Conditions: Primary Biliary Cholangitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of cilofexor in adults with primary biliary cholangitis (PBC).

Detailed description:

Arms:
arm 1: Cilofexor 30 mg + placebo to match cilofexor 100 mg for 12 weeks. arm 2: Cilofexor 100 mg + placebo to match cilofexor 30 mg for 12 weeks. arm 3: Placebo to match cilofexor 30 mg + placebo to match cilofexor 100 mg for 12 weeks. arm 4: Following the Blinded Study Phase, eligible participants may have the option to receive open-label cilofexor 100 mg for an additional 96 weeks.

Interventions: intervention 1: Cilofexor intervention 2: Placebo to match cilofexor
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily, with food intervention 2: Tablet(s) administered orally once daily, with food

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in 
Subjects with Primary Biliary Cholangitis Without Cirrhosis
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
131032
2016-002443-42
NCT02943447
Indication:
Primary Biliary Cholangitis (PBC)
Protocol ID:
GS-US-427-4024
Gilead Medical 
Monitor:
Name:
Telephone:
Fax:
Email:
Protocol Version/Date:
Original:
29 June 2016
Amendment 1:
30 September 2016
Amendment 2:
21 December 2016
Amendment 3:    09 February 2017
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The information contained in this document, particularly unpublished data, is the property or 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.
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................14
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
GS-9674 .................................................................................................................................................18
1.2.1.
General Information .............................................................................................................18
1.2.2.
Nonclinical Toxicology........................................................................................................19
1.2.3.
Nonclinical Pharmacology ...................................................................................................20
1.2.4.
Nonclinical Pharmacokinetics..............................................................................................21
1.2.5.
Clinical Trials of GS-9674 ...................................................................................................22
1.3.
Rationale for this Study..........................................................................................................................25
1.4.
Risk/Benefit Assessment for the Study..................................................................................................26
1.5.
Compliance ............................................................................................................................................27
2.
OBJECTIVES.....................................................................................................................................................28
3.
STUDY DESIGN................................................................................................................................................29
3.1.
Study Design..........................................................................................................................................29
3.2.
Treatment Plan and Regimen .................................................................................................................30
3.3.
Biomarker Testing..................................................................................................................................30
3.3.1.
Biomarker Samples to Address the Study Objectives:.........................................................30
3.3.2.
Biomarker Samples for Optional Future Research...............................................................31
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................36
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................36
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................36
5.2.
Description and Handling of GS-9674 and PTM GS-9674....................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................37
5.2.3.
Storage and Handling...........................................................................................................37
5.3.
Dosage and Administration of GS-9674/PTM GS-9674........................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................38
5.5.
Prohibited Medications ..........................................................................................................................38
5.6.
Accountability for GS-9674/ PTM GS-9674 .........................................................................................39
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................40
6.
STUDY PROCEDURES ....................................................................................................................................41
6.1.
Subject Randomization and Treatment Assignment ..............................................................................41
6.2.
Pretreatment Assessments-Screening Visit ............................................................................................41
6.3.
Blinded Study Phase: Baseline/Day 1 Randomization and Assessments...............................................43


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6.4.
Treatment Assessments (Blinded Study Phase) .....................................................................................44
6.4.1.
Weeks 1, 2, 4 and 8 (± 3 days) .............................................................................................44
6.4.2.
Week 12 (± 3 days) ..............................................................................................................45
6.5.
Blinded Study Phase follow-up Visit (±5 days).....................................................................................47
6.6.
Open Label Extension (OLE) Phase (± 3 days for Weeks 1–12 and ± 5 days for Weeks 24-96) ..........48
6.7.
Unscheduled Visits.................................................................................................................................49
6.8.
OLE follow-up Visit (±5 days) ..............................................................................................................50
6.9.
Assessments for Premature Discontinuation from Study.......................................................................51
6.10.
Criteria for Discontinuation of Study Treatment....................................................................................51
6.11.
PK and PD Substudy Visits....................................................................................................................52
6.12.
Procedures and Specifications................................................................................................................52
6.12.1.
Clinical Laboratory Analytes ...............................................................................................52
6.12.2.
Medical History....................................................................................................................53
6.12.3.
Physical Examination...........................................................................................................53
6.12.4.
Quality of Life (QoL) Measures and Pruritus Assessments .................................................54
6.12.5.
Electrocardiogram................................................................................................................54
6.12.6.
FibroScan® ...........................................................................................................................54
6.12.7.
Magnetic Resonance Elastography.......................................................................................55
6.13.
End of Study...........................................................................................................................................55
6.13.1.
Sample Storage.....................................................................................................................55
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................56
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................56
7.1.1.
Adverse Events.....................................................................................................................56
7.1.2.
Serious Adverse Events........................................................................................................56
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................57
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................57
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................57
7.2.2.
Assessment of Severity ........................................................................................................58
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................58
7.4.
Gilead Reporting Requirements.............................................................................................................60
7.5.
Toxicity Management ............................................................................................................................60
7.6.
Special Situations Reports......................................................................................................................63
7.6.1.
Definitions of Special Situations..........................................................................................63
7.6.2.
Instructions for Reporting Special Situations.......................................................................64
8.
STATISTICAL CONSIDERATIONS................................................................................................................66
8.1.
Analysis Objectives and Endpoints........................................................................................................66
8.1.1.
Analysis Objectives..............................................................................................................66
8.1.2.
Primary Endpoint .................................................................................................................66
8.1.3.
Exploratory Endpoints..........................................................................................................67
8.2.
Analysis Conventions.............................................................................................................................68
8.2.1.
Analysis Sets ........................................................................................................................68
8.2.2.
Analysis by Study Phase ......................................................................................................69
8.3.
Data Handling Conventions ...................................................................................................................69
8.4.
Demographic Data and Baseline Characteristics ...................................................................................69
8.5.
Efficacy Analysis ...................................................................................................................................70
8.6.
Exploratory Analyses.............................................................................................................................70
8.7.
Safety Analysis.......................................................................................................................................70
8.7.1.
Extent of Exposure...............................................................................................................70
8.7.2.
Adverse Events.....................................................................................................................70
8.7.3.
Laboratory Evaluations ........................................................................................................71


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8.7.4.
Other Safety Evaluations......................................................................................................71
8.8.
Pharmacokinetic Analysis......................................................................................................................71
8.9.
Pharmacodynamics Analysis..................................................................................................................71
8.10.
Biomarker Analysis................................................................................................................................71
8.11.
Sample Size............................................................................................................................................72
8.12.
Data Monitoring Committee ..................................................................................................................72
9.
RESPONSIBILITIES..........................................................................................................................................73
9.1.
Investigator Responsibilities ..................................................................................................................73
9.1.1.
Good Clinical Practice..........................................................................................................73
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................73
9.1.3.
Informed Consent.................................................................................................................73
9.1.4.
Confidentiality......................................................................................................................74
9.1.5.
Study Files and Retention of Records ..................................................................................74
9.1.6.
Case Report Forms...............................................................................................................75
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................76
9.1.8.
Inspections............................................................................................................................76
9.1.9.
Protocol Compliance............................................................................................................76
9.2.
Sponsor Responsibilities ........................................................................................................................77
9.2.1.
Protocol Modifications.........................................................................................................77
9.2.2.
Study Report and Publications .............................................................................................77
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
9.3.1.
Payment Reporting...............................................................................................................77
9.3.2.
Access to Information for Monitoring..................................................................................78
9.3.3.
Access to Information for Auditing or Inspections ..............................................................78
9.3.4.
Study Discontinuation..........................................................................................................78
10.
REFERENCES ...................................................................................................................................................79
11.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table for GS-US-427-4024 .......................................................................83
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities .........................................................................................................................87
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................88


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LIST OF IN-TEXT TABLES
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure After 
Administration of 100 mg GS-9674 Under Fed Conditions in Cohort 5 Compared to 
Exposures Observed at NOAEL Doses in Mouse and Cynomolgus Monkey........................20
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of DDIs on Administration of 100 mg GS-9674 with Food (Cohorts 1-3)..................24
Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of GS-9674 100 mg with Food on CYP3A, OATP/CYP3A, P-gp, OATP, or 
OATP/BCRP (Cohorts 5-6)....................................................................................................25
Table 5-1.
List of Medications Prohibited and to be used with Caution..................................................39
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in 
Subjects with Primary Biliary Cholangitis Without Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
131032
2016-002443-42
NCT02943447
Study Centers 
Planned:
Approximately 40 centers in North America and Europe
Objectives:
The primary objective of this study is to evaluate the safety and 
tolerability of GS-9674 in subjects with primary biliary cholangitis 
(PBC)
The exploratory objectives of this study are listed in Section 2. 
Study Design:
This is a Phase 2 randomized, double-blind, placebo-controlled study 
evaluating the safety, tolerability, and efficacy of GS-9674 in subjects 
with PBC without cirrhosis.
The study will consist of 2 phases, a Blinded Study Phase and an 
Open Label Extension (OLE) Phase. 
Blinded Study Phase: Includes a 4 week screening period, 12 weeks 
of blinded treatment, and a Blinded Study Phase follow-up visit 
4 weeks after completion of blinded treatment. 
Subjects completing the Blinded Study Phase without permanently 
discontinuing study drug will be eligible to participate in the OLE 
Phase of the study.
OLE Phase:  Includes a 96 week OLE and an OLE Phase follow-up 
visit 4 weeks after completion of open label treatment. 
Participation in the Blinded Study Phase can last up to 20 weeks and 
the OLE Phase can last up to 100 weeks, thus total study duration can 
be up to 120 weeks. 


