseline at 4 weeks and 8 weeks of treatment, and no subjects experienced treatment-emergent 
Grade 3 or 4 hypertriglyceridemia while on treatment.
Amendment 12 of this study adds two cohorts (12 and 13) to evaluate the effects of pre-treatment 
with triglyceride-lowering therapies, Vascepa® 4 g or fenofibrate 145 mg, on serum triglycerides 
in patients treated with GS-0976 + GS-9674. Treatment with Vascepa or fenofibrate will be 
initiated two weeks prior to dosing with GS-0976 and GS-9674 with the goal of lowering 
pre-treatment triglyceride concentrations in order to mitigate possible increases in triglycerides 
that result from combination treatment with GS-0976 and GS-9674. Based on prior studies, the 
effect of GS-0976 and GS-9674 on serum triglycerides plateaus after approximately 4 weeks of 
treatment. To ensure any trend in triglycerides is captured in this study, treatment will be 
maintained for 6 weeks.
1.8.1.
Rationale for Dose Selection of Selonsertib
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 or compared to historical placebo response rates, 18 mg (± SIM 125 mg) had a 
slightly higher response rate than 6 mg (± SIM 125 mg). An exposure-response relationship was 
identified for SEL exposure and % change from baseline of blood phosphorylated p38 measured 
in Phase 2 studies in PAH and DKD subjects 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)]. 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.
1.8.2.
Rationale for Dose Selection of GS-0976
The dose of GS-0976 chosen for evaluation in this study, 20 mg PO daily, 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. In these studies, single doses of GS-0976 up to 1000 mg or 
multiple daily doses (10 days) of GS-0976 up to 200 mg were administered to healthy subjects 
and a single dose of 20 mg of GS-0976 resulted in a mean inhibition of fractional DNL of 71%. 
Additionally, nonclinical toxicology studies up to 13 weeks in duration have been conducted in 
rats and dogs at exposure margins multiple folds above the expected clinical exposure. Based on 
preliminary data from Studies 0976-101 and 0976-102 (Please refer to the IB for additional 
information), GS-0976 exposures in non-cirrhotic subjects are expected to remain > 45 to 84-fold 
lower than the GS-0976 exposures observed at the NOAELs in the 13-week rat and dog studies, 
respectively. Based on preliminary data from Study GS-US-426-3988, GS-0976 exposures in 


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subjects with mild hepatic impairment (CPT A) are expected to remain > 20 to 37-fold lower 
than the GS-0976 exposures observed at the NOAELs in the 13-week rat and dog 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.
1.8.3.
Rationale for Dose Selection of GS-9674
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, by slowing oral absorption of GS-9674, resulted in prolonged 
elevation of plasma FGF19 concentrations. Exposure-response relationships showed that changes 
in C4 exposure are negatively correlated with changes in exposure of FGF19 and GS-9674. 
Based on these results, a GS-9674 dose of 30 mg with food has been selected for this study as it 
is expected to provide sufficient enteral FXR agonism and result in histologic improvements in 
subjects with NASH. At a dose of 30 mg once daily in subjects with normal hepatic function or 
mild hepatic impairment, exposure margins relative to preclinical NOAEL exposures for both 
parent and metabolite are expected to remain adequate. Based on the preliminary PK and PD 
data in subjects with mild hepatic impairment as well as the overall safety profile of GS-9674, 
dose adjustments are not considered necessary in subjects with compensated cirrhosis in this 
study.
1.8.4.
Rationale for Dose Selection of Selonsertib, GS-9674, and/or GS-0976 in 
Combination
SEL, GS-9674, and/or GS-0976 can be coadministered without dose modification, based on the 
available preclinical and clinical safety information on each single agent and the combination as 
well as the PK results from study GS-US-402-2101, showing no clinically meaningful changes in 
SEL, GS-9674, and GS-0976 exposure when coadministered (Please refer to GS-9674 IB for 
additional information). Based on the lack of PK DDIs between each of the pairwise 
combinations, there is no expected DDI in the triple combination of SEL, GS-9674, and 
GS-0976. Thus, doses of 18 mg SEL once daily, 30 mg GS-9674 once daily, and/or 20 mg 
GS-0976 once daily were selected for evaluation in combination in this study.
1.8.5.
Rationale for Dose Selection of GS-0976 + Fenofibrate in Combination
Data supporting the safety of fibrates in patients with advanced hepatic fibrosis are limited. The 
majority of the available data come from small studies of patients with primary biliary 
cholangitis (PBC) who have an inadequate response to ursodeoxycholic acid {Cheung 2016, 
Levy 2011}. Published data regarding safety in patients with bridging fibrosis and compensated 
cirrhosis due to NASH are lacking. In Gilead’s previous studies with simtuzumab in subjects 
with advanced fibrosis due to NASH (GS-US-321-0105, GS-US-321-0106), 32 out of 
477 subjects (6.7%) were treated with fibrates during the trials. No clear safety signals were 
attributed to fibrate therapy in these subjects. The doses of fenofibrate, 48 mg and 145 mg, to be 
coadministered with GS-0976 20 mg in Cohorts 10 and 11 of this study to overcome triglyceride 


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elevations induced by ACC inhibition and further increase fatty acid oxidation and cholesterol 
metabolism are based on the range of recommended starting doses of fenofibrate for treatment of 
hypertriglyceridemia, which will be present in all subjects at baseline. No pharmacokinetic 
interaction is expected between fenofibrate and GS-0976 based on a combination of non-clinical 
and clinical drug-drug interaction information. Cohorts 10 and 11 of this study will enroll 
subjects with bridging fibrosis or compensated cirrhosis. As fenofibrate is primarily hydrolyzed 
by esterases and excreted primarily in the urine as fenofibric acid and fenofibric acid 
glucuronide, compensated cirrhosis is not expected to alter the exposure of fenofibric acid or its 
glucuronide conjugate. The dose-ranging of fenofibrate in Cohorts 10 and 11 in this study will 
allow for the selection of a dose of fenofibrate that is most safe and effective at prevention of 
hypertriglyceridemia in subjects with advanced fibrosis due to NASH receiving treatment with 
GS-0976 20 mg.
1.8.6.
Rationale for Dose Selection of GS-0976 + GS-9674 + Vascepa® in 
Combination
The dose of Vascepa® to be administered in Cohort 13 was selected from a controlled clinical 
trial that showed a reduced risk of cardiovascular events among patients with 
hypertriglyceridemia and cardiovascular risk factors that were treated with this dose of Vascepa® 
compared with placebo (refer to section 1.7). The combination of GS-0976 + GS-9674 at the 
specified doses was selected based on data showing this regimen to be safe and potentially 
effective when co-administered in prior cohorts of this study. Vascepa® is not expected to have 
any drug interactions when given in combination with GS-0976 + GS-9674 or affect the 
pharmacokinetics of either compound.
1.8.7.
Rationale for Dose Selection of GS-0976 + GS-9674 + Fenofibrate in 
Combination
The dose selection for this combination treatment was selected as these have been shown to be 
safe and effective in prior cohorts. The dose of fenofibrate was selected based on data from 
Cohorts 10 and 11 (refer to section 1.8).
1.8.8.
Rationale for Study Population
The progression from NAFLD to NASH to cirrhosis occurs over decades. The highest levels of 
morbidity and mortality are found in NASH patients with advanced fibrosis and cirrhosis 
{Ekstedt 2014, Yeh 2014}. Thus, targeting interventions to help this population would have the 
greatest impact on morbidity and mortality. Inclusion criteria for this study were developed in 
order to enrich this small proof-of-concept study with subjects who have definite inflammatory 
and fibrotic processes that can be measured, including those with compensated cirrhosis.
Specifically, all subjects in Cohorts 1 through 6 and 9 will have a clinical diagnosis of NAFLD, 
evidence of ≥ 10% hepatic steatosis on MRI-PDFF {Bannas 2015}, and increased liver stiffness 
on MRE (≥ 2.88 kPa) {Chen 2011}, or histologic confirmation of NASH with moderate to 
severe fibrosis. Previous studies have shown that patients with NAFLD and increased liver 
stiffness on MRE have a high probability of NASH on liver biopsy. For example, Chen et al. 


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reported that an MRE liver stiffness cut-off of ≥ 2.90 kPa was 83% sensitive, 82% specific, and 
had an area under the receiver operating characteristic curve (AUROC) of 0.93 and positive 
predictive value of 88% for the differentiation of simple steatosis from NASH on biopsy. 
Moreover, in a meta-analysis of MRE for the diagnosis of NAFLD-related fibrosis {Singh 
2016}, a liver stiffness ≥ 2.88 kPa optimally identified the presence of at least stage 1 fibrosis 
(AUROC 0.86). Based on these criteria, subjects enrolled in Cohorts 1 through 6 and 9 have a 
high probability of NASH with fibrosis, a population with a large unmet medical need {Loomba 
2014}. With safety and PK data for GS-9674 and GS-0976 in subjects with hepatic impairment, 
these two compounds will be tested as monotherapy in patients with CPT A cirrhosis in 
Cohorts 7 (GS-0976) and 8 (GS-9674). For Cohorts 10 and 11, the diagnosis of advanced 
fibrosis will be based on a clinical diagnosis of NAFLD, a historical liver biopsy, or noninvasive 
tests of fibrosis (MRE) that are predictive of bridging fibrosis or compensated cirrhosis {Loomba 
2014, Munteanu 2016, Singh 2016}. Previous clinical trials with GS-0976 20 mg have 
demonstrated that subjects most at risk for Grade 3-4 hypertriglyceridemia have baseline 
elevations of triglycerides >150 mg/dL, with an increased risk for those with baseline levels 
>250 mg/dL. For this reason, Cohorts 10 and 11 will have a 60:40 ratio of patients that meet 
these baseline triglyceride thresholds. For Cohorts 12 and 13, the diagnosis of NASH/NAFLD 
will be based on clinical features along with criteria for metabolic syndrome or evidence of 
fibrosis based on liver biopsy or liver stiffness by FibroScan® or MRE. Since the objective of 
Cohorts 12-13 is to evaluate the effects of pre-treatment with either fenofibrate or Vascepa® on 
serum triglycerides in the setting of GS-0976 + GS-9674 combination treatment, patients in 
Cohorts 12 and 13 must have hypertriglyceridemia (triglycerides ≥150 and <500 mg/dL) during 
Screening. 
1.9.
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 objective of this study is as follows: 
Final 
Amendment 12 
• 
To evaluate the safety and tolerability of study dmg(s) in subjects with NAFLD/NASH. 
I 
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I 
I 
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3.
STUDY DESIGN
3.1.
Study Design
This is a proof of concept, open-label study evaluating the safety, tolerability, and efficacy of 
monotherapy and combination regimens in subjects with NAFLD/NASH.
3.2.
Treatment Plan and Regimen
Approximately 210 subjects total will be enrolled into one of 13 cohorts.
Eligible subjects for Cohorts 1-9 will be enrolled to receive treatment with SEL, GS-0976, 
GS-9674; the combination of SEL and GS-9674, SEL and GS-0976, GS-0976 and GS-9674; or 
SEL, GS-0976 and GS-9674 for 12 weeks as shown in the figure below.
Non-cirrhotic 
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6 Weeks 
2 Weeks 
12 Weeks 
4 Weeks 


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Cohort 1 (SEL) will consist of 10 enrolled subjects
Cohort 2 (GS-0976) will consist of 10 enrolled subjects
Cohort 3 (GS-9674) will consist of 10 enrolled subjects
Cohort 4 (SEL + GS-9674) will consist of up to 20 enrolled subjects
Cohort 5 (SEL + GS-0976) will consist of up to 20 enrolled subjects
Cohort 6 (GS-0976 + GS-9674) will consist of up to 20 enrolled subjects
Cohort 7 (GS-0976) will consist of up to 10 enrolled subjects with CPT A cirrhosis
Cohort 8 (GS-9674) will consist of up to 10 enrolled subjects with CPT A cirrhosis
Cohort 9 (SEL + GS-0976 + GS-9674) will consist of approximately 10 enrolled subjects
Cohorts 1 through 6 and 9 will be enrolled sequentially while Cohorts 7 and 8 will be 
randomized in parallel. The Biostatistics department at Gilead will generate a randomization list 
for cirrhotic subjects who qualify for Cohorts 7 and 8. Once subjects are deemed eligible and 
before they start kinetic labeling (Day -14), the site will contact the Clinical Operations team at 
Gilead by email or phone, and the Clinical Operations team will utilize the proper randomization 
list to assign the subject to the appropriate cohort.
For Cohorts 10 and 11, eligible subjects will be randomized to receive pretreatment with 
fenofibrate 48 mg or fenofibrate 145 mg from Day -14 to Day -1 and will be treated with 
GS-0976 20 mg and fenofibrate 48 mg or GS-0976 20 mg and fenofibrate 145 mg for 24 weeks 
as shown in the figure below.
Approximately 30 subjects will be randomized (1:1) into either Cohort 10 or 11; randomization 
will be stratified by (1) screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥ 250 mg/dL and < 500 mg/dL]), and (2) fibrosis stage [F3 defined by liver biopsy or screening 
MRE with liver stiffness < 4.67 kPa or F4 defined by liver biopsy or screening MRE with liver 
stiffness ≥ 4.67 kPa. Approximately 60% of subjects in each Cohort should have cirrhosis (F4) 
C: 
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Cohortll 
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GS-0976 20 mg+ Fenofibrat e 4S mg PO QD 
Treat ment 24 weeks 
GS-0976 20 mg+ Fenofibrat e 145 mg PO QD 
24 Weeks(Day 1 t hrough Week 24} 


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based on Inclusion Criteria 5. Approximately 60% subjects in each cohort should have screening 
serum triglycerides ≥ 150 mg/dL and < 250 mg/dL as below:

Cohort 10 (GS-0976 20 mg + Fenofibrate 48 mg) will consist of 15 subjects:
o
Approximately 9 subjects with Screening serum triglycerides ≥ 150 mg/dL and 
< 250 mg/dL
o
Approximately 6 subjects with Screening serum triglycerides ≥ 250 mg/dL and 
< 500 mg/dL

Cohort 11 (GS-0976 20 mg + Fenofibrate 145 mg) will consist of 15 subjects:
o
Approximately 9 subjects with Screening serum triglycerides ≥ 150 mg/dL and 
< 250 mg/dL
o
Approximately 6 subjects with Screening serum triglycerides ≥ 250 mg/dL and 
< 500 mg/dL
For Cohorts 12 and 13, eligible subjects will be randomized to receive pretreatment with 
Vascepa® 2 g twice daily or fenofibrate 145 mg once daily from Day -14 to Day -1 and will be 
treated with GS-0976 20 mg once daily, GS-9674 30 mg once daily, and Vascepa® 2 g twice 
daily; or GS-0976 20 mg once daily, GS-9674 30 mg once daily, and fenofibrate 145 mg once 
daily for 6 weeks as shown in the figure below.
Approximately 60 subjects will be randomized (1:1) into either Cohorts 12 or 13. Randomization 
will be stratified by screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥ 250 mg/dL and < 500 mg/dL]).

Cohort 12 (GS-0976 20 mg once daily + GS-9674 30 mg once daily + Vascepa® 2 g twice 
daily) will consist of 30 subjects

Cohort 13 (GS-0976 20 mg once daily + GS-9674 30 mg once daily+ fenofibrate 145 mg 
once daily) will consist of 30 subjects
Cohort 12 
(n = 30) 
Cohort 13 
(n = 30) 
Pretreatment 
Vascepa 
2 g PO BID 
Pretreatment 
Fenofibrate 
145 m POQD 
2 Weeks (Day-14 through Day -1) 
Treatment 6 weeks 
GS-0976 20 mg PO QD + GS-9674 30mg PO QD + 
Vascepa 2 g PO BID 
Treatment 6 w eeks 
GS-0976 20 mg PO QD + GS-9674 30 mg PO QD + 
Fenofibrate 145 mg PO QD 
6 Weeks (Day 1 through Week 6) 


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This trial will enroll approximately 230 subjects with NAFLD/NASH.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Males and females between 18-75 years (Cohorts 1-9) and ≥ 18 years (Cohorts 10-13) of age; 
inclusive based on the date of the Screening Visit;
2. Willing and able to provide informed consent prior to any study specific procedures being 
performed;
3. For Cohorts 1 through 6 and 9, subjects must meet all of the following conditions (a-d OR 
e&f):
a) Clinical diagnosis of NAFLD,
b) Screening FibroTest® < 0.75, unless a historical liver biopsy within 12 months of 
Screening does not reveal cirrhosis. In subjects with Gilbert’s syndrome or hemolysis, 
FibroTest® will be calculated using direct bilirubin instead of total bilirubin,
c) Screening MRI-PDFF with ≥ 10% steatosis,
d) Screening MRE with liver stiffness ≥ 2.88 kPa,
OR
e) A historical liver biopsy within 12 months of Screening consistent with NASH 
(defined as the presence of steatosis, inflammation, and ballooning) with stage 
2-3 fibrosis according to the NASH CRN classification (or equivalent),
AND
f)
No documented weight loss > 5% between the date of the liver biopsy and Screening;


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4. For Cohorts 7 and 8, subjects must have a clinical diagnosis of NAFLD and have at least one 
of the following criteria (a-d):
a) Screening MRE with liver stiffness ≥ 4.67 kPa,
b) A historical FibroScan® ≥ 14 kPa within 6 months of Screening,
c) Screening FibroTest® ≥ 0.75,
d) A historical liver biopsy consistent with stage 4 fibrosis according to the NASH CRN 
classification (or equivalent);
5. For Cohorts 10 and 11, subjects must have a clinical diagnosis of NAFLD and the following 
criteria:
a) At least two criteria for metabolic syndrome modified from the NCEP ATP III 
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,
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
AND one of the following criteria:
b) A historical liver biopsy within 6 months of Screening consistent with NASH and 
bridging fibrosis (F3) or within 12 months of Screening consistent with NASH and 
compensated cirrhosis (F4) in the opinion of the investigator,
c) Screening liver stiffness by MRE ≥ 3.64 kPa,
d) Screening liver stiffness by FibroScan® ≥ 9.9 kPa;