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Subjects meeting the study’s entry criteria will be randomly assigned 
in a 2:2:1 ratio to 1 of 3 treatment groups during the Blinded Study 
Phase as shown in the figure below:
Randomization will be stratified by the presence or absence of 
ursodeoxycholic acid (UDCA) use. 
Number of Subjects 
Planned:
Approximately 75 subjects
Target Population:
Males and non-pregnant females between 18-70 years of age with 
PBC without cirrhosis
Duration of 
Treatment:
Total study duration of up to 120 weeks with up to 20 weeks for the 
Blinded Study Phase and up to 100 weeks for the OLE Phase.
Diagnosis and Main 
Eligibility Criteria:
Key inclusion and exclusion criteria are as follows:
Inclusion Criteria

Meets all of the following conditions;
a) Definite or probable PBC as defined by at least 2 of the 3 
following criteria:
i. Serum alkaline phosphatase (ALP) > the upper limit of 
normal (ULN)
ii. Presence of anti-mitochondrial antibodies (AMA) in 
serum (≥ 1:40 on immunofluorescence)


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iii.
Liver histological findings consistent with PBC 
including nonsuppurative, destructive cholangitis 
affecting mainly the interlobular bile and septal bile 
ducts;
b) Serum ALP >1.67 x ULN and/or total bilirubin >ULN but 
≤2x ULN;
c) UDCA use at a stable dose for at least 12 months prior to 
screening through the end of treatment or intolerant of 
UDCA with no UDCA use for at least 12 months before 
screening through the end of treatment;

Screening FibroSURE/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, 
FibroSURE/FibroTest® will be calculated using direct 
bilirubin instead of total bilirubin. 
Exclusion Criteria

ALT > 5x ULN;

Total bilirubin > 2x ULN;

INR >1.2 unless on anticoagulant therapy;

Other causes of liver disease including viral, metabolic, alcoholic, 
and other autoimmune conditions. Subjects with hepatic steatosis 
may be included if there is no evidence of nonalcoholic 
steatohepatitis (NASH) in the opinion of the investigator or on 
liver biopsy;

Use of fibrates or obeticholic acid within 3 months prior to 
screening through the end of treatment;

Cirrhosis of the liver as defined by any of the following:
a) Historical liver biopsy demonstrating cirrhosis (e.g. Ludwig 
stage 4 or Ishak stage ≥5) 
b) History of decompensated liver disease, including ascites, 
hepatic encephalopathy or variceal bleeding
c) Liver stiffness >16.9 kPa by FibroScan®.
Please refer to section 4.2 and 4.3 of the protocol for detailed 
inclusion and exclusion criteria. 


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Study Procedures/
Frequency:
Blinded Study Phase
After signing the informed consent form, subjects will complete a 
screening visit which will include the following assessments: 
complete medical history, complete physical examination (PE), vital 
signs (heart rate, systolic and diastolic blood pressure, respiratory 
rate, and body temperature), cirrhosis assessments, laboratory 
assessments (blood chemistry, hematology, coagulation panel, and 
biomarkers), serum pregnancy test (for females of childbearing 
potential), urine drug test, review of adverse events (AEs) related to 
screening procedures, and concomitant medications (CMs). 
After the screening period, visits will occur at Baseline/Day 1, 
Weeks 1, 2, 4, 8, and 12. At minimum, vital signs, symptom-driven 
physical examination (PE), safety laboratory tests (blood chemistry, 
hematology, and coagulation panel), review of adverse events and 
concomitant medications will be done at every visit.
 
 
Eligible subjects will be randomized to one of three treatment groups 
of the Blinded Study Phase. Prior to initial dosing, required 
Baseline/Day 1 assessments will be performed and will include 
symptom-driven PE, vital signs, laboratory assessments, pregnancy 
tests (for females of child-bearing potential), urine, blood, and stool 
collection for biomarker assessments, pruritus assessments and 
Quality of Life (QoL) questionnaires, standard 12-lead ECG, 
FibroScan® (if available), review of AEs and CMs. 
 
 
 
 
 
While on study, subjects will undergo the following procedures and 
laboratory assessments:

Symptom-directed physical examination and vital signs, at 
Baseline/Day 1 and at Week 1, 2, 4, 8 and 12

Height at Baseline/Day 1 and weight at all visits  

FibroScan® (if available) at Baseline/Day 1 and Week 12

12-lead ECGs at Baseline/Day 1 and Week 12 

C-peptide, insulin and hemoglobin A1c (HbA1c) at Baseline/Day 
1 and Week 12
PPD
PPD


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
PK and PD sampling at Baseline/Day 1 (PD only) and at Weeks 
1, 2, 4, 8 and 12 

Blood for Biomarker assessments at Baseline/Day 1 and at Weeks 
1, 4, and 12 

Urine Biomarker collection at Baseline/Day 1 and at Weeks 1, 4,
and 12

Urine pregnancy testing (females of childbearing potential only) 
at Baseline/Day 1 and Weeks 1, 4, 8 and 12

Stool collection at Baseline/Day 1 and Week 12

Hematology, blood chemistry, coagulation panel (PT, PTT, INR) 
and fasting lipid profile at Baseline/Day 1 and Weeks 1, 2, 4, 8, 
and 12 

QoL Questionnaires: PBC-40 and  SF-36 at Baseline/Day 1 and 
Week 12 

Pruritus Assessments: Pruritus visual analog scale (VAS) and 
5D-Itch at Baseline/Day 1 and Weeks 1, 2, 4, 8, and 12
At the Blinded Study Phase follow-up visit, subjects will have a 
symptom-driven PE, vital signs, laboratory assessments, urine 
pregnancy tests (for females of childbearing potential), urine, stool 
and blood collection for biomarker assessments, QoL and pruritus 
questionnaires (PBC-40, SF-36, Pruritus VAS and 5D-Itch), weight, 
review of AEs, and review of CMs and serum will be drawn for 
hematology, blood chemistry, and a coagulation panel. 
Subjects will be unblinded to their Blinded Study Phase treatment 
assignment after the primary analysis has been completed, 
approximately 6 weeks after all subjects have completed the Blinded 
Study Phase.
During the Blinded Study Phase early termination (ET) visit, subjects 
who prematurely discontinue participation will complete Week 12 
assessments and will also complete the Blinded Study follow-up visit 
4 weeks after their last dose if possible.  
Open-Label Extension (OLE) Phase
Subjects who do not permanently discontinue study drug and 
complete the Blinded Study Phase follow-up visit will be eligible to 
enter into the OLE Phase of the study for 96 weeks. Subjects will 
begin open-label treatment with GS-9674 (100 mg po once daily).
The dose of GS-9674 may be reduced from 100 mg to 30 mg (or 
subsequently increased back to 100 mg) at the PI’s discretion with the 
approval of the Medical Monitor (MM), if required. In the OLE 
Phase, subjects will have in-clinic study assessments at OLE


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Baseline/Day 1, OLE Week 1, OLE Week 2, OLE Week 4, OLE 
Week 8, OLE Week 12, and every 12 weeks thereafter for 
symptom-driven PE, vital signs, laboratory assessments, urine 
pregnancy tests (for females of childbearing potential at OLE 
Baseline/Day 1 and every 4 weeks thereafter), urine, 
stool and blood collection for biomarker assessments (at OLE 
Baseline/Day 1, Weeks 4, 12 and every 12 weeks thereafter), QoL 
(PBC-40, SF-36 at OLE Baseline/Day 1, Weeks 4, 12 and every 
12 weeks thereafter) and pruritus questionnaires (Pruritus VAS and 
5D-Itch), weight, review of AEs and review of CMs.
Subjects in the OLE Phase will complete the treatment Week 96 visit 
and then return for their final visit, the OLE follow-up visit 4 weeks 
following the last dose of study drug. Subjects who prematurely 
discontinue participation in the OLE Phase will complete the 
Week 96 assessments and will also complete the follow-up visit 4
weeks after their last dose if possible.  
At the OLE follow-up visit, subjects will have a symptom-driven PE, 
measurement of vital signs, review of AEs, CMs, pruritus and 
assessment and serum will be drawn for hematology, blood 
chemistry, lipids, and a coagulation panel. A urine pregnancy test will 
be performed for females of childbearing potential only.
Test Product: 
GS-9674 30 mg tablet administered orally once daily with food.
GS-9674 100 mg tablet administered orally once daily with food.
Reference Product:
Placebo-to-match (PTM) GS-9674 30 mg tablet administered orally 
once daily with food.
Placebo-to-match (PTM) GS-9674 100 mg tablet administered orally 
once daily with food.
Dose and Mode of 
Administration:

Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet) + PTM 
GS-9674 100 mg (1 x PTM 100 mg tablet) administered orally 
once daily with food.

Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + 
PTM GS-9674 30 mg (1 x PTM 30 mg tablet) administered orally 
once daily with food.

Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg 
tablet) + PTM GS-9674 100 mg (1 x PTM 100  mg tablet) 
administered orally once daily with food.


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Criteria for 
Evaluation:
Safety:
The primary endpoint is the safety of GS-9674 in subjects with PBC 
without cirrhosis.
Safety will be assessed during the study through the reporting of AEs, 
and by clinical laboratory tests and vital sign assessments at various 
time points during the study. Concomitant medication usage will also 
be assessed throughout the study.
An independent, external Data Monitoring Committee (DMC) that 
consists of two hepatologists and a PhD statistician will convene once 
20 subjects have been randomized and every 3 to 4 months thereafter 
to monitor the study for safety events in the Blinded Study Phase and 
every 6 months in the OLE Phase . The DMC will meet on an ad hoc 
basis if there are at least 3 similar Grade ≥ 3 serious, treatment related 
Common Terminology Criteria for Adverse Events (CTCAE) 
observed in the study. In the event of two similar treatment related 
Grade 4 CTCAE events or one treatment related Grade 5 CTCAE, the 
DMC will review the data and advise the sponsor regarding stopping 
or continuing the study.
Efficacy:
Efficacy will be assessed through a number of exploratory endpoints. 
These exploratory endpoints are described in Section 8.1.3.
Pharmacokinetic and 
Pharmacodynamic:
Plasma concentrations of GS-9674, GS-716070 (metabolite of 
GS-9674), and other metabolites as appropriate, will be determined 
for PK analyses as applicable. Plasma or serum concentrations of 
FGF19, C4, and bile acids will be determined as applicable for PD 
analyses.
Statistical Methods:
Safety Analysis: 
All safety data collected will be listed and summarized, as 
appropriate, by treatment group.
Efficacy Analysis:
The biological and histological activity of study drugs will be 
evaluated using histologic endpoints and biomarker variables. 
Because efficacy endpoints will be evaluated for exploratory 
purposes, formal statistical comparisons will not be made for these 
endpoints. Ninety-five percent confidence intervals (95% CI) will be 
provided if applicable.
Exploratory 
Analysis:
 