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6. For Cohorts 12 and 13, subjects must have a clinical diagnosis of NAFLD/NASH and the 
following criteria:
a) At least two criteria for metabolic syndrome modified from the NCEP ATP III 
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,
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,
OR one of the following criteria:
b) A historical liver biopsy within 6 months of Screening consistent with NASH for subjects 
without compensated cirrhosis (F4); or within 12 months of Screening consistent with 
NASH for subjects with compensated cirrhosis (F4) in the opinion of the investigator,
c)  A historical MRE with liver stiffness ≥ 2.88 kPa within 6 months of Screening,
d)  A historical FibroScan® with liver stiffness ≥ 9.9 kPa within 6 months of Screening,
AND
e) No documented weight loss > 5% between the date of the historical liver biopsy, 
historical MRE, or historical Fibroscan and Screening;
7. A Platelet count ≥ 100,000/µL;
8. Serum creatinine < 2 mg/dL (Cohorts 1-9) at Screening;
9. Estimated glomerular filtration rate (eGFR) ≥ 80 mL/min (Cohorts 10-11) or ≥ 60 mL/min 
(Cohorts 12-13), as calculated by the Cockcroft-Gault equation at Screening;
10. For Cohorts 10-13, serum triglyceride level ≥ 150 mg/dL at Screening;
11. Female subjects of childbearing potential (see definition in Appendix 3) must have a negative 
serum pregnancy test prior to starting study treatment;


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12. All female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception during intercourse from the screening 
visit throughout the study period and for 90 days following the last dose of study drug as 
described in Appendix 3;
13. Male subjects must agree to use condoms during intercourse from screening through the 
study completion and for 90 days following the last dose of study drug;
14. Male subjects must refrain from sperm donation from screening through at least 90 days 
following the last dose of study drug;
15. Female subjects must refrain from egg donation or harvest for 90 days after last dose of study 
drug;
16. Must be able to read and complete Quality of Life questionnaires independently 
(Cohorts 1-11);
17. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, 
and other study procedures and study restrictions.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating females;
2. Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
3. Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or 
variceal bleeding;
4. For Cohorts 7-8 and 10-13, Child-Pugh-Turcotte (CPT) score > 6 (Appendix 4) at Screening, 
unless due to an alternative etiology such as Gilbert’s syndrome or therapeutic 
anticoagulation;
5. History of liver transplantation;
6. History of hepatocellular carcinoma;
7. Weight reduction surgery in the past 2 years or planned during the study;
8. Documented weight loss > 5% between the date of the historical liver biopsy and Screening, 
if applicable;
9. BMI < 18 kg/m2;
10. ALT > 5 x ULN at Screening;


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11. For Cohorts 10-13, HbA1c ≥ 9.5% (or serum fructosamine ≥ 381 µmol if HbA1c is unable to 
be resulted) at Screening;
12. For Cohorts 10-13, hemoglobin ≤ 10.6 g/dL at Screening;
13. INR > 1.2 (Cohorts 1-9) or INR > 1.4 (Cohorts 10-13) at Screening, unless on 
anticoagulation therapy;
14. Total bilirubin > 1x ULN (Cohorts 1 through 6 and 9), >1.5 x ULN (Cohorts 7 and 8), or  
>1.3 x ULN (Cohorts 10-13) except in confirmed cases of Gilbert’s syndrome;
15.  Triglycerides ≥ 500 mg/dL (Cohorts 5-8 and 10-13) or ≥ 250 mg/dL (Cohort 9) at Screening;
16. Model for End-Stage Liver Disease (MELD) score > 12 at Screening (Cohorts 10-13), unless 
due to an alternate etiology such as therapeutic anticoagulation;
17. Chronic hepatitis B (HBsAg positive);
18. Chronic hepatitis C (HCV RNA positive); Subjects cured of HCV infection less than 2 years 
prior to the Screening visit are not eligible (Cohorts 10-13);
19. HIV Ab positive;
20. Presence of gallstones within 6 months of Screening (Cohorts 10-13);
21. Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 
1 oz/30mL measure of 40% proof alcohol);
22. Positive urine screen for amphetamines, cocaine or opiates (i.e., 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 opioid-based medication are eligible if the prescription and 
diagnosis are reviewed and approved by the investigator;
23. Unstable cardiovascular disease as defined by any of the following:
a) Unstable angina within 6 months prior to screening,
b) Myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty 
within 6 months prior to screening,
c) Transient ischemic attack or cerebrovascular accident within 6 months prior to screening,
d) Obstructive valvular heart disease or hypertrophic cardiomyopathy,
e) Congestive heart failure;


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24. History of intestinal resection of the extent that would result in malabsorption;
25. Use of any prohibited concomitant medications as described in Section 5.8;
26. 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;
27. Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely 
affect the safety of the subject or impair the assessment of study results;
28. Participation in another investigational study of a drug or device within 1 month prior or 
within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening;
29. Concurrent participation in another therapeutic clinical study;
30. Known hypersensitivity to study drugs, the metabolites, or formulation excipients;
31. Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse or a psychiatric 
or medical condition;
32. Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures;
33. Contraindications to MRI scanning (e.g., presence of permanent pacemakers, implanted 
cardiac devices, etc.) (Cohorts 1-11);
34. For Cohorts 10 -13, any contraindication to fenofibrate, per the approved package insert, with 
the exception of advanced liver fibrosis;
35. For Cohorts 12 and 13, any contraindication to Vascepa®, per the approved package insert;
36. For Cohorts 12 and 13, history of acute or chronic pancreatitis;
37. For Cohorts 12 and 13, known hypersensitivity to fish and/or shellfish;
38. For Cohorts 12 and 13, poorly controlled hypertension despite anti-hypertensive therapy.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
Cohorts 1 through 6 and 9 will be enrolled sequentially without any randomization. Cohorts 7 
and 8 will be enrolled in parallel and randomized for this purpose. For Cohorts 10 and 11, 
randomization will be stratified by (1) screening serum triglyceride levels ([≥ 150 mg/dL and 
< 250 mg/dL] or [≥ 250 mg/dL and < 500 mg/dL]), and (2) fibrosis stage [F3 defined by liver 
biopsy or screening MRE with liver stiffness < 4.67 kPa or F4 defined by liver biopsy or 
screening MRE with liver stiffness ≥ 4.67 kPa]. For Cohorts 12 and 13, randomization will be 
stratified by screening serum triglyceride levels ([≥ 150 mg/dL and < 250 mg/dL] or 
[≥ 250 mg/dL and < 500 mg/dL]). The Biostatistics department at Gilead will generate a 
randomization list for subjects who qualify for randomized cohorts.  
Further details of the randomization can be found in the Randomization Schedule document.
5.2.
Description and Handling of Selonsertib
5.2.1.
Formulations
5.2.1.1.
Selonsertib Tablets
For Cohorts 1, 4, 5 and 9, SEL will be supplied as round, plain-faced, white film-coated tablets 
containing 18 mg of SEL. In addition to the active ingredient, SEL tablets contain the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, polyethylene glycol 3350, 
titanium dioxide and talc.
5.2.2.
Packaging and Labeling
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.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
SEL 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.


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Until dispensed to the subjects, all study drug(s) should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure the stability and proper identification, 
study drug should not be stored in a container other than the container in which they were 
supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Description and Handling of GS-0976
5.3.1.
Formulations
5.3.1.1.
GS-0976 Capsules and Tablets
For Cohort 2, GS-0976 will be supplied as white opaque size 0 hard gelatin capsules containing 
10 mg of GS-0976. In addition to the active ingredient, GS-0976 capsules contain the following 
inactive ingredients: lactose monohydrate, stearoyl polyoxylglycerides and croscarmellose 
sodium, which are common pharmaceutical excipients.
For Cohorts 5-7 and 9-13, GS-0976 will be supplied as 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.
5.3.2.
Packaging and Labeling
For Cohort 2, GS-0976 capsules are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 200 capsules. Each bottle is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced 
liner.
For Cohorts 5-7 and 9-13, GS-0976 tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.


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5.3.3.
Storage and Handling
GS-0976 capsules and tablets should be stored at controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.4.
Description and Handling of GS-9674
5.4.1.
Formulation
5.4.1.1.
GS-9674 Tablets
For Cohort 3, GS-9674 will be supplied as round, plain-faced, film-coated orange tablets 
containing 10 mg (as free form equivalent) of GS-9674. In addition to the active ingredient, 
GS-9674 tablets contain the following inactive ingredients: microcrystalline cellulose, lactose 
monohydrate, 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.
For Cohorts 4, 6, 8 and 9, GS-9674 will be supplied as round, plain-faced, film-coated orange 
tablets containing 30 mg (as free form equivalent) of GS-9674. In addition to the active 
ingredient, GS-9674 tablets contain the following 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.
For Cohorts 12 and 13, GS-9674 will be supplied as round, film-coated green tablets, debossed 
with “GSI” on one side of the tablet and “30” on the other side of the tablet, and containing 30 
mg (as free form equivalent) of GS-9674. In addition to the active ingredient, GS-9674 tablets 
contain the following inactive ingredients: microcrystalline cellulose, mannitol, crospovidone, 
magnesium stearate and film-coating material composed of polyvinyl alcohol, polyethylene 
glycol, talc, titanium dioxide, yellow iron oxide, and ferrosoferric oxide.
5.4.2.
Packaging and Labeling
GS-9674 tablets are packaged in white, high-density polyethylene (HDPE) bottle. Each bottle 
contains 30 tablets, a silica gel desiccant, and polyester packing material. Each bottle is enclosed 


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with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.4.3.
Storage and Handling
GS-9674 tablets should be stored below 30 °C (86 °F). Storage conditions are specified on the 
label.
Until study drug tablets are 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, the drug products should not be stored in a container other than the 
container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling GS-9674 tablets.
5.5.
Description and Handling of Fenofibrate
5.5.1.
Formulation
5.5.1.1.
Fenofibrate Tablets
Commercially available fenofibrate 48 mg and 145 mg tablets will be used for the study. 
Information regarding the formulation of commercially available fenofibrate can be found in the 
prescribing information.
5.5.2.
Packaging and Labeling
Commercially available fenofibrate will be used for the study. Fenofibrate is packaged in bottles 
of 90 tablets. Fenofibrate to be distributed to centers in the US and other participating countries 
shall be labeled to meet applicable requirements of the United States Food and Drug 
Administration (FDA), EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products), and/or other local regulations.
5.5.3.
Storage and Handling
Commercially available fenofibrate will be used for the study. Further information regarding 
storage and handling is available in the Prescribing Information for commercial products.


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5.6.
Description and Handling of Vascepa®
5.6.1.
Formulation
5.6.1.1.
Vascepa® Capsules 
Commercially available Vascepa® 1g capsules will be used for this study. Information regarding 
the formulation of commercially available Vascepa® can be found in the prescribing information.
5.6.2.
Packaging and Labeling
Commercially available Vascepa® will be used for the study. Vascepa® is packaged in bottles of 
120 capsules. Vascepa® to be distributed to centers in the US and other participating countries 
shall be labeled to meet applicable requirements of the United States Food and Drug 
Administration (FDA), EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products), and/or other local regulations.
5.6.3.
Storage and Handling
Commercially available Vascepa® will be used for the study.  Further information regarding 
storage and handling is available in the Prescribing Information for commercial products.
5.7.
Dosage and Administration
The administration of study drug will be recorded in the source documentation and in the eCRF.
5.7.1.
Selonsertib
SEL tablets will be provided by Gilead Sciences. Subjects will take one tablet of SEL (18 mg) 
once daily at approximately the same time each morning. Study drug should be swallowed whole 
with water and may be taken with or without food. A dose will be considered missed if the 
subject cannot take the 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.
5.7.2.
GS-0976
GS-0976 capsules and tablets will be provided by Gilead Sciences. For Cohort 2, subjects will 
take two capsules of GS-0976 (10 mg) once daily at approximately the same time each morning. 
For Cohort 7, subjects will take 1 tablet of GS-0976 (20 mg) once daily at approximately the 
same time each morning. Study drug should be swallowed whole with water and may be taken 
with or without food. A dose will be considered missed if the subject cannot take the 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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5.7.3.
GS-9674
GS-9674 tablets will be provided by Gilead Sciences. For Cohort 3, subjects will take 
three tablets of GS-9674 (10 mg) once daily at approximately the same time each morning. For 
Cohort 8, subjects will take one tablet of GS-9674 (30 mg) once daily at approximately the same 
time each morning. Study drug should be swallowed whole with water and should be taken with 
food. A dose will be considered missed if the subject cannot take the 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.
5.7.4.
Selonsertib + GS-9674
For Cohort 4, SEL and GS-9674 tablets will be provided by Gilead Sciences. Subjects will take 
one tablet of SEL (18 mg) and one tablet of GS-9674 (30 mg) once daily at approximately the 
same time each morning. Study drugs should be swallowed whole with water and should be 
taken with food. A dose will be considered missed if the subject cannot take the 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.
5.7.5.
Selonsertib + GS-0976
For Cohort 5, SEL and GS-0976 tablets will be provided by Gilead Sciences. Subjects will take 
one tablet of SEL (18 mg) and one tablet of GS-0976 (20 mg) once daily at approximately the 
same time each morning. Study drugs should be swallowed whole with water and can be taken 
with or without food. A dose will be considered missed if the subject cannot take the 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.
5.7.6.
GS-0976 + GS-9674
For Cohort 6, GS-0976 and GS-9674 tablets will be provided by Gilead Sciences. Subjects will 
take one tablet of GS-0976 (20 mg) and one tablet of GS-9674 (30 mg) once daily at 
approximately the same time each morning. Study drugs should be swallowed whole with water 
and should be taken with food. A dose will be considered missed if the subject cannot take the 
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.
5.7.7.
SEL + GS-0976 + GS-9674
For Cohort 9, SEL, GS-0976 and GS-9674 will be provided by Gilead Sciences. Subjects will 
take one tablet each of SEL (18 mg), GS-0976 (20 mg), and GS-9674 (30 mg) once daily at 
approximately the same time each morning. Study drugs should be swallowed whole with water 
and should be taken with food. A dose will be considered missed if the subject cannot take the 
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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5.7.8.
GS-0976 + Fenofibrate
GS-0976 and fenofibrate will be provided by Gilead Sciences. For Cohort 10, subjects will take 
one tablet of GS-0976 (20 mg) and one tablet of fenofibrate (48 mg) once daily at approximately 
the same time each morning. For Cohort 11, subjects will take one tablet of GS-0976 (20 mg) 
and one tablet of fenofibrate (145 mg) once daily at approximately the same time each morning. 
Study drugs should be swallowed whole with water and may be taken with or without food. A 
dose will be considered missed if the subject cannot take the 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.
5.7.9.
GS-0976 + GS-9674 + Vascepa®
For Cohort 12, GS-0976, GS-9674, and Vascepa® will be provided by Gilead Sciences. Subjects 
will take one tablet of GS-0976 (20 mg) once daily, one tablet of GS-9674 (30mg) once daily, 
and 2 capsules of Vascepa® (1 g) two times daily at approximately the same time each day. 
Vascepa® should be swallowed whole with water and should be taken with food. GS-9674 and 
GS-0976 should be swallowed whole with water and may be taken with or without food. A dose 
will be considered missed if the subject cannot take the 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.
5.7.10.
GS-0976 + GS-9674 + Fenofibrate
For Cohort 13, GS-0976, GS-9674, and fenofibrate will be provided by Gilead Sciences. 
Subjects will take one tablet of GS-0976 (20 mg), one tablet of GS-9674 (30 mg), and one tablet 
of fenofibrate (145 mg) once daily at approximately the same time each morning. Study drugs 
should be swallowed whole with water and may be taken with or without food. A dose will be 
considered missed if the subject cannot take the 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.
5.8.
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 
to the end of the follow-up period.
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 Screening Visit.
Any investigational medication (e.g., obeticholic acid, elafibranor, and cenicriviroc) within 
30 days or within 5 half-lives prior to Screening and through follow-up is prohibited.


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The following medications are prohibited for all treatment groups within 30 days prior to 
Screening through Follow-Up Visit:

The use of any investigational device,

Chronic systemic immunosuppressant’s including but not limited to: corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab). Use for ≤ 2 weeks total is allowed,

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents [ESAs]; granulocyte 
colony stimulating factor [GCSF]; thrombopoietin [TPO] mimetics),

Any medication or supplement prescribed for weight loss,

Fibrate or fish oil treatment (not including the fenofibrate or Vascepa® administered as study 
drugs in this protocol); subjects can be screened after washout period of 30 days 
(Cohorts 10-13).
Medications for disease conditions excluded from the protocol (e.g., HIV-1, HBV, or HCV 
infection, active cancer, transplantation) are not listed under this prohibited medications section 
however they are disallowed in the study.
5.8.1.
Prohibited Medications for Use with Administration of Selonsertib
Caution should be exercised when co-administering sensitive P-gp substrates with narrow 
therapeutic index with SEL 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.
Strong CYP3A4 inducers may decrease the exposure of SEL and could lead to decreased 
efficacy. Use of strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s 
wort) is prohibited from 28 days prior to Day 1 through end of treatment.
Examples of representative medications which are prohibited from 28 days prior to Day 1 up to 
and including the day of the last dose of study drug and those to be used with caution are listed 
below in Table 5-1:


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Table 5-1.
List of Medications Prohibited and to Be Used with Caution
Drug Class
Agents Disallowed
Agents to be used with Caution
Anticonvulsantsa
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsa
Rifampin, Rifabutin, Rifapentine
Cardiac Medicationsb
Digoxinc, Ranolazine, Dabigatran etexilate, 
Aliskiren
Herbal/Natural 
Supplementsa
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
a
May result in a decrease in the concentration of study drug.
b
SEL may increase the exposure of these drugs.
c
For subjects on digoxin at start of study: Obtain digoxin level prior to starting SEL, reduce dose of digoxin by 15-30%, and 
follow digoxin level at the Week 1 Visit with digoxin level checks during the study period per investigator discretion 
(none to as frequent as needed).
5.8.2.
Prohibited Medications for Use with Administration of GS-0976
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters P-gp or OATP 1B1 or 1B3) with GS-0976 may result in PK interactions 
resulting in increases or decreases in exposure of GS-0976 or concomitant medications. 
Examples of representative medications which are prohibited from 28 days prior to Day 1 
through end of treatment are listed below in Table 5-2.
Table 5-2.
List of Disallowed Medications
Drug Class
Agents Disallowed
Agents to be used with Caution
Antibiotics
Azithromycin, Clarithromycin, 
Erythromycin
Anticonvulsantsa
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsa
Rifamycins, Isoniazid
Bile acid sequestrantsb
cholestyramine, colestipol, colesevelem
Cardiac Medications
Bosentan
Herbal/Natural 
Supplementsa
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Other
Modafinil
a
May result in a decrease in the concentrations of study drugs.
b
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) study drug administration.