 
 
PPD


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Sample Size:
Due to the exploratory nature of this study, no formal power 
calculations were used to determine sample size. The number of 
subjects was chosen based on clinical experience with other similar 
proof of concept studies.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AMA
anti-mitochondrial antibodies
Apo B
apolipoprotein B
aPTT
activated partial thromboplastine time
AST
aspartate aminotransferase
ATV
atorvastatin
ATP
Adenosine triphosphate
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration 
versus time curve
-hCG
beta human chorionic gonadotropin
BAP
Biomarker Analysis Plan
BCRP
breast cancer resistance protein
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CFR
code of federal regulations
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
CMs
concomitant medications
CNS
central nervous system
CRO
contract (or clinical) research organization 
CTCAE
Common Terminology Criteria for Adverse Events
CSR
clinical study report
DAB
metabolite of dabigatran etexilate
DDI
drug-drug interaction
DE
dabigatran etexilate
CYP3A
cytochrome P4503A
CV
Cardiovascular
CsA
cyclosporin
DDI
drug-drug interaction
DILI
drug induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid


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DSPH
Drug Safety and Public Health
EC50
Concentration of drug that gives half-maximum response
ECG
Electrocardiogram
ET
early terminated
eCRF
electronic case report form
EDC
electronic data capture
e.g.
Example
ELF™Test
enhanced liver fibrosis test
EU
European Union
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FSH
Follicle-stimulating hormone
FGF
Fibroblast growth factor
FXR
Farnesoid X Receptor
GCP
good clinical practice
GCSF
granulocyte colony stimulating factor
GFZ
gemfibrozil
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
Hct
Hematocrit
HDPE
High-density polyethylene
HCV
Hepatitis c virus
Hg
Hemoglobin
HIV
Human immunodeficiency virus
HLT
high-level term
HLGT
high-level group term
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HOMA-IR
homeostatic assessment of insulin resistance
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
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board


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IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
LDH
lactate dehydrogenase
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
g
Microgram
mg
Milligram
min
Minute
mL
Milliliter
MDZ
midazolam
mm
Millimeter
mm Hg
millimeters of mercury
MM
MRE
Medical Monitor
Magnetic Resonance Elastography 
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NTCP
sodium-taurocholate cotransporting polypeptide
NMR
nuclear magnetic resonance spectroscopy
NOAEL
no observed adverse event level
OATP
Organic anion-transporting polypeptide
OLE
Open Label Extension
PRA
pravastatin
PBC
Primary Biliary Cholangitis
PBMCs
peripheral blood mononuclear cell(s)
PD
Pharmacodynamic
PK
Pharmacokinetic
P-gp
P-glycoprotein
PO
taken by mouth
PSC
Primary Sclerosing Cholangitis
PT
preferred term
PT
prothrombin time
PTT
Partial prothrombin time
QoL
Quality of Life
RBC
red blood cell count
RIF
rifampin
RNA
ribonucleic acid
RXR
Retinoid X receptor
SADR
serious adverse drug reaction
SAE
serious adverse event


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SAP
statistical analysis plan
SF-36
Short Form (36) Health Survey
SD
standard deviation
SOC
System Organ Class
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
Time required for the terminal elimination half-life of the drug
TEAEs
Treatment emergent adverse events
TGR5
bile acid receptor
TPO
thrombopoietin
TR-FRET
Time-resolved fluorescence resonance energy transfer
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
UDCA
ursodeoxycholic acid
UGT
uridine dophosphate glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
USPI
United States product insert
Vss
Volume of distribution at steady state
VAS
visual analog scale
VORI
voriconazole
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Primary Biliary Cholangitis (PBC) is a disorder of unknown etiology characterized by 
lymphocytic cholangitis and intralobular bile duct destruction that result in the impairment of 
bile flow (cholestasis). According to a recent systematic review {Boonstra 2012}, the incidence 
rate for PBC has ranged from 0.33 to 5.8 per 100,000 inhabitants/year and the prevalence has 
ranged from 1.91 to 40.2 per 100,000 inhabitants. PBC disproportionately affects women as over 
90% of patients diagnosed with PBC are female and are generally between the fifth and seventh 
decades of life. Several studies {Boonstra 2014, Hamlyn 1983, Metcalf 1997} with available data for 
several consecutive years have demonstrated an increasing prevalence of PBC over time.
The pathophysiology of PBC is complex and is likely related to interplay between genetic and 
environmental factors. Genetics play an important role as evidence by first degree relatives of 
patients with PBC having an increased risk of developing the disease with daughters of women 
with PBC having the highest risk {Gershwin 2005}. Studies including genome wide association 
have implicated HLA alleles, as well as immune pathways involving antigen presentation, T-cell 
differentiation and natural-killer T-cells in the pathogenesis of PBC {Carbone 2014}. Biliary 
epithelial cells are targeted in PBC and may amplify the immune response by acting as antigen 
presenting cells {Selmi 2009}. The autoimmune destruction of biliary epithelial cells leads to 
cholestasis and resulting liver injury. 
Cholestasis results in increased hepatic and serum bile acids and eventually to liver toxicity, 
fibrosis, and cirrhosis {Woolbright 2012}. Increasing concentrations of bile acids including via 
bile duct ligation or direct administration to cultured hepatocytes are frequently used models for 
hepatotoxicity. While the exact mechanism of bile acid induced hepatotoxicity remains to be 
elucidated, bile acids have been shown to increase apoptosis, hepatic inflammation, and necrosis. 
Reduction of toxic bile acids with UDCA {Hirschfield 2015} or by agonism of the farnesoid X 
receptor (FXR) {Hirschfield 2015} has been shown to be protective both in models of cholestatic 
liver disease as well as in patients with PBC.
1.2.
GS-9674
1.2.1.
General Information
GS-9674 is a potent agonist of Farnesoid X Receptor (FXR) whose activity in intestinal 
epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is an 
endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. 


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Please refer to the Investigator’s Brochure (IB) for additional information on GS-9674 including:

In Vitro FXR agonism

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology
1.2.2.
Nonclinical Toxicology
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally up to 26 and 39 weeks, respectively. GS-9674-related effects were 
primarily limited to non-adverse findings in the liver for both species that are likely related to the 
pharmacology of the compound. Mild increases in alkaline phosphatase (ALP) activity and liver 
weights were observed in the 4 week and chronic (26 or 39 week) studies. In the 4-week studies 
and 26-week mouse study, these findings were associated with hepatocellular hypertrophy (both 
species) and minimal oval cell hyperplasia (monkeys). In the chronic monkey study, there were 
no correlating histological changes in the liver after 39 weeks of dosing. The above findings 
were observed at ≥100 mg/kg/day after 4 weeks of dosing and at all doses (≥20mg/kg/day) after 
26 weeks of dosing in mice. In monkeys, the above findings were observed at doses of 300 
mg/kg/day after both 4 and 39 weeks of dosing. The decreases in cholesterol (≥60 mg/kg/day) 
and triglycerides (≥100 mg/kg/day) as well as increased albumin (≥60 mg/kg/day) observed in 
mice after 4 and/or 26 weeks of dosing as well as the decrease in serum bile acids (300 
mg/kg/day) in monkeys 39 weeks of dosing are also likely to be related to the pharmacology of 
GS-9674. Other minimal to mild, non-adverse findings observed after 26 or 39 weeks of dosing 
in mice or monkeys, respectively, that were considered GS-9674-related included decreased red 
blood cell parameters (mouse; ≥20 mg/kg/day), increased platelets (mouse; 600/300 mg/kg/day), 
shortened activated partial thromboplastin time (monkey; 300 mg/kg/day), and increased 
phosphorus (mouse; 600/300 mg/kg/day). All findings showed evidence of reversibility after a
4-week recovery period. The no-observed-adverse effect levels (NOAEL) in mice after 26 weeks 
of dosing and in monkeys after 39 weeks of dosing were 60 and 300 mg/kg/day, respectively. 
Preliminary PK data from Cohort 5 (administration of GS-9674 100 mg with food) in the 
ongoing Phase 1 study of GS-9674 (GS-US-402-1851: included in IB) indicate adequate safety 
margins based on GS-9674 exposures at the nonclinical NOAEL doses in mouse and 
cynomolgus monkey (Table 1-1).


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Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 
Exposure After Administration of 100 mg GS-9674 Under Fed
Conditions in Cohort 5 Compared to Exposures Observed at NOAEL 
Doses in Mouse and Cynomolgus Monkey 
Species
NOAEL
Exposure Margina
Dose 
mg/kg/day
AUCtau
µg*hr/mL
Mouse
60
Male: 66
Female: 110
Male: 13
Female: 22
Cynomolgus Monkey
300
163
32
a
Calculated using observed human AUCinf of 5.02 µg*hr/mL at 100 mg QD dose administered fed from cohort 5 in Study 
GS-US-402-1851.
1.2.3.
Nonclinical Pharmacology
GS-9674 is a potent and selective agonist of FXR. This conclusion is supported by the following 
data: 1) modeling demonstrated an interaction of GS-9674 with the binding domain of FXR 
consistent with agonist activity, 2) GS-9674 induced an agonist response in a time-resolved 
fluorescence resonance energy transfer (TR-FRET) biochemical assay with an EC50 of 16 nM, 
which was comparable to that of other known FXR agonists, and 3) GS-9674 did not activate the 
structurally similar bile acid receptor TGR5, did not activate other nuclear hormone receptors, 
and did not bind to a panel of other off-target receptors and enzymes.
The cellular potency of GS-9674 to activate FXR-mediated transcription was characterized using 
a firefly luciferase reporter gene engineered under the control of a FXR/Retinoid X receptor 
(RXR) response element (PC-402-2012). GS-9674 caused complete FXR activation with an EC50
value of 43 nM, which was more potent than chenodeoxycholic acid (EC50 of 1770 nM).
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in
plasma FGF19 at a dose of 5 mg/kg (PC-402-2016). In addition, the oral administration of 
GS-9674 (30 mg/kg) to cynomolgus monkeys directly activated intestinal FXR, as measured by 
the expression of FXR-target genes in the ileum (15-fold increase in FGF19 mRNA, and a 2-fold 
increase in organic solute transporter (OSTα and OSTβ mRNA) (PC-402-2005).
The effects of GS-9674 on FGF19 levels were compared in cynomolgus monkeys following both 
oral and intravenous (IV) administration (PC-402-2016). Despite greater exposures following IV 
administration, only the oral administration of GS-9674 increased circulating FGF19 levels. 
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.
GS-9674 was evaluated in a choline-deficient high fat diet /NaNO2 rat model of liver fibrosis 
(PC-402-2015). This in vivo model utilized “2 hits” to mimic the metabolic and oxidative stress 
components of NASH disease in humans {Murakami 2013, Nakamoto 2009}. Treatment with 


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GS-9674 dose-dependently reduced both biochemical and histological measures of liver fibrosis 
in this model.
Safety pharmacology studies have been conducted to examine the potential effects of GS-9674 
on the cardiovascular (CV), respiratory, and central nervous system (CNS) systems. There were 
no GS-9674-related effects on the CNS or respiratory system in mice administered up to 
600 mg/kg. In addition, there was no significant human ether-a-go-go-related gene inhibition at 
concentrations up to 100 μM or GS-9674-related effects on the CV system in monkeys 
administered up to 300 mg/kg. 
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 PBC patients by inducing FGF19 
production.
1.2.4.
Nonclinical Pharmacokinetics
GS-9674 has shown low oral bioavailability in nonclinical species (approximately 10% and 20% 
when dosed as partially crystalline zwitterion or tromethamine salt, respectively). Low, 
pH-dependent solubility and efflux transport have been identified as factors likely limiting 
GS-9674 absorption. 
The low systemic clearance (CL) of GS-9674 in rats, dogs and monkeys was considerably lower 
than the predicted hepatic clearance based on in vitro studies with hepatocytes. This discrepancy 
is most likely a result of protein-restricted clearance in vivo due to the very high plasma protein 
binding (> 99.6%) across species. The volume of distribution (Vss) of GS-9674 was consistent 
with extracellular fluid (ranging from 0.16-0.21 L/kg) in rats, dogs, and monkeys.
After oral dosing to albino and pigmented mice, [14C] GS-9674-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. Generally similar distribution patterns and 
tissue concentrations of [14C]GS-9674-derived radioactivity were observed in albino and 
pigmented mice with no observed binding to melanin. In both strains, no quantifiable 
radioactivity was detected in brain, suggesting [14C] GS-9674-derived radioactivity did not cross 
the blood-brain barrier. Fecal elimination was a predominant route of elimination of [14C]
GS-9674-derived radioactivity in both mice (85.7% and 5.45% recovered in feces and urine, 
respectively) and monkeys (78.2% and 69.7% recovered in feces in intact and bile duct 
cannulated animals) likely representing drug not absorbed from the gastrointestinal tract. 
Approximately 6% of the administered radioactivity was excreted in bile and urine in monkeys. 
Radiolabeled material was primarily excreted within the first 48 hours.
GS-9674 undergoes oxidative metabolism in human hepatocytes. Comparison of metabolism in 
hepatocytes from mice, rats, dogs, monkeys, and humans did not identify any metabolites unique 
to humans, supporting the selection of mice and monkeys for the assessment of the toxicology of 
GS-9674. Of the recombinant human CYP isozymes tested, CYP2C8, CYP3A4, and CYP2C19 
were shown to metabolize GS-9674. Potent inhibitors of these CYPs therefore may affect 
metabolism of GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, 


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CYP2B6, CYP2C19 or CYP2D6 (IC50 > 25 μM). For CYP2C8, CYP2C9, and CYP3A, IC50
values of 2.4 to 13.6 μM were obtained but 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 pump (IC50 2.8-7.7 μM). GS-9674 
inhibited human OATP1B1, OATP1B3, and OATP2B1 with IC50 values of 0.68, 0.41, and 
0.21 μM, respectively. GS-9674 therefore has the potential to affect hepatic/intestinal uptake of 
OATP substrates or metabolism of CYP2C8, CYP2C9, or CYP3A4 substrates when its 
concentrations are sufficiently high. However, low solubility, high protein binding (> 99.98%) 
and low systemic levels reduce the potential for GS-9674 to cause drug-drug interactions via 
inhibition of metabolic enzymes and transporters.
GS-9674 was a substrate for efflux transporters P-glycoprotein and breast cancer resistance 
protein, as well as the 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. This was illustrated in an in vivo study in monkeys where 
pretreatment with cyclosporin A, a known inhibitor of efflux transporters, increased the 
bioavailability of GS-9674 approximately 5-fold.
GS-9674 is highly selective for FXR over other nuclear hormone receptors in cell-based reporter 
assays, including those associated with potential for induction of human drug metabolizing 
enzymes and transporters (eg, pregnane X receptor, constitutive androstane receptor). Thus the 
liability of GS-9674 to cause drug-drug interactions through proteins regulated by these nuclear 
receptors is low.
1.2.5.
Clinical Trials of GS-9674
As of 23 Sept 2016, 4 Phase 1 clinical studies are ongoing (GS-US-402-1851, GS-US-402-3885, 
GS-US-402-2102, and GS-US-402-2101), and 4 Phase 2 studies in subjects with NAFLD, 
NASH, PBC, and PSC are ongoing or planned (GS-US-384-3914, GS-US-402-1852, 
GS-US-427-4024, and GS-US-428-4025, respectively). These Phase 1 and 2 studies are 
described in the IB.
A brief summary of preliminary results, not included in the IB from ongoing study GS-US-402-
2102 is presented below.
1.2.5.1.
GS-US-402-2102
Study GS-US-402-2102 is an ongoing Phase 1, open-label, multicenter, multiple-cohort study 
designed to evaluate transporter and CYP-mediated drug-drug interactions (DDIs) between 
GS-9674 100 mg and various probe drugs in healthy subjects. A total of approximately 180 
subjects are planned to be enrolled.


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Preliminary PK results from the following cohorts are presented below and in Table 1-2 and 
Table 1-3:

Cohort 1: Impact of OATP/MRP2/P-gp inhibition (single dose cyclosporine 600 mg: CsA) or 
OATP1B1/1B3 inhibition (single dose rifampin 600 mg: RIF) on single dose administration 
of GS-9674 100 mg with food (N=24).  Single doses of CsA or RIF significantly increased 
GS-9674 exposure (6.5- and 8.0-fold respectively), with more modest increases in 
GS-716070 exposure (3.3- and 4.9-fold respectively).These data indicate the GS-9674 is a 
sensitive substrate of hepatic OATP with intestinal P-gp playing a minimal to no role in 
GS-9674 absorption as seen by a smaller increase in GS-9674 by CsA compared to single 
dose RIF.  Based on these data coadministration of GS-9674 with potent inhibitors of OATP 
is not recommended and moderate inhibitors of OATP should be used with caution whereas 
GS-9674 may be coadministered with P-gp inhibitors.

Cohort 2: Impact of CYP3A inhibition (multiple dose voriconazole 200 mg BID 4 days: 
VORI) and CYP2C8 inhibition (multiple dose gemfibrozil 600 mg BID 4 days: GFZ) on 
single dose administration of GS-9674 100 mg with food (N=18).  Coadministration of 
GS-9674 with VORI did not result in clinically meaningful changes in GS-9674 or 
GS-716070 exposures indicating that CYP3A plays a minimal role in the disposition of 
GS-9674 and GS-716070.  As such, GS-9674 may be coadministered with CYP3A 
inhibitors. Coadministration of GS-9674 with GFZ increased GS-9674 exposure 75% with 
reduction of GS-716070 exposure by 55% indicating that biotransformation of GS-9674 to 
GS-716070 is predominantly mediated by CYP2C8.  Based on the less than 2-fold increase 
in GS-9674 exposure, GS-9674 may be coadministered with inhibitors of CYP2C8.

Cohort 3: Impact of CYP3A/2C8/OATP/P-gp induction (multiple dose rifampin 600 mg QD 
7 days in the evening: RIF) on single dose AM administration of GS-9674 100 mg with 
food(N=18).  Plasma exposure of GS-9674 and GS-716070 were substantially reduced after 
multiple dose administration of RIF indicating that GS-9674 and GS-716070 are sensitive to 
induction of OATP and CYP2C8.  As such coadministration of GS-9674 with potent or 
moderate inducers of OATP or CYP2C8 is not recommended.

Cohort 5: Impact of single dose administration of GS-9674 100 mg with food on CYP3A 
activity (single dose midazolam: MDZ) or OATP/CYP3A activity (single dose atorvastatin: 
ATV) (N=24).  GS-9674 did not alter MDZ exposure (90%CIs of the %GMR for AUC and 
Cmax were contained within the predetermined lack of effect bounds of 70-143%) indicating 
that GS-9674 is not an inhibitor of CYP3A. As such GS-9674 may be coadministered with 
CYP3A substrates.  GS-9674 modestly increased ATV exposure (39%).  Similar increases in 
ATV exposure do not necessitate a priori dose modification as per the LIPITOR® United 
States product insert (USPI). As such, ATV may be coadministered with GS-9674.