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5.8.3.
Prohibited Medications for Use with Administration of GS-9674
The following medications are prohibited from 28 days prior to Day 1 up to and including the 
day of the last dose of study drug:

Vitamin E,

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics),

Chronic systemic immunosuppressant’s including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab). Use for < 2 weeks total is allowed,

Investigational agents or devices for any indication,

Concomitant use of certain medications or herbal/natural supplements (potent inhibitors of 
OATP or potent or moderate inducers of OATP, CYP2C8, P-gp, or CYP3A) with study 
drug(s) may result in PK interactions leading to increases or decreases in exposure of study 
drug. Examples of representative medications which are prohibited from 28 days prior to 
Day 1 up to and including the day of the last dose of study drug, are listed below in 
Table 5-3:
Table 5-3.
List of Medications Prohibited and to Be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Antibiotics
Clarithromycin, Erythromycin
Acid Reducing Agents
H2-Receptor Antagonistsa
Antacidsb
Anticonvulsantsc
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antimycobacterialsc
Rifapentine, Rifampin
Endothelin Receptor 
Antagonists
Bosentan
Herbal/Natural Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Other
Modafinil
a
H2-Receptor Antagonists should be held 3 days prior to first dose of study drug.
b
Antacids that directly neutralize stomach pH (i.e., Tums, Maalox) are permitted but may not be taken within 4 hours 
(before or after) study drug administration.
c
May result in a decrease in the concentrations of study drug.
5.8.4.
Medications to Be Used with Caution with Fenofibrate
The prescribing information for fenofibrate should be consulted for medications that are 
prohibited and/or to be used with caution with fenofibrate.
Examples of representative medications that should be used with caution are listed in Table 5-4.


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Table 5-4.
List of Medications to Be Used with Caution
Drug Class
Use with Caution
Anticoagulantsa
Coumarin, coumadin, warfarin
Anti-gout agentsb
Colchicine
Bile acid sequestrantsc
Cholestyramine, colestipol, colesevelem
Lipid modifying agentsd
Simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, 
cerivastatin, rosuvastatin, pitavastatin
a
Fenofibrate can increase PT/INR. Increased frequency of PT/INR assessments when the subject is started on fenofibrate is at 
the investigators discretion. Monitor and adjust anticoagulant dose as necessary based on prescribing information.
b
Concomitant use of colchicine with fenofibrates can increase the risk of rhabodmyolysis.
c
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) study drug administration.
d
Concomitant use of statins with fenofibrates can increase the risk of rhabodmyolysis.
5.8.5.
Medications to Be Used with Caution with Vascepa®
The prescribing information for Vascepa® should be consulted for medications that are 
prohibited and/or to be used with caution with Vascepa®.
Examples of representative medications that should be used with caution are listed in Table 5-5.
Table 5-5.
List of Medications to Be Used with Caution
Drug Class
Use with Caution
Anticoagulantsa
Coumarin, coumadin, warfarin
Antiplateletsb 
P2Y12 inhibitors, NSAIDS, SSRIs, Ibrutinib
a
Omega-3 fatty acids may enhance the anticoagulant effect of anticoagulants. Patients receiving treatment with Vascepa® and 
drugs affecting coagulation should be monitored periodically.
b
Omega-3 fatty acids may enhance the antiplatelet properties of agents with antiplatelet properties. Patients receiving 
treatment with Vascepa® and antiplatelet agents should be monitored periodically. 
5.9.
Study Drug Accountability
The investigator or designee (e.g., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug bottles. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition), subject dispensing records, and 
returned or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including the lot/kit number, date 
dispensed, subject identification number, subject initials, and the initials of the person dispensing 
the medication. All used and unused study drug bottles dispensed to subjects must be returned to 
the site.
Investigational Drug Accountability records will be provided to each study site to:

Record the date received and quantity of study drug bottles.

Record the date, subject number, subject initials, and the study drug kit/lot number and 
bottles assigned.


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
Record the date, quantity of used and unused study drug bottles. Dispensing records will 
include the initials of the person recording the information.
5.9.1.
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 drug will be 
destroyed at the site. Upon study completion, a copy of the Investigational Drug and Device 
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.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject 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 Biomarkers Manual.
The investigator must document any deviation from protocol procedures and notify the Sponsor 
or the Contract Research Organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the screening process.
6.2.
Screening Assessments for Cohorts 1-11
6.2.1.
Screening Visit (Cohorts 1-11)
Subjects will be screened within 6 weeks prior to Day -14 to determine eligibility for 
participation in the study. The screening period also may be extended under special 
circumstances with the explicit approval of Gilead Sciences.
Screening information for subjects screened under prior protocol amendments may be used to 
determine eligibility and fulfill screening visit assessments for this amendment.
Subjects who previously failed screening in study GS-US-384-3914 can be re-screened in the 
following situation (Cohorts 1-9):

Previously screen failed due to a low MRE or MRI-PDFF measurement and have a historical 
liver biopsy within 12 months of Screening/Re-screening that is consistent with NASH 
(defined as the presence of steatosis, hepatocellular ballooning, and lobular inflammation) 
with fibrosis (for Cohorts 4, 5, 6 and 9: F2-F3; for Cohorts 7 and 8: F4 by NASH CRN 
criteria or equivalent),

Previously screen failed due to a FibroTest® ≥ 0.75 in whom Gilbert’s syndrome or 
hemolysis is present; a repeat FibroTest® calculated using direct bilirubin instead of total 
bilirubin will be used to determine eligibility (for Cohorts 4, 5, 6 and 9),

Previously screen failed due to a FibroTest® ≥ 0.75 and with a historical liver biopsy within 
12 months of Screening that does not reveal cirrhosis; FibroTest® score will not be used to 
determine eligibility (for Cohorts 4, 5, 6 and 9).


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historical MRE and MRI-PDFF within 
6 months of screening in another Gilead study (i.e., GS-US-384-3914, GS-US-402-1852, and 
GS-US-426-3989) may be used to detennine eligibility into this study. All other screening 
procedures must be repeated to meet eligibility criteria. 
Screening labs may be repeated once within the screening period, prior to Day -14. This will be 
done at the discretion of the investigator. 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
screening visit to ensure an approximate 10-hour fast prior to the fasting blood sample collection 
the next morning. 
The following assessments will be perfonned and documented at the Screening Visit: 
• 
Obtain written info1med consent before initiation of any screening procedures 
• 
Review and record whether the subject has met eligibility criteria 
• 
Assess presence and severity of ascites and hepatic encephalopathy for CPT score 
(for Coho1is 7, 8, 10 and 11 only) 
• 
Obtain medical histo1y including, but not limited to infonnation related to the following: 
Type 2 Diabetes Mellitus, NAFLD, and NASH 
• 
Review historical liver biopsy, obtained within 12 months of Screening (date of initial 
info1med consent) for noncinhotics and at any time for cinhotics, to assess subject eligibility 
for Coho1is 1-9; or review historical liver biopsy obtained within 6 months of Screening ( date 
of initial info1med consent) for subjects with bridging fibrosis (F3) and within the last 
12 months for subjects with cnThosis (F4), to assess subject eligibility for Cohorts 10-11 
(if applicable) 
• 
Complete physical examination including height, vital signs, 
• 
Conduct standard 12-lead ECG 
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
Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
Hemoglobin A1c (Cohorts 10-11)
 
o
HIV-1, HBV & HCV Serology
o
Serum pregnancy test (only for female subjects of childbearing potential)

Obtain urine sample for drug screen

Record all concomitant medications that the subject has taken within 30 days prior to 
screening

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form
NOTE: Screening 
, 
 
 
must be performed regardless of presence of historical liver biopsy to establish a baseline value.
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
6.3.
Pretreatment Assessments for Cohorts 1-11
6.3.1.
Day -14 Visit (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
After review of the inclusion and exclusion criteria to confirm eligibility, subjects will return to 
the site for the initiation of Kinetic Biomarkers – Cycle 1.
The following assessments will be performed and documented at the visit:

Review and record whether the subject has met eligibility criteria 

Update medical history if a change has occurred during screening (Cohorts 10-11)
CCI
CCI
CCI
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·--


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
Symptom driven physical examination (Cohorts 10-11)

Record vital signs 
 (Cohorts 10-11)

Obtain blood samples:
o
Chemistry and hematology (Cohorts 10-11)
o
Coagulation panel (Cohorts 10-11)
o
ApoA1, ApoB (Cohorts 10-11)
o
Lipidomics and NMR Lipoprofile (Cohorts 10-11)
o
Adiponectin (Cohorts 10-11)
o
Total Bile Acids (Cohorts 10-11)
o
Beta-hydroxybutyrate (Cohorts 10-11)
o
Hemoglobin A1c (Cohorts 10-11)
o
hsCRP (Cohorts 10-11)
o
Kinetic Biomarkers

Obtain urine samples:
o
Kinetic Biomarkers

Dispense deuterated water. The first dose of 50 mL deuterated water will be administered 
under the supervision of investigative site personnel and monitored for at least 30 minutes 
after for any side effects.

Dispense fenofibrate, and provide subject with dosing instruction on appropriate dosing and 
administration; subject will take the Day -14 dose of study drug on-site (Cohorts 10-11)

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
CCI
CCI
CCI
CCI
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Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.3.2.
Day -11 and Day -7 Visits (± 1 Day) (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at each visit:

Obtain blood samples:
o
Chemistry and hematology (Cohorts 10-11)
o
Coagulation panel (Cohorts 10-11)
o
Kinetic Biomarkers

Obtain urine samples
o
Kinetic Biomarkers 

Record any serious adverse events and all adverse events (related to protocol mandated 
procedures for Cohorts 1-9) since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.
Treatment Assessments for Cohorts 1-11
6.4.1.
Day 1 Visit (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at the Day 1 Visit prior to dosing:

Review and record whether the subject has met eligibility criteria (Cohorts 1-9)

Update medical history if a change has occurred during screening 
CCI
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
Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score 
(Cohorts 10 and 11)

Record vital signs 

QoL questionnaires (CLDQ, SF-36, &WPAI)

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
ApoA1, ApoB
o
FGF19 (Cohorts 1-9)
o
Phospho-p38 (if reagent is available) (Cohorts 1-9)
o
Lipidomics and NMR Lipoprofile
o
C4 (Cohorts 1-9)
o
Adiponectin 
o
Total Bile Acids 
o
Beta-hydroxybutyrate 
o
hsCRP (Cohorts 10-11)
o
Hemoglobin A1c
o
Genomic sample
o
Kinetic Biomarkers

Obtain urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers
CCI
CCI
CCI
CCI
CCI
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
Dispense study drug (GS-0976), and provide subject with dosing instruction on appropriate 
dosing and administration; subject will take the Day 1 dose of study drug on-site

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events related to protocol mandated 
procedures since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.2.
Day 7 (Week 1) Visit (± 3 days) (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. Subjects in Cohort 5, 6, 7, 9, 10 and 11 should also be instructed to hold their dose of 
study drug on the morning of the visit until all fasting visit procedures have been completed and 
take their study drug(s) as instructed during the visit.
The following assessments will be performed and documented at this visit:

Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score 
(Cohorts 10 and 11)

Record vital signs 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
ApoA1, ApoB
o
FGF19 (Cohorts 1-9)
o
Adiponectin (Cohorts 1-9)
CCI


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o Total Bile Acids 
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o Saliva collection for Kinetic Biomarkers (Coho1is 1-3) Refer to the laborato1y manual for 
additional infonnation. 
o Predose Kinetic Biomarkers (Coho1is 4-11) 
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o 2 hour (± 1 hour) postdose Kinetic Biomarkers (Coho1is 5, 6, 7, 9, 10 and 11) 
• 
Obtain urine samples for: 
o Predose Kinetic Biomarkers (Coho1is 4-11) 
o 2 hour (± 1 hour) postdose Kinetic Biomarkers (Coho1is 5, 6, 7, 9,10 and 11) 
• 
Verify that study drng was taken co1Tectly eve1y day 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events since the previous visit 
6.4.3. 
Day 14 (Week 2) Visit {±1 day) (Cohorts 1-9) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. The following assessments will be perfo1med and documented at the visit: 
• 
Obtain blood samples: 
o Kinetic Biomarkers 
• 
Obtain urine samples: 
o Kinetic Biomarkers 
• 
Dispense deuterated water 
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
Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.4.
Day 17 (± 1 day) and Day 21 (Week 3) Visits (± 1 day) (Cohorts 1-9)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at each visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples:
o
Kinetic Biomarkers

Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.5.
Day 28 (Week 4) Visit (± 3 days) (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination (Cohorts 1-11)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score 
(Cohorts 10 and 11)

Record vital signs 
 (Cohorts 1-11)
CCI


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 99
11 September 2019

Obtain blood samples for:
o
Chemistry and hematology (Cohorts 1-11)
o
Coagulation panel (Cohorts 1-11)
o
Phospho-p38 (if reagent is available) (Cohorts 1-9)
o
Lipidomics and NMR Lipoprofile (Cohorts 1-11)
o
ApoA1, ApoB (Cohorts 1-11)
o
Adiponectin (Cohorts 1-9)
o
Beta-hydroxybutyrate (Cohorts 1-9)
o
Total Bile Acids (Cohorts 1-11)
o
FGF19 (Cohorts 1-9)
o
C4 (Cohorts 1-9)
o
Kinetic Biomarkers (Cohorts 1-9)

Collect urine samples for: (Cohorts 1-9)
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers

Verify that study drug was taken correctly every day (Cohorts 1-11)

Dispense study drug (Cohorts 1-9); dispense study drug (GS-0976) (Cohorts 10-11)

Record all concomitant medications that the subject has taken since the previous visit 
(Cohorts 1-11)

Record any serious adverse events and all adverse events since the previous visit 
(Cohorts 1-11)
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
CCI
CCI
CCI
CCI
I 
I 
I 
I 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
6.4.6. 
Day 35 (Week 5) Visit {:I: 3 days) (Cohorts 1-3) 
Final 
Amendment 12 
Coho1is 1-3 subjects will collect a saliva sample at home and provide it to the site at the next 
visit. Refer to the laborato1y manual for additional infonnation. 
6.4.7. 
Day 56 (Week 8) Visit {:I: 3 days) (Cohorts 1-11) 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. Subjects in Cohorts 5, 6, 7, 9, 10 and 11 should also be instructed to hold their dose of 
study drng on the morning of the visit until all fasting visit procedures have been completed and 
take their study drng(s) as instructed during the visit. The following assessments will be 
perfo1med and documented at the visit: 
• 
Symptom driven physical examination 
• 
Assess presence and severity of ascites and hepatic encephalopathy for CPT score 
(Coho1is 10 and 11) 
• 
Record vital signs 
• 
Obtain blood samples for: 
o Chemistry and hematology 
o Coagulation panel 
o Lipidomics and NMR Lipoprofile 
o Total Bile Acids 
o ApoAl, ApoB 
o FGF19 (Coho1is 1-9) 
o C4 (Coho1is 1-9) 
I 
o Predose Kinetic Biomarkers (Coho1is 4-11) 
I 
• 
2 hour (± 1 hour) postdose Kinetic Biomarkers (for Coho1is 5, 6, 7, 9, 10 and 11) 
CONFIDENTIAL 
Page 100 
11 September 2019 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 101
11 September 2019

Obtain urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Predose Kinetic Biomarkers (for Cohorts 4-11)
o
2 hour (± 1 hour) postdose Kinetic Biomarkers (for Cohorts 5, 6, 7, 9,10 and 11)

Verify that study drug was taken correctly every day

Dispense study drug (Cohorts 1-9); dispense study drugs (GS-0976 and fenofibrate) 
(Cohorts 10-11)

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
6.4.8.
Day 70 (Week 10) Visit (± 1 Day) (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. The following assessments will be performed and documented at the visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples:
o
Kinetic Biomarkers

Dispense deuterated water

Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.9.
Day 73 and Day 77 (Week 11) Visits (± 1 day) (Cohorts 1-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 102
11 September 2019
The following assessments will be performed and documented at each visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples
o
Kinetic Biomarkers

Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.10.
Day 84 (Week 12) Visit (±3 days) / End of Treatment (Cohorts 1-9)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs, 

Conduct standard 12-Lead ECG

QoL questionnaires (CLDQ, SF-36, & WPAI)

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
Phospho-p38 (if reagent is available)
o
Lipidomics and NMR Lipoprofile
CCI
CCI
CCII 
I 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 103
11 September 2019
o
Total Bile Acids
o
ApoA1, ApoB
o
FGF19
o
C4
o
Adiponectin
o
Beta-hydroxybutyrate
o
Hemoglobin A1c
o
Kinetic Biomarkers

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers

Verify that study drug was taken correctly every day

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.11.
Day 84 (Week 12) Visit (±3 days) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
CCI
CCI
CCI
CCI
CCII 
I ·-
·--
I ·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 104
11 September 2019
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Record vital signs, 

Conduct standard 12-Lead ECG

QoL questionnaires (CLDQ, SF-36, & WPAI)
 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
Lipidomics and NMR Lipoprofile
o
Total Bile Acids
o
ApoA1, ApoB
o
hsCRP
o
Adiponectin
o
Beta-hydroxybutyrate
o
Hemoglobin A1c
o
o
Kinetic Biomarkers
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
I ·--
I 
I ·-
I ·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 105
11 September 2019

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers

Dispense study drug (GS-0976)

Verify that study drug was taken correctly every day

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.12.
Day 91 (Week 13) Visit (± 3 days) (Cohorts 1-3)
Cohorts 1-3 subjects will collect a saliva sample at home and provide it to the site at the next 
visit. Refer to the laboratory manual for additional information.
6.4.13.
Day 112 (Week 16) Follow up Visit (± 5 days) (Cohorts 1-9)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs, 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
CCI