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
Cohort 6: Impact of single dose administration of GS-9674 100 mg with food on P-gp (single 
dose dabigatran etexilate 75 mg: DE), OATP (single dose pravastatin 40 mg: PRA) or 
OATP/BCRP (single dose rosuvastatin 10 mg: ROS) (N=24). GS-9674 did not alter DE (free 
or total dabigatran: DAB metabolite of DE), PRA, or ROS exposures (90%CIs of the %GMR 
for AUC and Cmax were contained within the predetermined lack of effect bounds of 
70-143%) indicating the GS-9674 is not an inhibitor of P-gp, OATP, or BCRP.  As such 
GS-9674 may be coadministered with P-gp, OATP, or BCRP substrates.
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of DDIs on Administration of 100 mg GS-9674 
with Food (Cohorts 1-3)
%GMR (90%CI) Test/Reference
Cohort 1 (N=24)
Cohort 2 (N=18)
Cohort 3 (N=18)
Analyte
PK 
Parameter
CsA
RIFa
VORI
GFZ
RIFb
GS-9674
AUCinf
655 
(577, 743)
796
(719, 880)
95.9
(81.0, 114)
175
(149, 206)
32.8
(27.9, 38.4)
Cmax
512
(448, 584)
547
(497, 603)
76.8
(60.2, 97.9)
139
(115, 168)
35.5
(29.1, 43.3)
GS-716070
AUCinf
331
(297, 369)
493
(442, 551)
129
(109, 154)
44.5
(38.7, 51.1)
12.6
(10.5, 15.0)
Cmax
211
(191, 232)
301
(274, 331)
99.2
(81.1, 121)
31.2
(26.1, 37.4)
17.0
(13.7, 21.2)
Data are presented to 3 significant digits
a
Single Dose
b
Multiple Dose


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Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of GS-9674 100 mg with Food on CYP3A, 
OATP/CYP3A, P-gp, OATP, or OATP/BCRP (Cohorts 5-6)
Cohort
Enzyme/ 
Transporter
Analyte
PK Parameter
Test
Reference
% GMR 
(90%CI) 
Test/Reference
5 
(N=24)
CYP3A
MDZ
AUCinf
37.3 (27.5)
63.9 (29.1)
102 (95.8, 108)
Cmax
7.79 (27.6)
7.92 (35.6)
100 (94.8, 106)
OATP/
CYP3A
ATV
AUCinf
15.5 (33.5)
10.8 (39.0)
139 (124, 156)
Cmax
1.06 (35.6)
0.98 (35.9)
107 (94.6, 120)
6
(N=24)
P-gp
Total 
DAB
AUCinf 
624 (32.0)
535 (34.3)
118 (109, 128)
Cmax 
84.4 (40.0)
68.0 (37.8)
125 (112, 139)
Free 
DAB
AUCinf 
543 (32.0)
477 (37.3)
116 (108, 124)
Cmax 
75.0 (39.6)
60.8 (42.5)
125 (114, 138)
OATP
PRA
AUCinf 
109 (55.6)
99.6 (66.7)
115 (104, 126)
Cmax 
41.7 (58.8)
42.4 (66.5)
104 (91.5, 117)
OATP/ 
BCRP
ROS
AUCinf 
38.3 (40.3)
34.9 (39.5)
111 (101, 121)
Cmax 
3.06 (40.4)
2.86 (43.4)
108 (98.3, 119)
Data are presented as mean (%CV) to three significant 
1.3.
Rationale for this Study
PBC is an autoimmune disorder characterized by lymphocytic cholangitis and intralobular bile 
duct destruction that result in the impairment of bile flow (cholestasis). Accumulation of excess 
bile acids causes hepatocellular cytotoxicity that may lead to progressive liver fibrosis, including 
cirrhosis in some patients. In pre-clinical and clinical studies, FXR agonism has been shown to 
reduce bile acid levels via FGF19-mediated suppression of cholesterol-7-hydroxylase 
(CYP7A1), the rate-limiting enzyme in bile acid biosynthesis {Inagaki 2005, Mudaliar 2013, 
Pellicciari 2002}. In addition, in a murine model of fibrosis caused by administration of a
methionine choline deficient diet and sodium nitrite injections, GS-9674 has demonstrated an 
anti-fibrotic effect. Clinical data with obeticholic acid, a semi-synthetic analog of the primary 
bile acid chenodeoxycholic acid (CDCA) which activates FXR, has also demonstrated 
improvements in liver biochemistry in subjects with PBC supporting the potential of FXR 
agonists in this condition {Hirschfield 2015}. Thus, GS-9674 is postulated to be beneficial in 
subjects with PBC. 
This study will evaluate the safety, tolerability, and efficacy of 30 mg and 100 mg GS-9674 
administered with food for 12 weeks in subjects with PBC. The doses were selected based on 
short-term safety, PD and PK results from Study GS-US-402-1851 in healthy subjects. 
Across the range of GS-9674 doses evaluated (10 to 300 mg QD), doses > 30 mg provide 
comparable intestinal FXR agonism assessed by increases in plasma FGF19 exposure. Food, by 


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slowing oral absorption of GS-9674, results in prolonged elevation of plasma FGF19 
concentrations. Exposure-response relationships show that changes in C4 exposure are 
negatively correlated with changes in FGF19 exposure as well as GS-9674 exposure. Based on 
these results, GS-9674 doses of 30 and 100 mg with food are selected for further study as they 
are expected to 1) provide enteral FXR agonism, reductions in bile acid pools, and liver 
biochemical improvements in subjects with PBC; and 2) inform regarding the impact of 
increasing systemic GS-9674 exposure on safety and efficacy.
In the Phase 1 study, GS-US-402-1851, GS-9674 was tested at doses up to 300 mg once daily for 
up to 14 days and was well-tolerated. Taken together, these data support the evaluation of 
GS-9674 30 and 100 mg in subjects with PBC.
Inclusion criteria for this study were developed to identify subjects with PBC who have 
persistently abnormal liver biochemistry despite treatment with UDCA and subjects intolerant of 
UDCA. Compared with individuals with normal liver biochemistry, these subjects are at an 
increased risk of PBC-related complications including the need for liver transplantation and 
death {Carbone 2016, Corpechot 2008, Lammers 2015}. Subjects with clinical and histologic 
evidence of cirrhosis will be excluded from this study due to the uncertain PK and PD properties 
of GS-9674 to the setting of subjects with cirrhosis. Targeting interventions in the proposed 
study population will provide evidence for the safety and efficacy of GS-9674 in subjects at risk 
for progressive hepatic fibrosis and cirrhosis.
1.4.
Risk/Benefit Assessment for the Study
This study will provide information on the safety and efficacy of GS-9674 for the treatment of
patients with PBC. Alternate therapies for the treatment of PBC include UDCA and obeticholic 
acid. The potential benefits of GS-9674 for the treatment of PBC in the current study population 
include hypothesized improvements in hepatic injury due to reduced bile acid synthesis 
attributable to FXR agonism. Improvements in liver biochemistry, hepatic fibrogenesis, and 
potentially quality of life, would be expected to ensue based on these effects. Subjects with PBC 
randomized to the placebo control arm in the study may benefit from frequent medical 
monitoring and close assessment of their PBC and associated pathologies during the duration of 
placebo treatment. Moreover, all subjects, including those treated with placebo during the 
randomized phase, have the opportunity to receive GS-9674 treatment during a long-term 
open-label extension phase.
In the Phase 1 study, 94 subjects have received GS-9674 in single or multiple doses (14 days) up 
to 300 mg. All treatment emergent adverse events (TEAEs) were mild to moderate (Grade 1 or 
2), and overall, the rate of any adverse events (AEs) was similar between subjects treated with 
GS-9674 or placebo. The predominant toxicities were anemia, back pain, diarrhea, and headache. 
Grade 2 or 3 elevations in serum ALT were seen in five (5%) GS-9674 treated subjects and one 
(4%) placebo treated subject. Grade 2 or 3 ALT elevations that occurred on-treatment were 
observed in 2/23 (9%) BID treated subjects, but none of the 71 subjects who received once daily 
(QD) GS-9674 dosing. In these cases, elevations in serum bilirubin or prolongation of INR were 
not observed, serum ALT levels normalized upon treatment cessation, and no evidence of drug 
hypersensitivity syndrome (e.g., fever, rash, eosinophilia) was noted. In nonclinical studies, 


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effects on the liver have been limited to non-adverse mild increases in alkaline phosphatase and 
liver weights and minimal hepatocellular hypertrophy that are likely a pharmacological response 
to FXR agonism. There were no elevations in liver transaminases or changes in liver pathology 
(degeneration/necrosis) in the nonclinical studies to suggest direct cellular damage. In order to 
mitigate the potential risk of hepatotoxicity with GS-9674, QD dosing of GS-9674 has been 
chosen for this study. Moreover, close monitoring of liver biochemistry values will be performed 
and parameters for discontinuation of the study drugs due to liver test abnormalities have been 
defined (see Section 7.5, Toxicity Management: Observation for Drug-Induced Liver Injury) and 
will be closely followed.
Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-hepatic laboratory abnormalities are also defined and will be closely followed.
Overall, the nonclinical and limited preliminary clinical data show a positive benefit/risk ratio in 
support of the study in subjects with PBC. 
1.5.
Compliance
The study will be conducted in accordance with Good Clinical Practice (GCP), and all applicable 
rules and regulations. 


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2.
OBJECTIVES
The primary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9674 in subjects with PBC
The exploratory objectives of this study are as follows: 
 
 
 
 
 
 
 
PPD


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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2 randomized, double-blind, placebo-controlled study evaluating the safety, 
tolerability, and efficacy of GS-9674 in subjects with PBC without cirrhosis.
The study will consist of 2 phases, a Blinded Study Phase and an OLE Phase. 
Blinded Study Phase: Includes a 4 week screening period, 12 weeks of blinded treatment, and a 
Blinded Study Phase follow-up visit 4 weeks after completion of blinded treatment. 
Subjects completing the Blinded Study Phase without permanently discontinuing study drug will 
be eligible to participate in the OLE Phase of the study.
OLE Phase: Includes a 96 week OLE and an OLE Phase follow-up visit 4 weeks after 
completion of open label treatment. 
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design 


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3.2.
Treatment Plan and Regimen
Subjects meeting the study’s entry criteria will be randomly assigned in a 2:2:1 ratio to 1 of 
3 different treatment groups during the Blinded Study Phase as shown in Figure 3-1. 
Randomization will be stratified by the presence or absence of UDCA use.
Study drug(s) will be administered for a total of 12 weeks from the Baseline/Day 1 visit during 
the Blinded Study Phase and 96 weeks during the OLE Phase. During the OLE Phase subjects 
will begin open label treatment with GS-9674 (100 mg po daily). The dose of GS-9674 may be 
reduced from 100 mg to 30 mg (or subsequently increased back to 100 mg) at the PI’s discretion 
with the approval of the MM, as required.
Subjects will be unblinded to their Blinded Study Phase treatment assignment after the primary 
analysis has been completed, approximately 6 weeks after all subjects have completed the 
Blinded Study Phase.
Dosage and administration of the study drug(s) and reference product are described in 
Section 5.3.
3.3.
Biomarker Testing
3.3.1.
Biomarker Samples to Address the Study Objectives:
 
 
 
 
 
 
 
 
 
 
PPD


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3.3.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
3.3.3.
Biomarker Samples for Optional Genomic Research
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 75 adults, between 18-70 years old with non-cirrhotic PBC.
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 18-70 years of age; inclusive based on the date of the screening 
visit;
2) Willing and able to give informed consent prior to any study specific procedures being 
performed;
3) Meets all of the following conditions:
a) Definite or probable PBC as defined by at least 2 of the 3 following criteria:
i.
Serum alkaline phosphatase (ALP ) > the upper limit of normal (ULN)
ii.
Presence of anti-mitochondrial antibodies (AMA) in serum (≥1:40 on 
immunofluorescence)
iii.
Liver histological findings  consistent with PBC including nonsuppurative, 
destructive cholangitis affecting mainly the interlobular bile and septal bile ducts;
b) Serum ALP >1.67 x ULN and/or total bilirubin >ULN but ≤2x ULN;
c) UDCA use at a stable dose for at least 12 months prior to screening through the end of 
treatment or intolerant of UDCA with no UDCA use for at least 12 months before 
screening through the end of treatment;
4) Screening FibroSURE/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, 
FibroSURE/FibroTest® will be calculated using direct bilirubin instead of total bilirubin. 
5) Platelet count ≥ 150,000/mm3;
6) Albumin ≥3.3 g/dL;
7) Serum creatinine ≤ULN;


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8) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at the Screening visit and a negative urine pregnancy test on the Baseline/Day 
1 visit prior to the first dose of study drug(s);
9) All female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception from the screening visit throughout 
the study period and for 30 days following the last dose of study drug (see definition  in 
Appendix 4);
10) Male subjects with female partners of childbearing potential must use condoms during 
treatment and for 90 days after the last dose of study drug(s);
11) Male subjects must agree to avoid  sperm donation from Baseline/Day 1 visit throughout the 
study period and for  90 days after the  last dose of study drug(s);
12) Female subjects must refrain from egg donation and in-vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug(s);
13) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, 
liver biopsies, other study procedures, and study restrictions;
14) Must be able to read and complete QoL questionnaires independently.
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; lactating females must agree to discontinue nursing before the 
study drug (s) is administered;
2) ALT > 5x ULN;
3) Total bilirubin > 2x ULN;
4) INR > 1.2 unless on anticoagulant therapy;
5) Other causes of liver disease including viral, metabolic, alcoholic, and other autoimmune 
conditions. Subjects with hepatic steatosis may be included if there is no evidence of 
nonalcoholic steatohepatitis (NASH) in the opinion of the investigator or on liver biopsy;
6) Cirrhosis of the liver as defined by any of the following:
a) Historical liver biopsy demonstrating cirrhosis (e.g. Ludwig stage 4 or Ishak stage ≥5)
b) History of decompensated liver disease, including ascites, hepatic encephalopathy or 
variceal bleeding


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c) Liver stiffness >16.9 kPa by FibroScan®;
7) History of intestinal resection or malabsorptive condition that may limit the absorption of 
GS-9674. Prior cholecystectomy and appendectomy are permitted;
8) History of liver transplantation;
9) History of hepatocellular carcinoma or cholangiocarcinoma;
10) Chronic hepatitis B (HBsAg positive);
11) Chronic hepatitis C (HCV antibody and RNA positive);
12) HIV Ab positive;
13) 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/30 mL measure of 40% proof alcohol);
14) 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;
15) 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;
16) Known hypercoagulable condition or history of venous or arterial thromboembolic disease;
17) Use of immunosuppressive drugs including systemic corticosteroids (intra-articular, topical, 
nasal, or inhaled steroids are allowed), methotrexate, tacrolimus, sirolimus, cyclosporine, 
azathioprine, and mycophenolate mofetil within 30 days of screening through the end of 
treatment;
18) Use of any prohibited concomitant medications as described in Section 5.5;


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19) Use of fibrates or obeticholic acid within 3 months prior to screening through the end of 
treatment;
20) 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;
21) 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;
22) 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;
23) Concurrent participation in another therapeutic clinical study;
24) Known hypersensitivity to GS-9674, the metabolites, or formulation excipient;
25) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, including a history of substance abuse or 
psychiatric conditions;
26) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of UDCA use.
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment.
Study drug(s) will be dispensed by the study pharmacist, or designee, in a blinded fashion to the 
subjects.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject (refer to the Study Reference Binder for IWRS unblinding instructions). Gilead 
recommends but does not require that the investigator contact the Gilead medical monitor before 
breaking the blind. Treatment assignment should remain blinded unless that knowledge is 
necessary to determine subject emergency medical care. The rationale for unblinding must be 
clearly explained in source documentation and on the case report form/ electronic case report 
form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in case of any treatment 
unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of GS-9674 and PTM GS-9674
5.2.1.
Formulation
GS-9674 is supplied as 30 mg and 100 mg strength (as free form equivalent) tablets. The tablets 
contain GS-9674-02 (tromethamine salt) and inactive ingredients microcrystalline cellulose, 
mannitol, crospovidone, magnesium stearate and film-coating material comprised of polyvinyl 
alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron oxide, red iron oxide and black 
iron oxide. GS-9674 tablets, 30 mg, are round, plain-faced, film-coated orange tablets and 
GS-9674 tablets, 100 mg are capsule-shaped, plain-faced, film-coated orange tablets.


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Placebo-to-match (PTM) GS-9674 tablets are identical in size, shape, color and appearance to 
their corresponding strengths of active GS-9674 tablets. PTM GS-9674 tablets contain the 
following ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, 
magnesium stearate, and film-coating material comprised of polyvinyl alcohol, polyethylene 
glycol, talc, titanium dioxide, yellow iron oxide, red iron oxide and black iron oxide.
5.2.2.
Packaging and Labeling
GS-9674 tablets and PTM GS-9674 tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed, aluminum-faced liner.
Study drug(s) to be distributed to centers in the US 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
Study drug GS-9674 and PTM GS-9674 tablets should be stored at controlled room temperature 
of 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).  Storage 
conditions are specified on the label.  
Until dispensed to the subjects, all bottles of study drugs should be stored in a securely locked 
area, accessible only to authorized site personnel. To ensure the stability and proper 
identification, study 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 GS-9674 tablets and PTM GS-9674 
tablets.
5.3.
Dosage and Administration of GS-9674/PTM GS-9674
GS-9674 and PTM GS-9674 tablets will be provided by Gilead Sciences. In order to maintain the 
blind, each subject will be supplied with 2 bottles of tablets during the blinded phase of the trial. 
One bottle will contain GS-9674 30 mg or PTM GS-9674 30 mg; the second bottle will contain 
GS-9674 100 mg or PTM GS-9674 100 mg.
Dosing for each treatment group will be as follows:

Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet) + PTM GS-9674 100 mg (1 x PTM 
100 mg tablet) administered orally once daily with food

Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM GS-9674 30 mg (1 x 
PTM 30 mg tablet) administered orally once daily with food


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
Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) + PTM GS-9674 
100 mg (1 x PTM 100 mg tablet) administered orally once daily with food
During the OLE Phase of the study, subjects will be provided with 100 mg bottles of GS-9674
only, unless reassigned to the 30 mg dose due to tolerability. The dose of GS-9674 may be 
reduced from 100 mg to 30 mg (or subsequently increased back to 100 mg) at the PI’s discretion 
with the approval of the MM, as required.
The study drug dose should be taken at approximately the same time each day 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.
5.4.
Prior and Concomitant Medications
Concomitant use of certain medications or herbal/natural supplements with study drug (s) may 
result in PK and/or PD interactions resulting in increases or decreases in exposure of study 
drug(s) or these medications. 
Concomitant medications taken within 28 days of screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
Subjects with co-morbid diseases requiring medication(s) must be taking the medication(s) 
without a change in dose within 28 days of Baseline/Day 1.
GS-9674 increased atorvastatin exposure (39%) which does not necessitate a priori dose 
modification based on the LIPITOR USPI.  Subjects taking atorvastatin with GS-9674 should be 
monitored as per label recommendations.
5.5.
Prohibited Medications
The following medications are prohibited from 28 days prior to Baseline/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 immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for <2 weeks total is allowed

Investigational agents or devices for any indication


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
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 resulting in increases or decreases in exposure of study 
drug(s) or concomitant medications. Examples of representative medications which are 
prohibited from 28 days prior to Baseline/Day 1 through the treatment period are listed below 
in Table 5-1
Table 5-1.
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 Antagonists a
Antacidsb
Anticonvulsantsc
Carbamazepine, Oxcarbazepine, Phenobarbital, 
Phenytoin
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Endothelin Receptor 
Antagonists
Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea. Milk thistle (ie,
silymarin), Chinese herb sho-saiko-to (or Xiao-
Shai-Hu-Tang)
Bile Acid Sequestrantsd
Cholestyramine, Colesevelam, 
Colestipol
Other c
Modafinil
a
H2-Receptor Antagonists can be taken up to 3 days prior to study drug dosing
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
d 
Bile acid sequestrants are permitted but must not be taken within 4 hours (before or after) of study drug administration
Medications for disease conditions excluded from the protocol (eg, HIV-1, HBV, or HCV 
infection, active cancer, transplantation) are not listed under this prohibited medication section 
and are disallowed in the study.
5.6.
Accountability for GS-9674/ PTM GS-9674 
The investigator or designee (eg, 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. All used and unused study drug bottles dispensed to subjects must be 
returned to the site.