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 106
11 September 2019
6.4.14.
Day 112 (Week 16) Visit (± 3 days) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Record vital signs, 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
Lipidomics and NMR Lipoprofile
o
Total Bile Acids
o
ApoA1, ApoB
 

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only

Dispense study drug (GS-0976)

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
6.4.15.
Day 126 Visit (Week 18) (± 3 days) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
CCI
CCI
CCI
I ·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 107
11 September 2019
The following assessments will be performed and documented at each visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples:
o
Kinetic Biomarkers

Dispense study drug (GS-0976)

Dispense study drug fenofibrate

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
6.4.16.
Day 154 (Week 22) Visit (± 1 day) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. The following assessments will be performed and documented at the visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples:
o
Kinetic Biomarkers

Dispense deuterated water

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only

Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
CCI
CCI
·-
·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 108
11 September 2019
6.4.17.
Day 157 (± 1 day) and Day 161 Visits (± 1 day) (Week 23) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at each visit:

Obtain blood samples:
o
Kinetic Biomarkers

Obtain urine samples
o
Kinetic Biomarkers

Record any serious adverse events and all adverse events since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.18.
Day 168 (Week 24) Visit (±3 days) / End of Treatment (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Record vital signs, 

Conduct standard 12-Lead ECG

QoL questionnaires (CLDQ, SF-36, & WPAI)
 
CCI
CCI
CCI
CCI
I 
I ·--


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 109
11 September 2019

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
Lipidomics and NMR Lipoprofile
o
Total Bile Acids
o
ApoA1, ApoB
o
hsCRP
o
Adiponectin
o
Beta-hydroxybutyrate
o
Hemoglobin A1c
o
o
Kinetic Biomarker

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers

Verify that study drug was taken correctly every day

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
CCI
CCI
CCI
CCI
CCI
CCI
CCII 
I 
I ·-
I ·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 110
11 September 2019
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
6.4.19.
Day 196 (Week 28) Follow up Visit (± 5 days) (Cohorts 10-11)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at the visit:

Symptom driven physical examination

Record vital signs,

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
6.4.20.
Early Termination (ET) Visit (Cohorts 10 - 11)
For subjects who have completed an ET visit, the follow-up visit will be scheduled after last dose 
of study drugs. 
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
The following procedures are to be completed at an Early Termination visit:

Symptom driven physical examination

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Record vital signs, 

Conduct standard 12-Lead ECG

QoL questionnaires (CLDQ, SF-36, & WPAI)
CCI
CCI


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 111
11 September 2019
 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
NMR Lipoprofile
o
Total Bile Acids 
o
ApoA1, ApoB
o
hsCRP 
o
Adiponectin 
o
Beta-hydroxybutyrate
o
Hemoglobin A1c
o
Kinetic Biomarker

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only
o
Kinetic Biomarkers 

Verify that study drug was taken correctly every day

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
Refer to the laboratory manual for additional information on the Kinetic Biomarkers 
assessments.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
I ·--
I ·-
·--
I ·-


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 112
11 September 2019
6.4.21.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator. At a 
minimum, the following will be performed and documented.

Record all concomitant mediations that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
6.5.
STUDY PROCEDURES FOR COHORTS 12-13
6.5.1.
Screening Assessments for Cohorts 12-13
6.5.1.1.
Screening Visit 
Subjects will be screened within 4 weeks prior to Day -14 to determine eligibility for 
participation in the study. The screening period also may be extended under special 
circumstances with the explicit approval of Gilead Sciences.
Screening information for subjects screened under prior protocol amendments may be used to 
determine eligibility and fulfill screening visit assessments for this amendment.
Screening labs may be repeated once within the screening period, prior to Day -14. This will be 
done at the discretion of the investigator.
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
screening visit to ensure an approximate 8-hour fast prior to the fasting blood sample collection 
the next morning.
The following assessments will be performed and documented at the Screening Visit:

Obtain written informed consent before initiation of any screening procedures

Review and record whether the subject has met eligibility criteria

Assess presence and severity of ascites and hepatic encephalopathy for CPT score 

Obtain medical history including, but not limited to information related to the following: 
Type 2 Diabetes Mellitus, NAFLD, and NASH

Review historical liver biopsy obtained within 6 months of Screening (date of initial 
informed consent) for subjects without compensated cirrhosis (F4) or within the last 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
12 months for subjects with compensated cinhosis (F4) to assess subject eligibility 
(if applicable) 
• 
Review historical MRE and/or historical FibroScan® obtained within 6 months of screening 
to assess subject eligibility (if applicable) 
• 
Complete physical examination including height, vital signs 
• 
Conduct standard 12-lead ECG 
• 
Obtain blood samples for: 
o 
Chemistry and hematology 
o 
Coagulation panel 
o 
Hemoglobin Ale 
o 
HIV-1, HBV & HCV Serology 
o 
Sernm pregnancy test ( only for female subjects of childbearing potential) 
I 
• 
Obtain urine sample for drng screen 
• 
Record all concomitant medications that the subject has taken within 30 days prior to 
screemng 
• 
Record any serious adverse events and all adverse events related to protocol mandated 
procedures occmTing after signing of the consent fonn 
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
tr·ial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or tr·ial-wide at any time 
6.5.2. 
6.5.2.1. 
Pretreatment Assessments for Cohorts 12-13 
Day-14 Visit 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 8-hour fast prior to the fasted blood sample collection the next 
mommg. 
CONFIDENTIAL 
Page 113 
11 September 2019 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 114
11 September 2019
The following assessments will be performed and documented at the Day -14 Visit prior to 
dosing:

Review and record whether the subject has met eligibility criteria 

Update medical history if a change has occurred during screening 

Symptom driven physical examination

Record vital signs 

Obtain blood samples:
o
Chemistry and hematology 
o
Coagulation panel 
o
ApoA1, ApoB 
o
NMR Lipoprofile 
 

Obtain urine samples:
o
Urine pregnancy test for females of childbearing potential only 

Dispense Vascepa® (Cohort 12) or fenofibrate (Cohort 13) and provide subject with dosing 
instruction on appropriate dosing and administration; subject will take the Day -14 dose of 
study drug on-site 

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the previous visit

Record all concomitant medications that the subject has taken since the previous visit
6.5.3.
Treatment Assessments for Cohorts 12-13
6.5.3.1.
Day 1 Visit 
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 8-hour fast prior to the fasted blood sample collection the next 
morning.
The following assessments will be performed and documented at the Day 1 Visit prior to dosing:

Symptom driven physical examination
CCI
CCI
I 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
CONFIDENTIAL
Page 115
11 September 2019

Record vital signs 

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
ApoA1, ApoB
o
NMR Lipoprofile
o
Hemoglobin A1c
 
o
Genomic sample 

Obtain urine samples for:
o
Urine pregnancy test for females of childbearing potential only

Verify that study drug was taken correctly every day (Vascepa® [Cohort 12] or fenofibrate 
[Cohort 13] only)

Dispense GS-0976 and GS-9674 and provide subject with dosing instruction on appropriate 
dosing and administration; subject will take the Day 1 dose of study drugs on-site

Dispense Vascepa® (Cohort 12) 

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events related to protocol mandated 
procedures since the previous visit
6.5.3.2.
Day 28 (Week 4) Visit (± 3 days)
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 8-hour fast prior to the fasted blood sample collection the next 
morning. All subjects should also be instructed to hold their dose of study drug on the morning 
of the visit until all fasting visit procedures have been completed and take their study drug(s) as 
instructed during the visit.
The following assessments will be performed and documented at the Day 28 (Week 4) Visit:

Symptom driven physical examination 

Record vital signs 
 
CCI
CCI
CCI
I 


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
o Chemistry and hematology 
o Coagulation panel 
o NMR Lipoprofile 
o ApoAl, ApoB 
I 
I 
• 
Collect urine samples for: 
o Urine pregnancy test for females of childbearing potential only 
• 
Verify that study chug was taken coITectly eve1y day 
• 
Dispense GS-967 4 and GS-097 6 
Final 
Amendment 12 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events since the previous visit 
6.5.3.3. 
Day 42 (Week 6) Visit(± 3 days) 
Subjects should be instructed to fast (no food or ch·ink, except water) on the evening prior to the 
visit to ensure an approximate 8-hour fast prior to the fasted blood sample collection the next 
mommg. 
The following assessments will be perfonned and documented at the Day 42 (Week 6) Visit: 
• 
Symptom ch·iven physical examination 
• 
Conduct standard 12-Lead ECG 
• 
Record vital signs 
• 
Obtain blood samples for: 
o Chemistry and hematology 
o Coagulation panel 
o NMR Lipoprofile 
o ApoAl, ApoB 
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
Obtain Urine Samples for: 
o
Urine pregnancy test for females of childbearing potential only 

Provide females of childbearing potential with urine pregnancy test to be completed on the 
day of the Phone Follow-Up Visit

Verify that study drug was taken correctly every day 

Record all concomitant medications that the subject has taken since the previous visit 

Record any serious adverse events and all adverse events since the previous visit 
6.5.3.4.
Early Termination (ET) Visit
Subjects should be instructed to fast (no food or drink, except water) on the evening prior to the 
visit to ensure an approximate 8-hour fast prior to the fasted blood sample collection the next 
morning. 
The following assessments will be performed and documented the ET Visit:

Symptom driven physical examination

Record vital signs, 

Conduct standard 12-Lead ECG

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
o
NMR Lipoprofile
o
ApoA1, ApoB
 

Collect urine samples for:
o
Urine pregnancy test for females of childbearing potential only
CCI
CCI
CCI
CCI
CCI


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
Provide females of childbearing potential with urine pregnancy test to be completed on the 
day of the ET Phone Follow-Up Visit

Verify that study drug was taken correctly every day

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit
6.5.3.5.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator. 
At a minimum, the following assessments will be performed and documented:

Record all concomitant mediations that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Obtain blood samples for:
o
Chemistry and hematology
o
Coagulation panel
If the Unscheduled Visit is performed for the sole purpose of distribution of study drug, the 
assessments noted above do not need to be performed.  
6.5.4.
Posttreatment Assessments for Cohorts 12-13
6.5.4.1.
Day 56 (Week 8) Phone Follow-Up Visit (± 5 days) 
A Phone Follow-Up Visit will be conducted 2 weeks after the Day 42 (Week 6) Visit.
The following assessments will be performed and documented at the Phone Follow-Up Visit:

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit

Record results from home urine pregnancy test for females of childbearing potential only. 
Note: home urine pregnancy test should be provided to the subject at the Day 42 (Week 6) 
Visit
6.5.4.2.
Early Termination (ET) Phone Follow-Up Visit 
For subjects who prematurely discontinue the study, an ET Phone Follow-Up Visit will be 
conducted 2 weeks after the date of the last dose of study drug. 


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The following assessments will be performed and documented at the ET Phone Follow-Up Visit:

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events since the previous visit

Record results from home urine pregnancy test for females of childbearing potential only. 
Note: home urine pregnancy test should be provided to the subject at the Early Termination 
Visit 
6.6.
Assessments for Premature Discontinuation from Study
Subjects discontinuing prematurely from the study should have an ET Visit performed upon 
discontinuing. They should also have a Follow-Up Visit performed 4 weeks after the date of the 
last dose of study drugs (Cohorts 1-11); or a Phone Follow-Up Visit performed 2 weeks after the 
date of the last dose of study drugs (Cohorts 12-13). When medically feasible, the medical 
monitor must be consulted prior to subject discontinuation. The subject will be considered off-
study after completion of these visits.
If these visits are not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study.
6.7.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Subject who develops a serious adverse event consisting of a serious hypersensitivity 
reaction

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest (see Section 7.5).

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 3

Sponsor discretion

Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB/IEC


SEL, GS-0976, GS-9674 
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6.8. 
6.8.1. 
Chemistry : 
Description of Assessments 
Clinical Laboratory Analytes 
Final 
Amendment 12 
albumin,_ 
bicarbonate, blood urea niti·ogen (BUN),) creatine kinase (CPK) 
Co 01is 10 an 11 , Creatinine Clearance , calcium, chloride, creatinine, glucose, lactate 
dehydrogenase (LDH), 
h 
h 
t 
sodium, total and 
• 
• • 
• 
total protein, uric acid, 
C-peptide testing, lipid panel, 
insulin, pro-insulin, free fatty acids, lactate, and leptin. 
Hematology: 
Hematocrit (Hct), hemoglobin (Hb ), platelet count, red blood cell count (RBC), white blood cell 
count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neuh'ophils, eosinophils, basophils, reticulocyte count and mean co1puscular volume (MCV). 
Coagulation Panel: 
INR, prothrombin time (PT), paiiial thromboplastin time (PTT). 
Pregnancy Tests: 
Sernm P-hCG or urine P-hCG (if positive, requires immediate confinnation with sernm P-hCG). 
Additional Tests: 
HIV-1, HBV & HCV (Reflex to HCV RNA) serology, _ 
urine diug screen 
(for amphetamines, cocaine, methadone, opiates), HbAlc, lipidomics, genomic sample 
collection, NMR lipoprofile, ApoAl ~tyrate, sennn frnctosamine, 
adiponectin, hsCRP, total bile acids,_ .  
Biomai·ker Tests: 
6.8.2. 
Electrocardiogram 
Standai·d 12-lead electi·ocai·diogram (ECG) assessments will be perfonned. The Investigator will 
review the ECGs for any clinically significant abno1malities to ensure subject safety. Abno1mal 
ECG findings that ai·e considered clinically significant by the Investigator and meet the 
definition of an AE should be repo1ied and recorded in the AE eCRF page. 
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6.8.5. 
Medical History 
Final 
Amendment 12 
Medical histo1y, including details regarding illnesses and allergies, date (s) of onset, and whether 
condition (s) is cmTently ongoing, and medication histo1y will be collected on all subjects dming 
screemng. 
6.8.6. 
Physical Examination 
A complete physical examination must include somce documentation of general appearance, and 
the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; 
chest (excluding breasts); respirato1y ; cardiovascular 1 
h nodes· abdomen; skin, hair, nails; 
musculoskeletal; nemological. Height, vital signs, 
will also be collected. 
6.8.7. 
Vital Signs 
Assessment of vital signs will include measmement of resting blood pressme, pulse, respirato1y 
rate and temperatme. 
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Blood pressure will be measured using the following standardized process: 
Final 
Amendment 12 
• 
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 brachia! aiie1y; 
• 
Measure and record the blood pressure to the neai·est 2 mrnHg mark on the manometer or to 
the nearest whole number on an automatic device. 
6.8.8. 
Pregnancy Testing 
For Coho1is 1-11, urine pregnancy testing will occur at Day 1 (prior to dosing), 
eve1y 4 weeks during the dosing period, and at 30 days following the last dose of study dmg. For 
Coho1is 12-13, urine pregnancy testing will occur at Day-14, Day 1 (prior to dosing), Week 4, 
Week 6, and at two weeks following the last dose of study diug. In the event of a positive urine 
pregnancy result, subjects will be instmcted to stop study diug immediately (if applicable) and 
return to the clinic as soon as possible for a sennn pregnancy test. 
6.8.9. 
Quality of Life (QoL) Measures 
The Chronic Liver Disease Questionnaire (CLDQ), SF-36 Health Smvey, and Work Productivity 
and Activity Impainnent Questionnaire (WPAI) will be collected at Day 1 and Week 12 visits 
(Coho1is 1-11) and Week 24 (Coho1is 10-11). It is recommended to adininister these 
questionnaires prior to the clinical and laborato1y assessments. The subject should read the 
questionnaires by himself/herself and record the answers by himself/herself. 
6.8.10. 
Child-Pugh-Turcotte Score 
For Cohorts 7-8 and 12-13, the CPT score will be calculated from the central laborato1y values 
attained at the Screening Visit. Assessment of ascites and hepatic encephalopathy will be 
dete1mined by the site at the Screening Visit, as in Appendix 4 and will be entered into the 
eCRF. Records of concomitant medications for ascites and hepatic encephalopathy will be 
collected in the eCRF. 
For Cohorts 10 and 11, the sites will calculate CPT scores per Appendix 4 from the central 
laborato1y values and assessments of ascites and hepatic encephalopathy attained at visits 
outlined in Appendix Table 2. Records of concomitant medications for ascites and hepatic 
encephalopathy will be collected in the eCRF. 
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6.8.11. 
Creatinine Clearance 
Final 
Amendment 12 
Creatinine clearance will be calculated by the Central Laborato1y, using the Cockcroft-Gault 
equation {Cockcroft 1976}. 
Male: 
CLcr (mL/min) = [140 - age (years)] x BW(kg) 
72 X Ser 
Female: CLcr (mL/min) = [140 - age (years)] x BW(kg) x 0.85 
72 X Ser 
Ser = sennn creatinine (mg/dL) 
Actual body weight will be used for the CLer 
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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 the following:

Pre- or post-treatment complications that occur as a result of protocol mandated procedure, 
overdose, or drug abuse/misuse reports.

Any pre-existing condition that increases in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.

Complications of pregnancy and non-elective termination of pregnancy (See Section 7.6.2.1)
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 (e.g., 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.

Uncomplicated pregnancy.

An induced elective abortion to terminate a pregnancy without medical reason


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7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules.
Examples of medically important events include:
o
intensive treatment in an emergency room or at home for allergic bronchospasm
o
blood dyscrasias or convulsions that do not result in hospitalization
o
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.
Clarification on Serious Adverse Events

Death is an outcome of an AE, and not an adverse event in itself.

An SAE may occur even if the subject was not on investigational medicinal product at the 
occurrence of the event. Dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE.

“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity.


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
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE.

“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department.

The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.
A distinction should be drawn between seriousness and severity of AEs. For example, an AE that 
is potentially life-threatening but not an immediate risk of death may be graded with the severity 
of Grade 4 and not be a SAE. Severity is a category utilized for rating the intensity of an event; 
and both AEs and SAEs can be assessed as Grade 4. An event is defined as “serious” when it 
meets one of the predefined outcomes described above.
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 (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to investigational medicinal product (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 (e.g., 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 (e.g., anemia), 
not the laboratory result (i.e., decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub investigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment describing the event as either unrelated (No) or related (Yes) 
consistent with the following definitions:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the IMP.