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Study 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 bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for instructions regarding study drug return or disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject randomized in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in Study Reference Binder.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Randomization and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to randomization and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments-Screening Visit
Subjects will be screened within 4 weeks before randomization to determine eligibility for 
participation in the study. The screening period may be extended under special circumstances 
with the explicit approval of the Medical Monitor. 
Subjects who fail to meet eligibility criteria may be rescreened. Retesting of subject’s screening 
labs may be permitted if there are reasons to believe that the retest values will be within protocol 
specified parameters.  Reasons may include but will not be limited to sample processing errors
during initial sampling and extenuating circumstances such as inter-current infections, lab 
mishandling and results abnormal from historic.
Screening labs may be repeated once within the screening period, prior to administration of study
drug to rule out laboratory error, if any. This will be done at the discretion of the investigator.
The following will be performed and documented at Screening:

Obtain written informed consent before initiation of any screening procedures

Review and record whether the subject meets inclusion and exclusion criteria

Obtain screening number from IWRS

Obtain medical history 


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
Complete physical examination 

Record vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature), body weight, and height

Obtain blood samples for
Chemistry
Hematology 
Coagulation Panel
Biomarkers
HIV-1/2, HBV and HCV Serology
Serum pregnancy test (female subjects of child bearing potential only)
Serum FSH (only for some female subjects - see Appendix 4) 

Cirrhosis assessment: FibroSURE/FibroTest® and review of historical liver biopsy or 
FibroScan® if available.

Urine drug screen for amphetamines, cocaine and opiates (ie, heroin, morphine)

Record any SAEs and all AEs related to protocol mandated procedures occurring after 
signing of the consent form.

Record all concomitant medications (CMs) that the subject has taken within 28 days prior to 
screening
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 4 weeks after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any AEs related to 
protocol-mandated procedures on the adverse events case report form (eCRF).  All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF.  See Section 7
Adverse Events and Toxicity Management for additional details.


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6.3.
Blinded Study Phase: Baseline/Day 1 Randomization and Assessments
Subjects returning to the clinic for randomization at Baseline/Day 1 will be instructed to fast (no 
food or drink, except water), starting from midnight or earlier, as appropriate, on the evening 
prior to the Baseline/Day 1 visit to ensure an approximate 8-hour fast prior to the blood sample 
collection under fasting condition the next morning.
After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will be 
randomized to study drug assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study drug. Randomization will be stratified by the presence or 
absence of UDCA use.
The following will be performed and documented at the Baseline/Day 1 visit prior to dosing:

QoL Questionnaires (PBC-40 and SF-36,)

Pruritus assessments (Pruritus VAS and 5D-Itch)
Note: It is recommended that QoL questionnaires be completed prior to any study procedures 
being performed and prior to the subject seeing a health care provider. Refer to the Study 
Reference Binder for guidance on QoL questionnaire administration.

Symptom-driven physical examination 

Record vital signs, weight and height

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
C-peptide, insulin and hemoglobin A1c (HbA1c)
Biomarker
Single PD Sampling
 

Conduct standard 12-Lead ECG
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
Perform FibroScan®(if available)

Perform MRE (if available)

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only 
Biomarkers

Collect stool sample

Dispense study drug, and provide subject with instruction on appropriate dosing and 
administration 

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the Screening visit
Once all visit procedures have been completed, subjects will take their Baseline/Day 1 dose of 
study drug with food while at the investigative site
Subjects will return to the investigative site at Week 1 (±3 days). 
6.4.
Treatment Assessments (Blinded Study Phase)
6.4.1.
Weeks 1, 2, 4 and 8 (± 3 days)
Subjects will be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to ensure an approximate 8-hour fast prior 
to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their visit until 
all visit procedures have been completed. The study drug dose should be taken with food after 
the visit.
The following treatment procedures/assessments are to be completed at the end of Weeks 1, 2, 4, 
and 8 for all subjects (see Appendix 2).

Pruritus assessments (Pruritus VAS and 5D-Itch)

Symptom-driven physical examination

Record vital signs, and body weight


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
Obtain blood samples for:
Chemistry 
Hematology 
Coagulation Panel 
Lipid Profile at Weeks 1, 4 and 8
Biomarker at Weeks 1 and 4 
Single PK and PD sampling 
 
 

Obtain urine sample for:
Urine pregnancy testing (female of childbearing potential only) at Week 1, 4 and 8
Biomarkers at Weeks 1 and 4

Dispense the study drug as directed by IWRS
Review study drug compliance and drug administration instructions with subject
Reconcile study drug administration using pill counts at Weeks 4 and 8 

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit
6.4.2.
Week 12 (± 3 days) 
Subjects will be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 visits to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
The following treatment procedures/assessments are to be completed at this visit.

QoL Questionnaires (PBC-40 and SF-36) 

Pruritus assessments (Pruritus VAS and 5D-Itch)
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
Symptom-driven physical examination

Record vital signs and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
C-peptide, insulin, and hemoglobin A1c
Biomarkers
Single PK and PD sampling

Obtain urine samples:
Urine pregnancy testing (female of childbearing potential only)
Biomarker assessments

Collect stool sample 

Conduct standard 12-Lead ECG

Perform FibroScan® (if available) 

Review study drug compliance
Reconcile study drug administration using pill counts
All study drugs should be returned at this visit

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit
Once all visit procedures have been completed, subjects will self-administer their last dose of 
study drug while at the investigative site.


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If a subject discontinues treatment early for any reason they should complete the 12 week 
treatment visit assessment/ Early Termination Visit (ET) assessments and then the follow-up
visit (4 weeks following the last dose of the study drug) should be completed (see Appendix 2).
6.5.
Blinded Study Phase follow-up Visit (±5 days)
Subjects will return for a Blinded Study Phase follow-up visit after completing their 12 weeks of 
treatment. The ET subjects should also complete the follow-up visit after completing the ET 
visit. 
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to their visits to ensure an approximate 
8-hour fast prior to the fasted blood sample collection the next morning.
The Blinded Study Phase follow-up visit will be completed 4 week post last dose of study drug.
The following will be performed and documented at this visit (see Appendix 2).

QoL Questionnaires (PBC-40 and SF-36) 

Pruritus assessments (Pruritus VAS and 5D-Itch)

Symptom-driven physical examination

Record vital signs and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
Biomarkers 

Obtain urine samples for:
Urine pregnancy testing (females of childbearing potential only)
Biomarkers

Collect stool sample 

Record all CMs that the subject has taken since the previous visit


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
Record any SAEs and all AEs occurring since the previous visit
Subjects will be unblinded to their Blinded Study Phase treatment assignment after the primary 
analysis has been completed, approximately 6 weeks after all subjects have completed the 
Blinded Study Phase or early terminated. 
Subjects must have their OLE Baseline/Day 1 visit within 30 days of completing the Blinded 
Study Phase follow-up.
If OLE Baseline/Day 1 and Blinded Study Phase follow-up visit is on the same day subjects 
should only complete OLE Baseline /Day 1 assessments.
6.6.
Open Label Extension (OLE) Phase (± 3 days for Weeks 1–12 and ± 5 days
for Weeks 24-96)
Subjects will be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to their visits to ensure an approximate 
8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of the 
Baseline/Day 1 visit until all visit procedures have been completed. The study drug dose should 
be taken with food after the visit.
The following treatment procedures/assessments are to be completed at the OLE Baseline/Day 1
Visit, followed by OLE Weeks 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96 weeks (see 
Appendix 2).

QoL Questionnaires (PBC-40 and SF-36) at OLE Baseline/Day 1, Weeks 4, 12 and every 
12 weeks thereafter

Pruritus assessments (Pruritus VAS and 5D-Itch)

Symptom-driven physical examination

Record vital signs and body weight

Perform MRE at weeks 48 and 96 (if available)

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel


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Lipid Profile
Biomarkers at OLE Baseline/Day 1, Weeks 4, 12 and every 12 weeks thereafter

Obtain Urine samples for:
Urine pregnancy testing (females of childbearing potential only) at OLE Baseline/Day 1
and every 4 weeks thereafter 
Biomarkers at OLE Baseline/Day 1, Weeks 24, 48, 72 and 96 only 

Collect stool sample at OLE Baseline/Day 1, Week 48 and Week 96 only

Dispense the study drug as directed by IWRS at OLE Baseline/Day 1, Weeks 4, 8, 12 and 
every 12 weeks thereafter 
Review study drug compliance and drug administration instructions with subject
Reconcile study drug administration using pill counts
Study drug should be returned at 96 week visit

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit
6.7.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator.
Subjects returning to the clinic for an unscheduled visit will be instructed to fast (no food or 
drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensure an approximate 8-hour fast prior to the blood sample collection under 
fasting condition the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of an 
unscheduled visit until all visit procedures have been completed. The study drug dose should be 
taken with food after the visit.
At a minimum, the following will be performed and documented.

Symptom-driven physical examination


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
Obtain blood samples for:
Chemistry
Hematology
Single PK and PD should be collected for any unscheduled visit during Blinded Study 
Phase (Weeks 1 to 12 visits).

Record body weight

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit
6.8.
OLE follow-up Visit (±5 days)
Subjects will return for OLE follow-up visit after completing their OLE Week 96 visit. Subjects 
should also complete the follow-up visit after completing the ET visit for the OLE Phase. 
The OLE follow-up visit will be completed 4 week post last dose of study drug.
The following will be performed and documented at this visit (see Appendix 2).

Pruritus assessments (Pruritus VAS and 5D-Itch)

Symptom-driven physical examination

Record vital signs and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile

Urine pregnancy test for female subjects of child bearing potential only 

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit


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6.9.
Assessments for Premature Discontinuation from Study
Subjects prematurely discontinuing from the study either during the Blinded Study Phase or 
during the OLE Phase (for example, as a result of an AE), should have an Early Termination 
(ET) visit completed followed by a follow-up visit 4 weeks after the last dose of the study 
medication. The study assessments to be performed at the ET visit are the same as those 
performed at the Week 12 visit (refer to Section 6.4.2) for ET subjects in the Blinded Study 
Phase and Week 96 visit for ET subjects in the OLE Phase (refer to Section 6.6). The study 
assessments to be performed at the follow-up visits are listed in Section 6.5 and 6.8 respectively. 
The subject will then be withdrawn from the study.
If these visits are not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study. 
6.10.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

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.