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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 of an AE or SAE to study procedures (e.g., invasive procedures such as 
venipuncture or biopsy) should be assessed using clinical judgement describing the event as 
either unrelated (No) or related (Yes) consistent with the following definitions:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
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 Reporting Requirements and Instructions for Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences 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 occurs after the subject first consents to 
paiticipate in the study (i.e., signing the infonned consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be repo1ted to the 
eCRF database and Gilead Phannacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures perfonned after infonned 
consent is signed. 
Any SAEs and deaths that occur after the post t:I'eatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be repo1ted. Investigators ai·e not 
obligated to actively seek SAEs after the protocol defined follow-up period however, if the 
investigator leains of any SAEs that occur after study paiticipation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and repo1t the event to 
Gilead PVE. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Elect:I'onic Serious Adverse Event ( eSAE) Reporting Process 
• 
Site personnel record all SAE data. in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead DSPH 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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
repo1t ing f01m and submit within 24 hours to: 
Gilead Sciences PVE: 
Fax: 
Email: 
IPIPD 
IPIPU 
As soon as it is possible to do so, any SAE repo1ted via paper must be tr·anscribed into the eCRF 
Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, no 
fuither action is necessaiy . 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug 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 regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management
7.5.1.
Observation for Drug Induced Liver Injury (DILI): (Cohorts 1-9)
At baseline, some subjects may have liver biochemistry levels above the upper limit of normal 
(ULN).
For subjects with 
, close observation for DILI 
(as described below) should be considered in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

INR > 1.5 x ULN (except for subjects on anticoagulant therapy)

Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%)
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For subjects with 
between 1 and 5 x ULN at study start, close observation for DILi 
(as described below) should be considered in subjects with any of the following criteria (all labs 
confinned by repeat testing): 
• 
INR > 1.5 x ULN (except for subjects on anticoagulant therapy) 
• 
Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfo1i, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%) 
Close observation includes: 
• 
Repeating liver biochemistries 
, INR) within 48 hours 
• 
Obtaining a more detailed histo1y of symptoms and prior or concunent disease 
• 
Obtaining a histo1y of concomitant diug use (including nonprescription medications and 
herbal and dieta1y supplement preparations), alcohol use, recreational di11g use, and special 
diets 
• 
Obtaining a histo1y of exposure 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 primaiy investigator) 
• 
Continue to monitor liver biochemistries twice weekly. Frequency can decrease to once a 
week or less if abno1malities stabilize or study diug has been discontinued and subject is 
asymptomatic 
During a period of close observation, study di11g can be continued, if desired, at the discretion of 
the Gilead Medical Monitor and the principal investigator during the DILi evaluation. 
However, for all subjects, study di11g should be withheld if any of the following criteria are met: 
I 
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AND

No other cause for the combination of laboratory abnormalities is immediately apparent 
(e.g., prolonged INR with warfarin use) important potential causes or contributors to 
abnormal 
 values include, but are not limited to:
o
Obstructive gall bladder or bile duct disease
o
Viral or alcoholic hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella)
o
Autoimmune hepatitis
o
Concomitant administration of other hepatotoxins, including excessive doses of 
acetaminophen, drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir, 
irinotecan), or herbal or dietary supplements
o
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure
o
Wilson disease
o
Progression of malignancy involving the liver (note that metastatic disease to the liver, by 
itself, should not be used as an explanation for significant 
)
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Medical Monitor. Whether or not considered treatment-related, all subjects experiencing AEs 
must be monitored periodically until symptoms subside, any abnormal laboratory values have 
resolved or returned to baseline levels or they are considered irreversible, or until there is a 
satisfactory explanation for the changes observed.

Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laboratory AEs should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results.

For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality.

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.5.2.
Observation for Drug Induced Liver Injury (DILI) (Cohorts 10-13)
At baseline, some subjects may have liver biochemistry levels above the ULN. Baseline values 
for liver tests 
 and total 
 will be determined by averaging the values 
obtained between and including Screening and Day 1. Please refer to the Covance Laboratory 
Manual or individual subject Covance laboratory report for gender and age specific reference 
ranges.
CCI
CCI
CCI
CCI
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SEL, GS-0976, GS-9674 
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On-ti·eatment elevations of 
should be confinned with repeat testing within 
48-72 hours of results. If confinned, and if no other cause of the laborato1y abno1malities is 
immediately apparent, notify the Medical Monitor. 
Subjects with 
elevations as per Figure 7-1 must be placed into close observation 
(as described below). 
I 
• 
Obtaining a more detailed histo1y of symptoms and prior or concunent disease 
• 
Obtaining a histo1y of concomitant drng use (including nonprescription medications and 
herbal and dieta1y supplement preparations), alcohol use, recreational drng use, and special 
diets 
• 
Obtaining a histo1y of exposure to environmental chemical agents 
• 
Ruling out other causes of liver disease as needed ( obtain viral hepatitis panel, imaging for 
evaluation of biliaiy ti-act disease, etc. if required in the opinion of the Investigator) 
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• 
Continue to monitor liver biochemisti·ies at least twice weekly. Frequency can decrease to 
once a week or less if abno1malities stabilize or study diugs have been discontinued and the 
subject is asymptomatic 
During a period of close observation for DILI, study di11gs can be continued, if desired, at the 
discretion of both the Medical Monitor and Investigator. 
If study diugs are withheld, they may be reinti·oduced 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 ti·eatment-related, all subjects experiencing AEs 
must be monitored periodically until symptoms subside, any abno1mal 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 
laboratory abnormalities should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results. For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
Any questions regarding toxicity management should be directed to the Medical Monitor.
7.5.3.
CPT Score (Cohorts 10-11)
If a subject in Cohorts 10 or 11 has an increase in their CPT score to ≥ 7, this should be 
confirmed with repeat testing within 72 hours of receipt of results. If confirmed, the 
Medical Monitor should be notified and the subject should be placed in close observation, unless 
an alternate etiology (e.g., therapeutic anticoagulation) is identified. If the CPT score remains ≥ 7 
for 2 consecutive weeks, and an alternate etiology has not been identified, study drugs must be 
discontinued.
7.5.4.
Hypertriglyceridemia
7.5.4.1.
Cohorts 10-11:
All subjects in Cohorts 10 and 11 will have baseline dyslipidemia. Figure 7-3 describes the 
recommended monitoring and intervention strategy for subjects that meet the criteria for 
treatment-emergent (on GS-0976 + fenofibrate) hypertriglyceridemia of Grade 3 or 4 
(≥ 500 mg/dL).


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Figure 7-3.
Algorithm for Monitoring and Treatment of Hypertriglyceridemia for 
Cohorts 10-11
Triglycerides Grade 3 or 4 
(:?:500 mg/dl) 
Within 72 Hours of receipt of results 
V' 
Repeat Fasting testing 
-
" 
.. 
-
-· 
-
Results :?:500 mg/dl 
'~ 
' 
Consider starting Vascepa 2000 mg , 
twice daily or equivalent or 
' 
increasing to fenofibrate 145 mg if 
the subject is taking fenofibrate 48 J 
mg 
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•. 
.. 
11, 
Repeat fasting 
triglycerides within 14 to 
28 days 
,< 
' 
~. 
•• , .. ..... 
,. .. 
"' ... . .. 
I, 
If repeat triglycerides >=500 mg/ 
dl, consult Medical Monitor 
,. _.._ 
.,:.,.,,:,,,..,., 
--
-·· 
Results< 500 mg/dl 
No treatment modifications 


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7.5.4.2.
Cohorts 12-13:
All subjects in Cohorts 12 and 13 will have baseline dyslipidemia. Figure 7-4 describes the 
recommended monitoring and intervention strategy for subjects that meet the criteria for 
treatment-emergent (on GS-0976 + GS-9674 + Vascepa® or fenofibrate) hypertriglyceridemia of 
Grade 3 or 4 (≥ 500 mg/dL).
Figure 7-4.
Algorithm for Monitoring and Treatment of Hypertriglyceridemia for 
Cohorts 12-13
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Results~ 500 mg/dl 
Please contact medical 
monitor 
Triglycerides Grade 3 or 4 
(~ 500 mg/dl) 
I 
Wit hin 72 Hours of receipt of results 
+ 
Repeat Fasting Testing 
Results< 500 mg/dl 
No t reatment modifications 


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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.
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 medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to and the eCRF completion guidelines for full instructions on the mechanism of 
pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email: 
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
PPD
PPD


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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
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
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8-
STATISTICAL CONSIDERATIONS 
Details will be provided in the Statistical Analysis Plan (SAP). 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objective of this study is as follows: 
Final 
Amendment 12 
• 
To evaluate the safety and tolerability of study dmg(s) in subjects with NAFLD/NASH. 
I 
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8.1.2. 
Primary Endpoint 
The prima1y endpoint is the safety of study dmg(s) in subjects with NAFLD/ NASH. 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
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The prirmuy analysis set for efficacy analyses will be the Full Analysis Set (FAS) which includes 
all subjects who were emolled into the study and received at least one dose of study drng. 
Subjects who receive study d.iugs other than that to which they were assigned will be analyzed 
according to the treatment group to which they were assigned or randomized. 
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8.2.1.2. 
Safety 
Final 
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The prirmuy analysis set for safety analyses will include all subjects who received at least one 
dose of study diug. Treatment-emergent data will be analyzed and defined as data collected from 
the first dose of study diug through the date of last dose of study drng plus 30 days. Subjects who 
received study drng other than that to which they were assigned will be analyzed according to the 
study diug received. 
For Cohorts 10-13, a pretreatment safety analysis set will be defined and used to analyze the 
safety data during the pretreatment phase. This analysis set will include all subjects who received 
at least one dose of Vascepa® or fenofibrate. Subjects who received study diug other than that to 
which they were assigned will be analyzed according to the study diug received. 
-
8.2.1.4. 
Biomarkers 
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessaiy baseline and on-study measurements to provide interpretable results for the 
specific pai·ameters of interest. 
8.2.2. 
Interim Analysis 
Administrative interim analyses may be perfonned to suppo1i safety review, for conferences and 
publications, or for regulato1y interaction. 
For Cohorts 1 to 9, adininistrative interim analyses will include data from the completed cohorts 
as well as the other ongoing cohorts. A fonnal interim analysis will be perfo1med after the first 9 
coho1is complete or eai·ly discontinue the study. 
For Coho1is 10 and 11, an administrative interim analysis will be perfonned after all subjects 
complete 12 weeks of treatment or eai·ly discontinue treatment. A final analysis for these two 
coho1is will be perfonned after both coho1is complete or eai·ly discontinue the study. 
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For Cohorts 12 and 13, an administrative interim analysis may be perfonned for regulato1y 
interaction or for conferences. A final analysis for these two coho1is will be perfonned after both 
coho1is complete or early discontinue the study. 
8.3. 
Data Handling Conventions 
Missing data can have an impact on the inte1pretation of the trial data. In general, values for 
inissing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summaiy statistics. For example, if a subject received study medication, the subject will be 
included in a summa1y of adverse events according to the treatment received; othe1wise, if the 
subject is not dosed then they will be excluded from the summa1y . If safety laborato1y results for 
a subject ai·e inissing for any reason at a time point, the subject will be excluded from the 
calculation of summaiy statistics for that time point. If the subject is inissing a pre-dose value, 
then the subject will be excluded from the calculation of summaiy statistics for the pre-dose 
value and the change from pre-dose values. 
Values for inissing safety laborato1y data and vital signs will not be imputed; however, a inissing 
baseline result will be replaced with a screening result, if available. If no pretreatment laborato1y 
value is available, the baseline value will be assumed to be nonnal (i.e., no grade [Grade O]) for 
the summaiy of graded laborato1y abnonnalities. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall. Demographic smnmai·ies will include sex, 
race/ethnicity, and age. 
Baseline characteristics smnmaiy will include_
, height, body mass index, presence or 
absence of diabetes, and other disease characteristic variables. 
8.5. 
Efficacy Analysis 
The biological and histological activity of study drng(s) will be evaluated using radiologic 
endpoints and biomarker vai·iables. Because efficacy endpoints will be evaluated for explorato1y 
pmpose, fo1mal statistical compai·isons will not be made for these endpoints. Descriptive 
statistics (n, mean, SD, median, Ql, Q3, minimum, and maximum) will be provided by treatment 
group. -
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8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration (up to and 
including 30 days after the last dose of study drug) will be summarized by treatment group 
according to the study drug received. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. Adverse event severity will be graded using the CTCAE 
Version 4.03.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no).
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values.
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 4.03.
The incidence of treatment-emergent laboratory abnormalities will be summarized by treatment 
group. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) will be 
considered treatment emergent.
8.6.4.
Other Safety Evaluations
Vital sign measurements will be summarized by treatment group and listed by subject. 12-lead 
ECG data will be listed by subject.


SEL, GS-0976, GS-9674 
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Gilead Sciences, Inc. 
8.8. 
8.8.1. 
Pharmacodynamic 
Kinetic Biomarker Analysis 
Analysis 
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Amendment 12 
The kinetic biomarker will be analyzed to evaluate the PD effects of study dmg(s). The 
assessment will involve the analysis of DNL values; specifically, the change (absolute and 
relative) from baseline between the post-dose and pre-dose deuterated water loading periods. 
-
8.9. 
Sample Size 
Due to the explorato1y nature of this study, no fonnal power calculations were used to detennine 
sample size in Coho1is 1 to 9. The number of subjects was chosen based on clinical experience 
with other similar proof of concept studies. 
In Coho1is 10 and 11, we assumed that among subjects with baseline hype1iriglyceridemia 
::::150 mg/dL (60% with semm triglycerides :::: 150 mg/dL and < 250 mg/dL and 40% with serum 
triglycerides:::: 250 mg/dL and < 500 mg/dL) thus grade 3-4 hypertriglyceridemia (>500 mg/dL) 
would be observed in 28% following treatment with GS-0976. Assuming that the 
co-administration of fenofibrate and GS-097 6 will reduce the incidence of Grade 3-4 
hype1i riglyceridemia to <5%, a sample size of 15 in each of Coho1is 10 and 11 will provide 82% 
power to detect the reduction based on a one-sided exact test at a significance level of 0.05. 
In Coho1is 12 and 13, we assumed that among subjects with baseline hype1iriglyceridemia 
(semm triglycerides:::: 150 mg/dL and < 500 mg/dL), GS-0976 20 mg + GS-9764 30 mg once 
daily treatment will lead to a mean increase in senun triglycerides of 60 mg/dL from baseline 
after 6 weeks of treatment. Assuming that the co-administration ofVascepa® or fenofibrate with 
GS-0976 20 mg + GS-9764 30 mg will mitigate this increase in semm triglycerides and that the 
standard deviation for semm triglycerides after 6 weeks of treatment is 120 mg/dL, a sample size 
of 30 subjects in each coho1i will provide 85% power to detect any increase based on a one-sided 
t-test at a significance level of 0.05. 
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8.10.
Data Monitoring Committee
An internal Gilead data monitoring committee (DMC) will review the progress of the study and 
perform interim reviews of safety data for Cohorts 1 through 9, due to the sequential enrollment 
design. The DMC will review cumulative data from these cohorts. The DMC will be notified of 
any case of suspected DILI by the medical monitor. The DMC will provide recommendations 
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’s 
specific activities will be defined by a mutually agreed charter, which will define the DMC’s 
membership, conduct, and meeting schedule.
There will be no formal DMC review for Cohorts 10-13. However, internal safety monitoring 
will be conducted continuously on an ongoing basis.


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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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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 (GCP), 
as outlined in 21 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 sub investigators 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 sub investigator’s) participation in the study. The investigator and sub 
investigator 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) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.


SEL, GS-0976, GS-9674 
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9.1.3. 
Informed Consent 
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The investigator is responsible for obtaining written infonned consent from each individual 
paiiicipating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazai·ds of the study and before unde1iaking any study-related procedures. The 
investigator must use the most cmTent IRB/IEC/-approved consent f01m for documenting written 
info1med consent. Each info1med consent 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 b an im aiiial witness if re uired b IRB/IEC local re uirements. 
9.1.4. 
Confidentiality 
The investigator must assure that subjects' anonymity will be strictly maintained and that their 
identities ai·e protected from unauthorized pa1iies. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
f01m or biological sample submitted to the Sponsor, IRB/IEC or laborato1y. Laborato1y 
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 laborato1y instructions for fmiher details. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects emolled in the trial. Subject data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRFs, the IMP, and any other study infonnation, remain the 
sole and exclusive prope1iy of Gilead during the conduct of the study and thereafter. This 
info1mation is not to be disclosed to any third paiiy ( except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator fmiher agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third pai·ty or othe1wise 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 que1y fo1ms, 
IRB/IEC and governmental approval with conespondence, info1med consent, dmg records, staff 
cmTiculum vitae and authorization fonns, and other appropriate documents and con espondence. 
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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug(s), including dates of dispensing 
and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (i.e., 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. The investigator may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 


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in case of an inspection. When source documents are required for the continued care of the 
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. The eCRF should 
be completed in a timely manner to enable the sponsor to perform central monitoring of safety 
data. 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. 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
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), subject dispensing records, and returned or destroyed 
study product. Dispensing records will document quantities received from Gilead and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, subject 
initials, and the initials of the person dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure of 
investigational medicinal product/destruction in order to ensure that it complies with 
Gilead requirements. Drug may be returned or destroyed on an ongoing basis during the study, if 
appropriate. At the end of the study, following final drug inventory reconciliation by the monitor, 
the study site will dispose of and/or destroy all unused investigational medicinal product 
supplies, including empty containers, according to these procedures. If the site cannot meet 
Gilead’s requirements for disposal, arrangements will be made between the site and Gilead or its 
representative for destruction or return of unused investigational medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
9.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences and its representatives, to IRBs/IECs, 
or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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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 Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Approval must be obtained before changes can be 
implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency (ies). 
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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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; o

The study has been completed at all study sites for at least 2 years
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
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. 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.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g., attendance at Investigator’s Meetings. If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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Amendment 12
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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.
Monitoring and Oversight of Biomarker Specimens
Biomarker research specimens will be tracked in a manner consistent with Good Clinical 
Practice (GCP) by a quality-controlled, auditable, and appropriately validated laboratory 
information management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the Informed 
Consent Form.
9.3.4.
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.
9.3.5.
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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Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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11 September 2019
10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic 
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
Allister CA, Liu LF, Lamendola CA, Craig CM, Cushman SW, Hellerstein MK, et al. In vivo 
2H2O administration reveals impaired triglyceride storage in adipose tissue of 
insulin-resistant humans. Journal of lipid research 2015;56 (2):435-9.
Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, et al. Quantitative 
magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human 
livers. Hepatology 2015;62 (5):1444-55.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular 
Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 
2019;380 (1):11-22.
Caligiuri A, Gentilini A, Marra F. Molecular Pathogenesis of NASH. International journal of 
molecular sciences 2016;17 (9).
Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of 
nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by 
using MR elastography. Radiology 2011;259 (3):749-56.
Cheung AC, Lapointe-Shaw L, Kowgier M, Meza-Cardona J, Hirschfield GM, Janssen HLA, et 
al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary 
cholangitis patients with incomplete UDCA response may improve outcomes. 
Aliment Pharm Ther 2016;43 (2):283-93.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, et al. A 
Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J 
Med 2018;378 (23):2171-81.
Decaris ML, Emson CL, Li K, Gatmaitan M, Luo F, Cattin J, et al. Turnover rates of hepatic 
collagen and circulating collagen-associated proteins in humans with chronic liver 
disease. PLoS ONE 2015;10 (4):e0123311.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. 
QJM 2010;103 (2):71-83.


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Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up [Accepted Article]. Hepatology 2014.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, et al. Acetyl-CoA Carboxylase 
Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes 
Hypertriglyceridemia in Rodents [Accepted Article]. Hepatology 2018.
Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of Action of Peroxisome Proliferators as 
Hypolipidemic Drugs. Suppression of apolipoprotein C-III. J Biol Chem 
1995;270 (22):13470-5.
Kim CW, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, et al. Acetyl CoA Carboxylase 
Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice 
and Humans: A Bedside to Bench Investigation. Cell metabolism 2017;26:394-
406.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.
Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. 
Gut 2015;64 (5):830-41.
Levy C, Peter JA, Nelson DR, Keach J, Petz J, Cabrera R, et al. Pilot study: fenofibrate for 
patients with primary biliary cirrhosis and an incomplete response to 
ursodeoxycholic acid. Aliment Pharmacol Ther 2011;33 (2):235-42.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance 
elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver 
disease: a prospective study. Hepatology 2014;60 (6):1920-8.
Makie T, Nagai S, Sasakawa A, Kawamura K, Kuwahara T. Predicting tenofovir concentration 
on the basis of renal factors determined by routine tests. Am J Ther 2007;14 
(6):514-8.
Munteanu M, Tiniakos D, Anstee Q, Charlotte F, Marchesini G, Bugianesi E, et al. Diagnostic 
performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using 
the SAF score as histological reference. Aliment Pharmacol Ther 2016;44 
(8):877-89.


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Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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11 September 2019
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. 
Hepatology 2010;52 (2):774-88.
Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 
2007;11 (1):1-16, vii.
Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic 
steatohepatitis. Free Radic Biol Med 2012;52 (1):59-69.
Singh S, Venkatesh SK, Loomba R, Wang Z, Sirlin C, Chen J, et al. Magnetic resonance 
elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a 
diagnostic accuracy systematic review and individual participant data pooled 
analysis. European radiology 2016;26 (5):1431-40.
Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in 
NAFLD/NASH. Free radical research 2013;47 (11):869-80.
Takeda K, Noguchi T, Naguro I, Ichijo H. Apoptosis signal-regulating kinase 1 in stress and 
immune response. Annu Rev Pharmacol Toxicol 2008;48:199-225.
Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-
induced activating phosphorylation of pre-formed oligomer. Journal of cellular 
physiology 2002;191 (1):95-104.
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.
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.


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Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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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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Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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11 September 2019
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Tables for GS-US-384-3914
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Child-Pugh-Turcotte Classification of the Severity of Cirrhosis


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc.
Amendment 12
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Appendix 1.
Investigator Signature Page
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
STUDY ACKNOWLEDGEMENT
A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of 
Regimens in Subjects with Nonalcoholic Steatohepatitis (NASH)
GS-US-384-3914, Amendment 12, 11 September 2019
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
Signature
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD


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Gilead Sciences, Inc. 
Amendment 12
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Appendix 2.
Study Procedures Tables for GS-US-384-3914
Appendix Table 1.
(Cohorts 1-9)
Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day
-14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Clinical Assessments
Informed Consent 
X
Determine 
Eligibilityc 
X
X
X
Medical History
X
X
Assess ascites and 
hepatic 
encephalopathyd
X
Physical 
Examination
X
Xe
Xe
Xe
Xe
Xe
Xe
Vital Signs
X
X
X
X
X
X
X
Height
X
12- lead ECG
X
X
QoLsf
X
X
Adverse Events
X
X
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
Dispense Study 
Drug
X
X
X
Dispense 
Deuterated Water
X
X
X
CCI
CCI
I 
I 


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Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
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Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day
-14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Laboratory Assessments
Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Coagulation Panel
X
X
X
X
X
X
X
Pregnancy Testh
X
X
X
X
X
X
ApoA1, ApoB, 
Total bile acids, 
NMR Lipoprofile
X
X
X
X
X
Phospho-p38i, 
adiponectin, beta-
hydroxybutyrate
X
X
X
Lipidomics
X
X
X
FGF19, C4
X
X
X
X
X
Hemoglobin A1c
X
X
Urine Drug 
Screening
X
HIV-1, HBV & 
HCV Serology
X
Stool Collection 
Xk
Xk
Genomic Samplel 
X
CCI
CCI
CCI
CCI
I 
I 


SEL, GS-0976, GS-9674
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Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
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11 September 2019
Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day
-14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Urine Collection for 
Kinetic Biomarkers
X
X
X
X
Xm
X
X
X
X
Xm
X
X
X
X
Blood Collection 
for Kinetic 
Biomarkers
X
X
X
X
Xm
X
X
X
X
Xm
X
X
X
X
Saliva Collection 
for Kinetic 
Biomarkersn
X
Xk
Xk
a
Screening assessments to be completed within 6 weeks prior to Day -14 visit. The screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences.
b
Day 1 assessments must be performed prior to dosing.
c
Includes review of historical liver biopsy, obtained within 12 months of Screening (date of initial informed consent) for subjects with bridging fibrosis (F3) and within the 
last 12 months for subjects with cirrhosis (F4), to assess subject eligibility.
d
Assess presence and severity of ascites and hepatic encephalopathy for CPT score (for Cohorts 7 and 8 only).
e
Symptom driven physical examination.
f
For subjects with Quality of Life questionnaires available at Day 1.
h
Females of childbearing potential only: Serum pregnancy testing at screening, urine pregnancy testing will occur at Day 1 and every 4 weeks during the dosing period and for 
30 days following the last dose of study drug.
i
Phospho-p38 will be collected if reagent is available.
k
To be collected at home and provided to the site at the next visit.
l
Genomic Sample collected for subjects who have not opted out of sample collection. No additional blood will be drawn.
m
Predose Kinetic Biomarkers (for Cohorts 4-9) and 2 hour (± 1 hour) postdose Kinetic Biomarkers (for Cohorts 5, 6, 7 and 9).
n
Saliva Collection for Kinetic Biomarkers to be collected for Cohorts 1-3 only.
CCI
CCI
CCI
I 
I 
I 
I 
- - - - - - - - - - - - - - - - - - - - -


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Final 
Gilead Sciences, Inc. 
Amendment 12 
Appendix Table 2. 
(Cohorts 10-11) 
Pltn~Petro/ 
Em~ 
Treatment Petro 
EOI 
EI 
FU 
Kmeoc.Bbmtia-s CytEl 
Kmeoc.Bbmtia·Cyde2 
Kmeoc.Bbmtia·C)de3 
D7 
D28 
D56 
D70 
D77 
D84 
D112 
D126 
D154 
D161 
D168 
D196 
D-11 
D-7 
(Wl) 
(W4) 
(W8) 
(WlO) 
D73 
(Wll) 
(Wl2) 
(W16) 
(W18) 
(W22) 
D157 
(W23) 
(W24) 
(W28) 
Scum• 
D-14 
(±ld) 
(±ld) 
Dlb 
(:8<1) 
(:8<1) 
(:8<1) 
(±ld) 
(±ld) 
(±ld) 
(:8<1) 
(:8<1) 
(:8<1) 
(±ld) 
(±ld) 
(±ld) 
(:8<1) 
EI 
(:15d) 
Intrun:d 
X 
CaB:lt 
D:a:nnn: 
X 
X 
Eiigb1tyt 
MecblHisby 
X 
X 
X 
A.=a!ak:s 
ml¢ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
en:q:lmµiiy 
CPTs:ae 
X 
X 
X 
X 
X 
X 
X 
X 
X 
'Riy.i:al 
X 
:xi 
:xi 
:xi 
:xi 
:xi 
:xi 
:xi 
:xi 
&annii:n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
reroliuie 
X 
X 
X 
X 
X 
X 
GSW76 
CONFIDENTIAL 
Page 161 
11 September 2019 


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Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 162
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Pretreatment Period /
Enrollment
Treatment Period
EOT
ET
FU
Kinetic Biomarkers Cycle 1
Kinetic Biomarker Cycle 2
Kinetic Biomarker Cycle 3
Screena
D -14
D -11 
(±1d)
D -7 
(±1d)
D1b
D7 
(W1) 
(±3d)
D28 
(W4) 
(±3d)
D56 
(W8) 
(±3d)
D70 
(W10) 
(±1d)
D73 
(±1d)
D77 
(W11) 
(±1d)
D84 
(W12) 
(±3d)
D112 
(W16) 
(±3d)
D126 
(W18) 
(±3d)
D154 
(W22) 
(±1d)
D157 
(±1d)
D161 
(W23) 
(±1d)
D168 
(W24) 
(±3d)
ET
D196 
(W28) 
(±5d)
Dispense 
Deuterated 
Water
Xk
X
X
Laboratory Assessments
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation 
Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testh
X
X
X
X
X
X
X
X
X
X
Adiponectin, 
beta-
hydroxybutyrate
X
X
X
X
X
hsCRP
X
X
X
X
X
ApoA1, ApoB, 
Total bile acids, 
NMR 
Lipoprofile
X
X
X
X
X
X
X
X
X
Lipidomics
X
X
X
X
X
X
X
X
Hemoglobin 
A1c
X
X
X
X
X
X
Urine Drug 
Screening
X
HIV-1, HBV & 
HCV Serology
X
CCI
CCI
CCI -------------------


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Pltn~Petro/ 
Em~ 
Kmeoc.Bbmtia-s CytEl 
Sa'ffli' 
D-14 
Um:Cdledm 
io:Kio::fu 
X 
Bnmkos 
Bhxl 
Cdledmio: 
X 
Bnmkos 
D-11 
(±ld) 
X 
X 
D-7 
(±ld) 
X 
X 
X 
X 
D7 
(Wl) 
(:8<1) 
D28 
(W4) 
(:8<1) 
D56 
(W8) 
(:8<1) 
Treatment Petro 
Kmeoc.Bbmtia·Cyde2 
D70 
(WlO) 
(±ld) 
X 
X 
D73 
(±ld) 
X 
X 
D77 
(Wll) 
(±ld) 
X 
X 
D84 
(Wl.2) 
(:8<1) 
X 
X 
D112 
(W16) 
(:8<1) 
D126 
(W18) 
(:8<1) 
X 
X 
Kmeoc.Bbmtia·C)de3 
D154 
(W22) 
(±ld) 
X 
X 
D1.57 
(±ld) 
X 
X 
D161 
(W23) 
(±ld) 
X 
X 
D168 
(W24) 
(:8<1) 
X 
X 
Final 
Amendment 12 
EI 
EI 
X 
X 
FU 
D196 
(W28) 
(:15d) 
a 
Screening assessments to be completed within 6 weeks prior to Day -14 visit. The screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences. 
b 
C 
d 
f 
r 
J 
k 
r 
m 
Day I assessments must be performed prior to dosing. 
Includes Review of historical liver biopsy obtained within the last 6 months of Screening (date of initial informed consent) for subjects with bridging fibrosis (F3) and within 
the last 12 months for subjects with cirrhosis (F4), to assess subject eligibility 
Symptom driven physical examination. 
For sub'ects with Quality of Life questionnaires available at Day 1. 
enormc amp e co ecte 
or su 1ects w o 1ave not opted out of sample collection. No additional blood will be drawn. 
The first dose of 50 mL deuterated water will be administered under the supervision of investigative site personnel and monitored for at least 30 minutes after for any side 
effects. 
. 
" 
. 
"' 
. 
. 
. 
etic Biomarkers. 
CONFIDENTIAL 
Page 163 
11 September 2019 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 164
11 September 2019
Appendix Table 3.
(Cohorts 12-13)
Pretreatm t Period/ 
Enrolment
Treatment Period
End of 
T eatment 
ET
Phone 
llow-Up
ET Phone 
Follow-Up
Screen a
D 14
D1 b
D28 (W4) (±3d)
42 (W6) 
(±3d)
ET
56 (W8)
( ±5d)
2 Weeks After 
Last Dose
Clinical Assessment
Informed  Consent
X
Determine  Eligibility c 
X
X
Medical  History
X
X
Assess Ascites and Hepatic 
Encephalopathy
X
CPT Score 
X
Physical  Examination
X
X d
X d
X d
X d
X d
Vital  Signs
X
X
X
X
X
X
Height
X
12- lead ECG
X
X
X
Adverse  Events
X
X
X
X
X
X
X
X
Concomitant  Medications
X
X
X
X
X
X
X
X
Dispense  Vascepa®  (Cohort 12) 
X
X
Dispense  Fenofibrate  (Cohort 13)
X
Dispense  GS-0976  and  GS-9674
X
X
Review of Study Drug Dosing 
Compliance (Pill Count)
X e
X
X
Chemistry
X
X
 X
X
X
X
Hematology
X
X
X
X
X
X
Coagulation  Panel
X
X
X
X
X
X
Pregnancy  Test f
X
X
X
X
X
X
X
X
ApoA1, ApoB,  NMR Lipoprofile
X
X
X
X
X
CCI
CCI
CCI
I -I -----1-1--


SEL, GS-0976, GS-9674 
Protocol GS-US-384-3914 
Gilead Sciences, Inc. 
Final 
Amendment 12 
PretreatmeutPeliod' 
Fa~ 
D-14 
TreatmeutPeliod 
D28(W4)(:±ad) 
Emof 
Treatment 
EI 
D42(W6) 
(±ad) 
EI 
lbXJe 
EilbXJe 
F<A11¥Up 
F<AJl,<Up 
D56(\.V8) 
2Week5.Allet· 
(:15d) 
l..astDose 
HIV-1, HBV & HCV SodJgy 
X 
G:m:nc&nµei 
X 
a 
b 
C 
d 
e 
f 
Screening assessments to be completed within 4 weeks prior to Day -14 visit. TI1e screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences. 
Day 1 assessments must be performed prior to dosing. 
Includes review of historical liver biopsy obtained within 6 months of the Screening Visit for subjects without compensated ci.ll'hosis (F4) or within 12 months of the 
Screening Visit for subjects with compensated cin-hosis (F4); or review of historical MRE or historical FibroScan® obtained within 6 months of the Screening Visit. 
Symptom driven physical exaniination. 
Vascepa® (Coho1t 12) or fenofibrate (Coho1t 13) only 
Females of childbearing potential only: Semm pregnancy testing at screening, urine pregnancy testing will occur at D-14, D1 , D28, D42, and 2 weeks after last dose of study 
dm . Home urine reimanc test for Phone Follow-U will be rovided at the D42 Visit or ET Visit. 
or su 1ects who have not opted out of sample collection. No additional blood will be drawn. 
CONFIDENTIAL 
Page 165 
11 September 2019 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 166
11 September 2019
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥ 54 years of age with 
cessation of previously occurring menses for ≥ 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age. 
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
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. Please refer to 
the latest version of the SEL Investigator’s Brochure for additional information.
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.


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 167
11 September 2019
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 the latest version of the 
GS-0976 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.
Drug-drug interaction (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 GS-9674 Investigator’s 
Brochure for additional information.
Please see fenofibrate label for further information regarding fenofibrate and pregnancy.
Please see Vascepa® label for further information regarding Vascepa® and pregnancy. 
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. All females of childbearing potential must have a negative serum 
pregnancy test at Screening. Cohorts 1-11 must have a negative pregnancy test on the 
Baseline/Day 1 visit prior to enrollment. Pregnancy tests will be performed at monthly intervals 
thereafter.  For Cohorts 12-13, urine pregnancy testing will occur at Day-14, Day 1 (prior to 
dosing), Week 4, Week 6, and at two weeks following the last dose of study drug. 
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.
o
Intrauterine device (IUD) with a failure rate of <1% per year
o
Tubal sterilization


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 168
11 September 2019
o
Essure micro-insert system (provided confirmation of success 3 months after procedure)
o
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)

The above described methods are considered preferred methods of highly effective 
contraception in this protocol.

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:
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
Contraceptive vaginal ring
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 (e.g., 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.
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 


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 169
11 September 2019
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.


SEL, GS-0976, GS-9674
Protocol GS-US-384-3914
Final
Gilead Sciences, Inc. 
Amendment 12
CONFIDENTIAL
Page 170
11 September 2019
Appendix 4.
Child-Pugh-Turcotte Classification of the Severity of Cirrhosis
1
2
3
Hepatic Encephalopathy
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject is receiving 
medical therapy for HE 
Medication-Refractory
Marked 
confusion/incoherent, 
rousable but sleeping 
unless aroused or 
comatosed
Ascites
None
No ascites and not on 
treatment for ascites
Mild/Moderate
Cross sectional imaging 
showing ascites
Abdominal distension
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3
CPT score is obtained by adding the score for each parameter.
CPT class:
A = 5-6 points
B = 7-9 points
C = 10-15 points

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Proof of Concept, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Regimens in Subjects with 
Nonalcoholic Steatohepatitis (NASH)
Name of Test Drugs:
Selonsertib (SEL, GS-4997); GS-0976; GS-9674
Study Number:
GS-US-384-3914
Protocol Version (Date):
Amendment 10: 13 July 2018
Analysis Type:
Interim Analysis, Cohorts 1-9 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
01 August 2018
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


GS-4997, GS-0976, GS-9674 
GS-US-384-3914 
Statistical Analysis Plan - Interim Analysis, Coho1ts 1-9 
Version 1.0 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................................ 2 
LIST OF TABLES .......................................................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ .4 
1. 
INTRODUCTION .................................................................................................................................................. 6 
1. 1. 
Study Objectives ........................................................................................................................................ 6 
1.2. 
Study Design ............................................................................................................................................. 7 
1.3. 
Sainple Size and Power ............................................................................................................................. 9 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 10 
2.1. 
Data Monitoring Conunittee Analyses .................................................................................................... 10 
2.2. 
Interi1n Analyses ...................................................................................................................................... 10 
2.3. 
Final Analysis .......................................................................................................................................... 10 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................. 11 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
3.8. 
Analysis Sets ........................................................................................................................................... 11 
3.1. 1. 
All Enrolled Analysis Set ...................................................................................................... 11 
3.1.2. 
Full Analysis Set. ................................................................................................................... 11 
3.1.3. 
Safe Anal sis Set ................................................................................................................ 11 
l!ct Grouping ..................................................................................................................................... 12 
Strata and Covariates ............................................................................................................................... 12 
Examination of Subject Subgroups ......................................................................................................... 12 
Multiple Co1nparisons ............................................................................................................................. 12 
Missing Data and Outliers ....................................................................................................................... 12 
3.6.1. 
Missing Data .......................................................................................................................... 12 
3. 6. 2. 
Outliers .................................................................................................................................. 12 
Data Handling Conventions and Transfo1mations .................................................................................. 12 
Analysis Visit Windows .......................................................................................................................... 13 
3.8.1. 
Definition of Study Day ........................................................................................................ 13 
3.8.2. 
Analysis Visit Windows ........................................................................................................ 13 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................. 15 
4. 
SUBJECT DISPOSITION ................................................................................................................................... 17 
4.1. 
Subject Enrollment and Disposition ........................................................................................................ 17 
4.2. 
Extent of Study Thug Exposw-e and Adherence ...................................................................................... 17 
4.2.1. 
Duration ofExposw·e to Study Tuug ..................................................................................... 18 
4.2.2. 
Adherence to Study D1ug ...................................................................................................... 18 
4.3. 
Protocol Deviations ................................................................................................................................. 19 
5. 
BASELINE CHARACTERISTICS ..................................................................................................................... 20 
5. 1. 
De1nographics .......................................................................................................................................... 20 
5.2. 
Other Baseline Characteristics ................................................................................................................ 20 
5.3. 
Medical Histo1y ....................................................................................................................................... 22 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 23 
I 
7. 
SAFETY ANALYSES ......................................................................................................................................... 26 
CONFIDENTIAL 
Page2 
01 August 2018 


GS-4997, GS-0976, GS-9674
GS-US-384-3914
Statistical Analysis Plan – Interim Analysis, Cohorts 1-9
Version 1.0
CONFIDENTIAL
Page 3
01 August 2018
7.1.
Adverse Events and Deaths.....................................................................................................................26
7.1.1.
Adverse Event Dictionary .....................................................................................................26
7.1.2.
Adverse Event Severity .........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................26
7.1.4.
Serious Adverse Events.........................................................................................................26
7.1.5.
Treatment-Emergent Adverse Events....................................................................................26
7.1.5.1.
Definition of Treatment-Emergent Adverse Events........................................26
7.1.5.2.
Incomplete Dates .............................................................................................27
7.1.6.
Summaries of Adverse Events and Deaths............................................................................27
7.2.
Laboratory Evaluations ...........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................29
7.2.2.
Graded Laboratory Values ....................................................................................................30
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................30
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities................................30
7.2.2.3.
Summaries of Laboratory Abnormalities ........................................................30
7.2.3.
Liver-related Laboratory Evaluations....................................................................................31
7.2.3.1.
Criteria for Close Observation.........................................................................31
7.2.3.2.
Criteria for Drug Withheld ..............................................................................31
7.2.3.3.
Summary of Liver-Related Laboratory Abnormalities....................................32
7.3.
 Height, and Vital Signs ....................................................................................................32
7.4.
Prior and Concomitant Medications........................................................................................................33
7.4.1.
Prior Medications ..................................................................................................................33
7.4.2.
Concomitant Medications......................................................................................................33
7.5.
Electrocardiogram Results.......................................................................................................................34
7.6.
Changes From Protocol-Specified Safety Analyses................................................................................34
9.
REFERENCES.....................................................................................................................................................36
10.
SOFTWARE.........................................................................................................................................................37
11.
SAP REVISION...................................................................................................................................................38
12.
APPENDICES......................................................................................................................................................39
LIST OF TABLES
Table 3-1.
Analysis Visit Windows for Vital Signs, Weight, Chemistry, Hematology, 
Coagulation Labs, Lipid Profiles, HOMA-IR, MELD Score, FGF19, C4, and 
ApoA1 .....................................................................................................................................14
Table 3-2.
Analysis Visit Windows for ECG, 
 
, 
, Alpha-2 Maroglobin, and Haptoglobin.................................................14
Table 3-3.
Analysis Visit Windows for 
 
 
, MRE, and MRI-PDFF .............................................................................15
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
-
I 
---


GS-4997, GS-0976, GS-9674
GS-US-384-3914
Statistical Analysis Plan – Interim Analysis, Cohorts 1-9
Version 1.0
CONFIDENTIAL
Page 4
01 August 2018
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ApoA1
apolipoprotein A1
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CFR
Code of Federal Regulations
CI
confidence interval
CK-18
cytokeratin 18
CLDQ
chronic liver disease questionnaire
CRF
case report form
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
eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis
ET
early termination
FAS
Full Analysis Set
FGF19
fibroblast growth factor 19
FU
follow up
GGT
Gamma glutamyl transferase
Gilead
Gilead Sciences
HA
hyaluronic acid
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDL-C
HDL-cholesterol
HLT
high-level term
HLGT
high level group term
HOMA-IR
homeostasis model assessment of insulin resistance
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
INR
International normalized ratio


GS-4997, GS-0976, GS-9674
GS-US-384-3914
Statistical Analysis Plan – Interim Analysis, Cohorts 1-9
Version 1.0
CONFIDENTIAL
Page 5
01 August 2018
LDL-C
low-density lipoprotein cholesterol
LTT
lower-level term
LOQ
limit of quantitation
ME
multiple-echo
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
NASH
nonalcoholic steatohepatitis
PIIINP
procollagen III amino terminal peptide
PK
pharmacokinetic
PT
preferred term
Q1, Q3
first quartile, third quartile
QoL
quality of life
SAE
serious adverse event
SAP
SD
statistical analysis plan
standard deviation
SF-36
short form (36) 
SI (units)
international system of units
SOC
system organ class
TE
treatment-emergent
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TIMP-1
tissue inhibitor of metalloproteinase 1
ULN
upper limit of normal
VLDL-C
very low density lipoprotein cholesterol
WHO
World Health Organization
WPAI
work productivity and activity impairment questionnaire


GS-4997, GS-0976, GS-9674 
GS-US-384-3914 
Statistical Analysis Plan - Interim Analysis, Coho1ts 1-9 
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 interim clinical study repo1t 
(CSR) for Study GS-US-384-3914, Coho1ts 1 through 9. This SAP is based on the study protocol 
amendment 10 dated 13 July 2018 and the electronic case repo1t fo1m (eCRF). This SAP covers 
the interim analyses for Coho1ts 1 through 9 and includes Coho1ts 1 through 9 data only. The 
SAP will be finalized before database finalization of Coho1ts 1 through 9. Any changes made 
after the finalization of the SAP will be documented in the interim CSR. There will be a separate 
SAP prepared for the Final Analysis. 
1.1. 
Study Objectives 
The prima1y objective of this study is as follows: 
• 
To evaluate the safety and tolerability of study dmg(s) in subjects with NASH as assessed by 
magnetic resonance imaging - proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE). 
I 
I 
I 
I 
I 
I 
I 
I 
CONFIDENTIAL 
Page6 
01 August 2018 


GS-4997, GS-0976, GS-9674
GS-US-384-3914
Statistical Analysis Plan – Interim Analysis, Cohorts 1-9
Version 1.0
CONFIDENTIAL
Page 7
01 August 2018
1.2.
Study Design
This is a proof of concept, open-label study evaluating the safety, tolerability, and efficacy of 
monotherapy and combination regimens in subjects with NASH as assessed by MRI-PDFF and 
MRE. 
For Cohorts 1 through 9, eligible subjects will be enrolled to receive treatment with selonsertib 
(SEL; GS-4997), GS-0976, GS-9674; the combination of SEL and GS-9674, SEL and GS-0976, 
GS-9674 and GS-0976; or SEL, GS-0976 and GS-9674 for 12 weeks as shown in the figure 
below.
Approximately 120 subjects total will be enrolled into 1 of 9 cohorts. 

Cohort 1 (SEL) will consist of 10 enrolled subjects

Cohort 2 (GS-0976) will consist of 10 enrolled subjects
Non-cirrhotic 
I 
Cohort 1 
r 
SEL 18 mg PO QD (n = 10) 
Cohort 2 
GS-0976 20 mg PO QD ( n = 10) 
Vl 
Cohort 3 
... 
>-
C: 
GS-9674 30 mg PO QD ( n = 10) 
"'C 
Q) 
:::, 
E 
... 
... 
Vl 
Cohort4 
C: 
Vl 
Vl 
Q) 
'+-
QO 
Q) 
... 
SEL 18 mg+ GS-9674 30 mg PO QD (ns 20) 
E 
0 
Vl 
C: 
C: 
Vl 
Q) 
... 
"'C 
C: 
<( 
E 
('IJ 
C: 
Q) 
Cohort 5 
Q) 
LU 
... 
.... 
Q) 
C: 
0 
SEL 18 mg+ GS-0976 20 mg PO QO (n s 20) 
f-
....... 
.... 
u 
Q) 
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'+-
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Vl 
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C: 
0 
::, 
LU 
... 
Cohort 6 
"'C 
('IJ 
C: 
Q) 
GS-9674 30 mg+ GS-0976 20 mg PO QD (n S 20} 
LU 
..Q 
.... ... 
Q) 
0 
.... 
u.. 
a.. 
Cohort 9 
SEL 18mg+GS-097620mg+GS-967430mg POQD(ns 10) 
Cirrhotic 
Cohort 7 
GS-0976 20 mg PO QD (ns 10} 
Cohort 8 
GS-9674 30 mg PO QD (ns 10} 
6 Weeks 
2 Weeks 
12 Weeks 
4 Weeks 


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
Cohort 3 (GS-9674) will consist of 10 enrolled subjects

Cohort 4 (SEL + GS-9674) will consist of up to 20 enrolled subjects

Cohort 5 (SEL + GS-0976) will consist of up to 20 enrolled subjects

Cohort 6 (GS-0976 + GS-9674) will consist of up to 20 enrolled subjects

Cohort 7 (GS-0976) will consist of up to 10 enrolled subjects with Child-Pugh-Turcotte 
(CPT) A cirrhosis

Cohort 8 (GS-9674) will consist of up to 10 enrolled subjects with CPT A cirrhosis

Cohort 9 (SEL + GS-0976 + GS-9674) will consist of approximately 10 enrolled subjects
Cohorts 1 through 6 and 9 will be enrolled sequentially while Cohorts 7 and 8 will be 
randomized in parallel.  
For Cohorts 10 and 11, eligible subjects will be randomized to receive pre-treatment with 
fenofibrate 48 mg or fenofibrate 145 mg from Day -14 to Day -1 and will be treated with 
GS-0976 20 mg and fenofibrate 48 mg or GS-0976 20 mg and fenofibrate 145 mg for 24 weeks 
as shown in the figure below.
A total of 30 subjects will be randomized (1:1) into either Cohort 10 or 11; randomization will be 
stratified by (1) screening serum triglyceride levels ([≥ 150 and < 250 mg/dL] or [≥ 250 and 
< 500 mg/dL]), and (2) fibrosis stage [F3 defined as protocol inclusion criteria 5a - 5b; or F4 
defined as inclusion criteria 5c - 5e]. Approximately 60% of subjects in each cohort should have 
cirrhosis (F4) based on inclusion criteria 5c – 5e. Approximately 60% subjects in each cohort 
should have screening serum triglycerides ≥ 150 and < 250 mg/dL as below:

Cohort 10 (GS-0976 20 mg + fenofibrate 48 mg) will consist of 15 subjects:
Approximately 9 subjects with screening serum triglycerides ≥ 150 and < 250 mg/dL
Approximately 6 subjects with screening serum triglycerides ≥ 250 and < 500 mg/dL
bl) 
C: ·c 
" 
.x 
C: 
_Q 
n, 
N 
CohortlO 
In= 15} 
Cohortll 
In= 15} 
Pre- Treatment 
Fenofibrate 
48 m POQD 
Pre- Treatment 
Fenofibrate 
145 m PO D 
2 Weeks IDay-14 through Day-1) 
Treatment24 weeks 
GS-0976 20 mg+ Fenofibrate48 mg PO QD 
Treatment24 weeks 
GS-0976 20 mg+ Fenofibrate 145 mg POQD 
24 Weeks I Day 1th rough Week 24) 


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
Cohort 11 (GS-0976 20 mg + fenofibrate 145 mg) will consist of 15 subjects:
Approximately 9 subjects with screening serum triglycerides ≥ 150 and < 250 mg/dL
Approximately 6 subjects with screening serum triglycerides ≥ 250 and < 500 mg/dL
1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size in Cohorts 1 to 9. The number of subjects was chosen based on clinical experience 
with other similar proof of concept studies.
In Cohorts 10 and 11, we assumed that among subjects with baseline hypertriglyceridemia 
≥ 150 mg/dL (60% with serum triglycerides ≥ 150 and < 250 mg/dL and 40% with serum 
triglycerides ≥ 250 and < 500 mg/dL) thus Grade 3-4 hypertriglyceridemia (> 500 mg/dL) would 
be observed in 28% following treatment with GS-0976. Assuming that the co-administration of 
fenofibrate and GS-0976 will reduce the incidence of Grade 3-4 hypertriglyceridemia to < 5%, a 
sample size of 15 in each of Cohorts 10 and 11 will provide 82% power to detect the reduction 
based on a one-sided Fisher’s exact test at a significance level of 0.05.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
An internal Gilead data monitoring committee (DMC) will review the progress of the study and 
perform interim reviews of safety data for Cohorts 1 through 9, due to the sequential enrollment 
design. The DMC will review cumulative data from these cohorts. The DMC will be notified of 
any case of suspected drug-induced liver injury (DILI) by the medical monitor. The DMC will 
provide recommendations whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant 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’s specific activities will be defined by a mutually agreed charter, which 
will define the DMC’s membership, conduct, and meeting schedule. 
There will be no formal DMC review for Cohorts 10 and 11. However, internal safety 
monitoring will be conducted continuously on an ongoing basis.
2.2.
Interim Analyses
A formal interim analysis will be performed after subjects in the first 9 cohorts complete or early 
discontinue the study. 
Administrative interim analyses will also be performed to support the safety review or for 
conferences and publications. For Cohorts 1 through 9, the administrative interim analyses will 
include data from the completed cohorts and also the other on-going cohorts. For Cohorts 10 and 
11, the administrative interim analysis will be performed after all subjects complete 12 weeks of 
treatment or early discontinue treatment.
Data from Cohort 10 and 11 will not be included in this interim analysis for Cohorts 1 through 9. 
2.3.
Final Analysis
After all subjects have completed or early discontinued the study, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the 
final analysis of the data will be performed. A separate SAP will be provided to describe the 
statistical analyses of the final analysis. 


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3_ 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each 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. 
By-subject listings will be presented for all subjects in the Safety Analysis Set, unless othe1wise 
specified, and so1ied by subject ID number, visit date, and time (if applicable). Data collected on 
log fonns, such as AEs, will be presented in chronological order within subject. The treatment 
group to which subjects were initially assigned will be used in the listings. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. 
A listing of reasons for exclusion from analysis sets will be provided by subject. 
3.1.1. 
All Enrolled Analysis Set 
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were enrolled into the study and received 
at least 1 dose of study dmg. This is the prima1y analysis set for efficacy analyses. 
3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who were administered at least 1 dose of study 
diug. This is the primaiy 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 ti-eatment to which 
they were assigned. For analyses based on the Safety Analysis Set, subjects will be grouped 
according to actual treatment received. The actual treatment received will differ from the 
emolled/randomized treatment only when their actual treatment differs from 
emolled/randomized treatment for the entire treatment duration. 
3.3. 
Strata and Covariates 
Coho1is 1 through 9 of this study do not use a stratified randomization schedule in emolling 
subjects. No covariates will be included in efficacy and safety analyses. 
3.4. 
Examination of Subject Subgroups 
There are no prespecified subject subgroupings for efficacy and safety analyses. 
3.5. 
Multiple Comparisons 
Adjustments for multiplicity will not be made, because no fo1mal statistical testing will be 
perfo1med in this study. 
3.6. 
3.6.1. 
Missing Data and Outliers 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study dmg, imputation mles 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 
In general, age in years on the date of the first dose of study dmg will be used for analyses and 
presentation in listings. If an emolled subject was not dosed with any study diug, the emollment 
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. If only bnih year is collected on 
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the CRF, “01 July” will be used for the unknown birth day and month for the purpose of age 
calculation. If only birth year and month are collected, “01” will be used for the unknown birth 
day.
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 for calculation of descriptive statistics if 
the datum is reported in the form of “ x” (where x is considered the LOQ). For example, if 
the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used for 
calculation of summary statistics. An exception to this rule is any value reported as < 1 or 
<0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used 
for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
Natural logarithm transformation will be used for plasma/blood concentrations. Plasma 
concentration values that are below the limit of quantitation (BLQ) will be presented as “BLQ” 
in the concentration data listing. 
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date 
Therefore, study day 1 is the day of first dose of study drug administration.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dosing date 
of study drug.  For 
, nominal baseline values will be used.
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On-ti·eatment visit windows will be calculated from Study Day 1 for selected efficacy measmes, 
vital signs, elecu-ocardiogram (ECG), and safety laborato1y data. The-
will not be 
windowed, but rather analyzed according to their nominal visit. 
Selected safety and efficacy data 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 
early tennination (ET) or follow-up (FU). The nominal visit name will be used for the ET and 
FU visits. 
The analysis windows for vital signs, -
chemistry, hematology, coagulation panel, lipid 
profile, homeostasis model assessment of insulin resistance (HOMA-IR), model for end-stage 
liver disease (MELD) score, fibroblast growth factor 19 (FGF19), 7-alpha-hydroxy-4-cholesten-
3-one (C4), and apolipoprotein Al (ApoAl ) are provided in Table 3-1. 
Table 3-1. 
Nominal Visit 
Baseline 
Week 1 
Week 4 
Weeks 
Week 12 
Analysis Visit Windows for Vital Signs,_ 
Chemistry, 
Hematology, Coagulation Labs, Lipid Proflles, HOMA-IR, MELD 
Score, FGF19, C4, and ApoAl 
Nominal Day 
Lowe1· Limit 
Uppe1· Limit 
1 
(none) 
1 
8 
2 
18 
29 
19 
42 
57 
43 
70 
85 
71 
:::: 85 
~
is windows for ECG, 
-
tissue inhibitor of m tal o 
-
ase 1 [PIIINP], and procollagen III amino terminal 
peptide [TIMP-1]) and 
, alpha-2 Maroglobin, and haptoglobin are provided 
in Table 3-2. 
Table 3-2. 
Nominal Visit 
Baseline 
Week 12 
CONFIDENTIAL 
~ws for ECG, __ 
and its components, 
_
, Alpha-2 Maroglobin, and Haptoglobin 
Nominal Day 
Lowe1· Limit 
Uppe1· Limit 
1 
(none) 
1 
85 
2 
:::: 85 
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Table 3-3. 
Anal sis Visit Windows for 
total 
p38, 
Nominal Visit 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
1 
(none) 
1 
Week 4 
29 
2 
56 
Week 12 
85 
57 
:::: 85 
Data from unscheduled visits may be assigned to a pa1ticular visit based on the visit windows. 
The following conventions will be followed: 
• 
An unscheduled visit prior to the first dosing of study drng may be included in the calculation 
of the baseline value, if applicable. 
• 
Unscheduled visits after the first dose of study drng will be included in detennining the 
maximum postbaseline toxicity grade. 
• 
Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
"Follow-up Visit" of each phase. 
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: 
• 
In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study diug. If multiple measurements occur on the same day, the last nonmissing 
value prior to the time of first dosing of study diug will be considered as the baseline value. 
If these multiple measurements occur at the same time or the time is not available, the 
average of these measurements (for continuous data) will be considered the baseline value. 
• 
For postbaseline visits: 
-
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. 
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If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple, valid nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety ECG findings).

For postbaseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected (eg, 
abnormal will be selected over normal for safety ECG findings).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects who met all eligibility criteria 
but were not enrolled with reasons subjects not enrolled, the number of subjects enrolled, the 
number of subjects enrolled but never treated, and the number of subjects in each of the 
categories listed below:

Safety Analysis Set 

FAS

Continuing study drug (if applicable)

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Continuing study if applicable

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.
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)
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.
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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, 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.
Total duration of exposure to study drug (weeks) = (last dose date – first dose date + 1)/7
The total duration of exposure to study drug will be summarized using descriptive statistics and 
percentage of subjects exposed through the following time periods: 1 day, 1 week, 2 weeks, 
4 weeks, 8 weeks, and 12 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 presumed total number of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















The level of prescribed 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 specified by the 
protocol for a subject who completes treatment.
The level of prescribed adherence will be expressed as a percentage using the following formula: 
Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol






Note: If calculated adherence is greater than 100%, the result will be set to 100%.
For subjects who complete treatment, the number of doses expected to be administered for each 
study drug is as below:

GS-4997: Cohorts 1, 4, 5 and 9 are expected to administer 84 doses

GS-0976: Cohort 2 is expected to administer 168 doses (1 dose contains 10 mg GS-0976); 
Cohorts 5, 6, 7 and 9 are expected to administer 84 doses (1 dose contains 20 mg GS-0976)


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
GS-9674: Cohort 3 is expected to administer 252 doses (1 dose contains 10 mg GS-9674); 
Cohorts 4, 6, 8 and 9 are expected to administer 84 doses (1 dose contains 30 mg GS-9674).
Summaries will be provided by treatment group and by study drug 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 by 
subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
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 Enrolled Analysis Set. A by-subject listing 
will be provided for those subjects with any 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.
Other Baseline Characteristics
Other baseline characteristics include:

height

body mass index as a continuous variable and as categories (< 18.5 kg/m2, 18.5 to < 25 
kg/m2, 25 to 30 kg/m2  and ≥ 30 kg/m2)

diabetes mellitus (absence or presence)

albumin

total bilirubin

fasting insulin

fasting glucose

homeostasis model assessment of insulin resistance (HOMA-IR)
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
international normalized ratio (INR)

MELD score

calculated fasting low density lipoprotein cholesterol (LDL-C) (= non-HDL-C minus 
VLDL-C)

smoking status

MRI-PDFF

MRE
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These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history (ie, conditions not specific to the disease being studied) data will be 
collected at screening and only included in the listing. General medical history data will not be 
coded. 
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order and abnormalities in chronological order. 
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EFFICACY ANALYSES 
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All analyses will be conducted at each administrative interim analysis and repeated at the Interim 
Analysis for Coho1is 1 through 9 when all subjects from cohorts 1 through 9 have completed the 
study or early tenninated. The administrative interim analyses will evaluate all available data at 
the time of the snapshot. The snapshot will be triggered by the completion of each coho1i(s), if 
completed around the same time. 
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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. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. The severity grade of events 
for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings. The missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious AEs captured and stored in the clinical database 
will be reconciled with the SAE database from the Gilead Pharmacovigilance and Epidemiology 
Department 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 study drug

Any AEs leading to premature discontinuation of 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, PT, and treatment group as follows:

All TEAEs

TEAEs of Grade 2 or higher 

TEAEs of Grade 3 or higher (by maximum severity)

All TE treatment-related AEs

TE Treatment-related AEs of Grade 2 or higher 

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug


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
All TEAEs leading to premature discontinuation of study

All TEAEs leading to dose interruption of study drug
A brief, high-level summary of AEs described above will be provided by treatment group and by 
the number and percentage of subjects who experienced the above AEs. All deaths observed in 
the study will be also included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence within the pooled treatment groups for:

All AEs

TEAEs of Grade 3 or higher

All treatment-related AEs

All SAEs

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to premature discontinuation of study 

All TEAEs leading to interruption of study drug
In addition, data listings will be provided for the following (with a variable indicating whether 
the event is treatment emergent):

All AEs

AEs of Grade 3 or higher

SAEs

Deaths

AEs leading to premature discontinuation of study drug 

AEs leading to premature discontinuation of study 


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7.2. 
Laboratory Evaluations 
Version 1.0 
Laborato1y data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. SUllllllaries of laborato1y data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study dmg plus 30 days 
for subjects who have pennanently discontinued study diug, 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 reported in conventional units. When values are below the LOQ, 
they will be listed as such, and the closest imputed value will be used for the pmpose of 
calculating Sllllllnaiy statistics as specified in Section 3. 7. Hemolized test results will not be 
included in the analysis, but they will be listed in by-subject laborato1y listings. 
A by-subject listing for laborato1y test results will be provided by subject ID number and visit in 
chronological order for hematology, semm chemistiy, and coagulation separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on CTCAE 
version 4.03 will be flagged in the data listings, as appropriate. 
No fonnal statistical testing is planned. 
7.2.1. 
Summaries of Numeric Laboratory Results 
tive statistics will be provided by tl'eatment group for 
, creatinine, fasting glucose, fasting insulin, WBC, neutl'ophils, lymphocytes, 
hemoglobin, platelets, INR and estimated glomernlai· filti·ation rate ( eGFR) using the 
Cockcroft-Gault equation, as follows: 
• 
Baseline values 
• 
Values at each postbaseline visit 
• 
Change from baseline at each postbaseline visit 
• 
Percent change from baseline at each postbaseline visit 
A baseline laborato1y value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study diug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Ql, Q3, minimmn, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
repo1ied number of digits plus 1. 
Median (Ql, Q3) of the observed value~,- - creatinine, fasting 
glucose, fasting insulin, 
, ~uti·ophils, lymphocytes, hemoglobin, 
platelets, INR, and eGFR, will be plotted using a line plot by ti·eatinent group and visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
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7.2.2.
Graded Laboratory Values
The CTCAE Version 4.03 will be used for assigning 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. 
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 
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. 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 


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results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades displayed. 
7.2.3. 
Liver-related Laboratory Evaluations 
Liver-related abno1malities after initial study diug dosing will be exainined and summarized for 
separately for subjects who meet the criteria for close observation and for subjects who meet the 
criteria for diug withheld. 
7.2.3.1. 
Criteria for Close Observation 
The number and percentage will be summarized according to different baseline -
level: 
• 
Nonnal 
• 
Elevated (:::: ULN) 
For subjects with nonnal baseline 
following criteria is met postbasehne: 
, close observation is considered if any of the 
o 
INR > 1.5 (except for subjects on anticoagulant therapy) 
For subjects with baseline 
between 1 and 5 x ULN, close observation is considered 
if any of the following criteria is met postbaseline: 
o 
INR > 1.5 (except for subjects on anticoagulant therapy) 
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7.2.3.3.
Summary of Liver-Related Laboratory Abnormalities
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. Number and percentage of subjects who were reported to meet each criterion will be 
summarized by treatment group. For individual laboratory tests, subjects will be counted once 
based on the most severe postbaseline values. For the composite endpoints of 
 total 
bilirubin, and INR, 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 on-treatment values of all relevant tests at the same postbaseline 
visit date. 
Listings of subjects who met the criteria for close observation and who meet the criteria for drug 
withheld will be provided. 
7.3.
Height, and Vital Signs
Descriptive statistics will be provided by treatment group for 
, height, BMI and vital 
signs 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. 
 and vital signs measured at 
unscheduled visits will be included for the baseline value selection. 
Median (Q1, Q3) of the observed values for 
 will be plotted by treatment group and 
visit.
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. High or low values for vital signs will be flagged. 
, height, and 
BMI will be listed separately.
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7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of the stop date. 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 preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in descending 
overall frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dosing date 
of study drug and continued 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 


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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
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.6.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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


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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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12.
APPENDICES
Appendix 1.
Study Procedures Tables for GS-US-384-3914 (Cohorts 1-9)
Appendix 2.
CTCTAE Grade for Laboratory Parameters
Appendix 3.
Programming Specifications


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Appendix 1.
Study Procedures Tables for GS-US-384-3914 (Cohorts 1-9)
Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day-
14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Clinical Assessments
Informed 
Consent 
X
Determine 
Eligibilityc 
X
X
X
Medical History
X
X
Assess ascites 
and hepatic 
encephalopathyd
X
Physical 
Examination
X
Xe
Xe
Xe
Xe
Xe
Xe
Vital Signs
X
X
X
X
X
X
X
Height
X
12- lead ECG
X
X
MRE, 
MRI-PDFF
Xg
X
X
Adverse Events
X
X
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
Dispense Study 
Drug
X
X
X
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Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day-
14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Dispense 
Deuterated 
Water
X
X
X
Laboratory Assessments
Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Coagulation 
Panel
X
X
X
X
X
X
X
Pregnancy Testh
X
X
X
X
X
X
ApoA1, ApoB, 
, 
NMR 
Lipoprofile
X
X
X
X
X
 
 
beta-
hydroxybutyrate
X
X
X
Lipidomics
X
X
X
FGF19, C4
X
X
X
X
X
Hemoglobin 
A1c
X
X
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Pretreatment
Period
Enrollment
Treatment Period
End of
Treatment
Follow
Up
Kinetic Biomarkers Cycle 1
Kinetic Biomarkers Cycle 2
Kinetic Biomarkers Cycle 3
Screena
Day-
14
Day 
-11
(±1d)
Day 
-7
(±1d)
Day 
1b
Day 7 
(WK1)
(±3d)
Day 14
(WK2)
(±1d)
Day 
17
(±1d)
Day 21
(WK3)
(±1d)
Day 28
(WK4)
(±3d)
Day 35 
(WK5)
(±3d)
Day 56
(WK8)
(±3d)
Day 70 
(WK10)
(±1d)
Day 
73
(±1d)
Day 77 
(WK11)
(±1d)
Day 84
(WK12)
(±3d)
Day 91 
(WK13)
(±3d)
Day 112 
(WK16)
(±5d)
Urine Drug 
Screening
X
HIV-1, HBV & 
HCV Serology
X
Genomic 
Samplel 
X
Urine Collection 
for Kinetic 
Biomarkers
X
X
X
X
Xm
X
X
X
X
Xm
X
X
X
X
Blood Collection 
for Kinetic 
Biomarkers
X
X
X
X
Xm
X
X
X
X
Xm
X
X
X
X
Saliva 
Collection for 
Kinetic 
Biomarkersn
X
Xk
Xk
a
Screening assessments to be completed within 6 weeks prior to Day -14 visit. The screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences.
b
Day 1 assessments must be performed prior to dosing.
c
Includes review of historical liver biopsy, obtained within 12 months of Screening (date of initial informed consent) for subjects with bridging fibrosis (F3) and within the 
last 12 months for subjects with cirrhosis (F4), to assess subject eligibility. 
d
Assess presence and severity of ascites and hepatic encephalopathy for CPT score (for Cohorts 7 and 8 only).
e
Symptom driven physical examination.
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' 
f o e co e.c.te. 
t 1ome an prov1 e. to t 1e site at e next v1s1t. 
m 
n 
Genomic Sample collected for subjects who have not opted out of sample collection. No additional blood will be drawn. 
Predose Kinetic Biomarkers (for Coho1ts 4-9) and 2 hom· (± 1 hour) post.dose Kinetic Biomarkers (for Coho1ts 5, 6, 7 and 9). 
Saliva Collection for Kinetic Biomarkers to be collected for Cohorts 1-3 only. 
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Appendix 2.
CTCTAE Grade for Laboratory Parameters
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Activated partial 
thromboplastin time 
(APTT) prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
-
-
Hypercalcemia
Corrected serum calcium of 
>ULN - 11.5 mg/dL; 
>ULN - 2.9mmol/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
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
CCI
CCI
CCI
CCI


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CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Chronic kidney disease
eGFR (estimated Glomerular 
Filtration Rate) or CrCl 
(creatinine clearance) 
<LLN – 60 ml/min/1.73 m2 or 
proteinuria 2+ present; urine 
protein/creatinine >0.5
eGFR or CrCl 
59 – 30 ml/min/1.73 m2
eGFR or CrCl 
29 – 15 ml/min/1.73 m2
eGFR or CrCl 
<15 ml/min/1.73 m2; dialysis 
or renal transplant indicated
Death
Creatinine increased
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN
>3.0 baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
-
Gamma-glutamyl 
transferase (GGT) 
increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Hyperglycemia 
Fasting glucose value 
>ULN - 160 mg/dL; Fasting 
glucose value 
>ULN - 8.9 mmol/L
Fasting glucose value 
>160 - 250 mg/dL; Fasting 
glucose value 
>8.9 - 13.9 mmol/L
>250 - 500 mg/dL; 
>13.9 - 27.8 mmol/L; 
hospitalization indicated
>500 mg/dL; >27.8 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
Hemoglobin increased
Increase in >0 - 2 gm/dL 
above ULN or above baseline 
if baseline is above ULN
Increase in >2 - 4 gm/dL 
above ULN or above baseline 
if baseline is above ULN
Increase in >4 gm/dL above 
ULN or above baseline if 
baseline is above ULN
 -
-


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Statistical Analysis Plan - Interim Analysis, Cohorts 1-9  
Version 1.0
CONFIDENTIAL
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01 August 2018
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
International normalized 
ratio (INR) increased
>1 - 1.5 x ULN; 
>1 - 1.5 times above 
baseline if on 
anticoagulation
>1.5 - 2.5 x ULN; 
>1.5 - 2.5 times above 
baseline if on anticoagulation
>2.5 x ULN; 
>2.5 times above 
baseline  if on anticoagulation
 -
-
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; 
life-threatening consequences
Death
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L; 
symptomatic; 
intervention Indicated 
<3.0 - 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; 
life-threatening consequences
Death
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
-
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
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
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
-
Hypophosphatemia
<LLN - 2.5 mg/dL; 
<LLN - 0.8 mmol/L
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 mmol/L
<2.0 - 1.0 mg/dL; 
<0.6 - 0.3 mmol/L
<1.0 mg/dL; <0.3 mmol/L; 
life-threatening consequences
Death
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
-
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L; 
hospitalization indicated
>160 mmol/L; life-threatening 
consequences
Death
Hyponatremia
<LLN - 130 mmol/L
-
<130 - 120 mmol/L
<120 mmol/L; life-threatening 
consequences
Death


GS-4997, GS-0976, GS-9674
GS-US-384-3914
Statistical Analysis Plan - Interim Analysis, Cohorts 1-9  
Version 1.0
CONFIDENTIAL
Page 47
01 August 2018
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Hyperuricemia
>ULN - 10 mg/dL 
(0.59 mmol/L) without 
physiologic consequences
-
>ULN - 10 mg/dL 
(0.59 mmol/L) with 
physiologic consequences
>10 mg/dL; >0.59 mmol/L; 
life-threatening consequences
Death
White blood cell (WBC) 
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
-
Note: Refer to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found at 
https://evs nci nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


GS-4997, GS-0976, GS-9674 
GS-US-384-3914 
Statistical Analysis Plan - Interim Analysis, Cohorts 1-9 
Appendix 3. 
Programming Specifications 
• 
MELD score calculation: 
Version 1.0 
MELD score = 3.8 [Ln total bilimbin (mg/dL)] + 11.2 [Ln INR] + 9.6 [Ln creatinine (mg/dL)] + 
6.43. Lab values less than 1 are set to 1. Round to integer. The lab parameters need to be 
measured from the same blood draw. 
I 
I 
I 
CONFIDENTIAL 
Page48 
01 August 2018 


GS-4997, GS-0976, GS-9674 
GS-US-384-3914 
Statistical Analysis Plan - Interim Analysis, Cohorts 1-9 
CONFIDENTIAL 
Page49 
Version 1.0 
01 August 2018