Subject noncompliance

Sponsor discretion
Study medication must be discontinued in the following instances:

Unacceptable toxicity,  or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject request to discontinue for any reason

Pregnancy 

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)


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6.11.
PK and PD Substudy Visits
 
 
 
 
 
 
 
 
6.12.
Procedures and Specifications
6.12.1.
Clinical Laboratory Analytes
Chemistry:
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline 
phosphatase (ALP), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, 
glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, sodium, total and 
direct bilirubin, total protein, uric acid, gamma-glutamyl transferase (GGT).  Also includes 
C-Peptide, insulin and hemoglobin A1c (HbA1c) for the Baseline/Day1 and Week 12 visits.
Hematology:
Hematocrit (Hct), hemoglobin (Hb), platelet count, red blood cell count (RBC), white blood cell 
count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neutrophils, eosinophils, and basophils and, reticulocyte count and mean corpuscular volume 
(MCV).
Coagulation Panel:
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio 
(INR)
Pregnancy Tests:
Serum β-hCG or urine β-hCG (if positive, requires immediate confirmation with Serum β-hCG)
Additional Tests:
Lipid Profile, Creatine Phosphokinase, HIV-1, HBV & HCV Serology, urine drug screen (for 
amphetamines, cocaine, opiates), and genomic sample collection
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Biomarker tests
Including, but not limited to, biomarkers of:
Circulating lipids - ApoB and NMR lipoprofile
Inflammation – hsCRP and TNF-α 
Autoimmune disease - AMA and Immunoglobulins (IgM, IgA, IgG)
Bone formation – bone specific ALP and PTH
Liver fibrosis – ELF Test and FibroSURE/FibroTest®
FXR pathway activity - FGF19, C4, bile acids
Urine samples:
Pharmacokinetic (PK) and Pharmacodynamic (PD) Assessments
Single PK and PD Sampling
Single PK and PD plasma samples will be collected and archived for 1) PK analysis of GS-9674, 
GS-716070 (metabolite of GS-9674), and other metabolites as applicable, 2) to measure the 
concentration of the PD biomarkers FGF19 and C4.
 
 
6.12.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including nicotine and alcohol use, 
will be collected on all subjects during screening.
6.12.3.
Physical Examination
A complete physical examination should include source documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and 
tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; neurological. 
PPD
PPD


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The focus of a symptom-driven physical examination will be determined by the investigator 
based on subject complaint. For eg, if a subject complains of a cough, a lung exam should be 
performed. If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented.
Height and body weight will be collected at specified time points.
6.12.4.
Quality of Life (QoL) Measures and Pruritus Assessments
It is recommended that these questionnaires be completed prior to the clinical and laboratory 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself.
6.12.4.1.
Short Form-36 (SF-36) Health Survey
The SF-36 Health Survey asks 36 questions to measure functional health and well-being from the 
subject’s point of view and consists of eight health domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health). These 
health domain scales contribute to the physical health and mental health summary measures). 
6.12.4.2.
Primary Biliary Cirrhosis-40 (PBC-40) Questionnaire
The PBC-40 is a health-related QoL questionnaire that includes 40 questions regarding 
PBC-related symptoms including itch, fatigue, cognition, and social and emotional assessments.  
6.12.4.3.
Pruritus Visual Analog Scale (VAS) Measure
Pruritus VAS is a tool for measuring the intensity of pruritus.
6.12.4.4.
5-D Itch Questionnaire
The 5-D Itch is a validated survey for the assessment of the severity of pruritus in patients with 
chronic pruritus due to dermatological and non-dermatological disorders. 
6.12.5.
Electrocardiogram
Standard 12-lead electrocardiogram (ECG) assessments will be performed. The Investigator will 
review the ECGs for any clinically significant abnormalities to ensure subject safety. Abnormal 
ECG findings that are considered clinically significant by the Investigator and meet the 
definition of an AE should be reported and recorded in the AE eCRF page.
6.12.6.
FibroScan® 
Liver stiffness will be assessed by FibroScan®. It is required that each subject’s FibroScan®
assessments be done with the same type of probe at each study visit. If FibroScan® is not 
available at a site the test may be omitted.
Please refer to the Study Reference Binder for instructions on FibroScan® measurements.


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6.12.7.
Magnetic Resonance Elastography 
Liver stiffness will be assessed by MRE. It is recommended that each subject’s MRE assessment 
is performed using the same procedure for each study visit.  If MRE is not available at the site, 
the procedure may be omitted.
Please refer to the Study Reference Binder for instruction on MRE imaging guidelines. 
6.13.
End of Study
End of study is defined as when the last patient last visit (LPLV) for the OLE follow-up visit 
occurs 4 weeks after completing OLE treatment or the OLE ET follow-up visit, whichever 
occurs later.
6.13.1.
Sample Storage
 
 
 
 
 
PPD


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, overdose, drug abuse/misuse reports, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to (Section 7.5).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
GS-9674 therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the GS-9674. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).


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
Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, 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_8.5x11.pdf
(Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed above.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study 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 GS-9674; AEs 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
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit and within 30 days of 
the last dose of study drug, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow-up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information 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 information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH
Email:
Fax:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a 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 drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent Data Monitoring 
Committee (DMC). The DMC may have access to partially blinded or unblinded data and will 
make recommendations regarding the study according to the DMC charter. See Section 8.12 for 
additional details regarding the DMC.
7.5.
Toxicity Management 
Observation for Drug Induced Liver Injury (DILI):
Although subjects randomized in this study will have baseline liver disease, their hepatic 
function should not be significantly impaired. However, at baseline, some may have liver 
biochemistry levels above the upper limit of normal (ULN). Baseline values for liver tests
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For subjects with ALT and/or AST below ULN at study start, close observation for DILI (as 
described below) will be performed in subjects with any of the following criteria (all labs 
confirmed by repeat testing), unless an alternative cause for the combination of laboratory 
abnormalities is apparent in the opinion of the principal investigator:

ALT or AST > 3 x ULN 

Total bilirubin > 2 x ULN

INR >1.5 (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%)
For subjects with ALT and/or AST between 1 and 5 x ULN at study start, close observation for 
DILI (as described below) will be performed in subjects with any of the following criteria (all 
labs confirmed by repeat testing), unless an alternative cause for the combination of laboratory 
abnormalities is apparent in the opinion of the principal investigator:

ALT or AST > 2 x baseline at any time

Total bilirubin > 2 x ULN  

INR >1.5 (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%).  
Close observation includes:

Repeating liver biochemistries (ALT, AST, ALP, total bilirubin, INR) and obtaining creatine 
phosphokinase (CPK) levels within 2 working calendar days upon receipt of the laboratory 
results.

Obtaining a more detailed history of symptoms and prior or concurrent disease

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets

Obtaining a history of exposure to environmental chemical agents

Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, imaging for 
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Continue to monitor liver biochemistries twice weekly. Frequency can decrease to once a 
week or less if abnormalities stabilize or study drug has been discontinued and subject is 
asymptomatic
During a period of close observation, study drug 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 drug should be withheld if any of the following criteria are met:

ALT or AST > 5 x baseline

ALT or AST >10 x ULN 

ALT or AST >3 x baseline with 1 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity

ALT or AST > baseline with any 2 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity
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 
AST/ALT or total bilirubin values include, but are not limited to:
Obstructive gall bladder or bile duct disease
Viral or alcoholic hepatitis (e.g. hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella)
Autoimmune hepatitis
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
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Wilson disease
Nonalcoholic fatty liver disease (NAFLD)
Progression of malignancy involving the liver (note that metastatic disease to the liver, by 
itself, should not be used as an explanation for significant AST/ALT elevations)
If study drugs are withheld, they may be reintroduced with approval from the Medical Monitor if 
another etiology for elevated liver tests is present. Study drug must be discontinued if close 
monitoring of a patient for DILI is not possible or if total bilirubin, ALT or AST elevation recurs 
following re-challenge with study drug.
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.
7.6.
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, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
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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 labeling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure with an AE: exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH 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 DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
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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 DSPH, fax number 
 
 or email 
 
Refer to Appendix 4 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 DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
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.
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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 primary objective of this study is: 

To evaluate the safety and tolerability of GS-9674 in subjects with PBC
The exploratory objectives of this study are: 
 
 
 
 
 
 
8.1.2.
Primary Endpoint
The primary endpoint is the safety of GS-9674 in subjects with PBC without cirrhosis. The 
safety and tolerability of GS-9674 will be evaluated by examining the incidence of 
treatment-emergent adverse events, including serious adverse events, clinical laboratory tests, 
and vital signs assessments at various time points during the study.
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8.1.3.
Exploratory Endpoints
 
 
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis will be the Full Analysis Set (FAS) which includes 
all subjects who were randomized into the study and received at least one dose of study drug.
Subjects who receive study drug other than that to which they were assigned will be analyzed 
according to the treatment group to which they were randomized.
8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who received at least one 
dose of study drug. Treatment-emergent data will be analyzed and defined as data collected from 
the first dose of study drug through the date of last dose of study drug plus 30 days. Subjects who 
received study drug other than that to which they were assigned will be analyzed according to the 
study drug received.
8.2.1.3.
Pharmacokinetics
There are two pharmacokinetic analysis sets: 1) the PK analysis set which includes 
concentration data from the single samples drawn at each visit
 
 
The PK analysis set will include all randomized subjects who took at least one dose of study
drug and for whom concentration data of analytes GS-9674 (and its metabolites as applicable) 
are available. The PK analysis set will be used for analyses of population PK.
 
8.2.1.4.
Pharmacodynamics
There are two pharmacodynamics analysis sets: 1) The PD analysis set which includes 
concentration data from the single samples drawn at each visit
 
The PD analysis set will include all randomized subjects who took at least one dose of study
drug and for whom concentration data of FGF19, C4, and bile acids are available. The PD 
analysis set may be used for descriptive and/or population based PD analyses as applicable.
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8.2.1.5.
Biomarkers
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessary baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest. 
8.2.2.
Analysis by Study Phase
Result of statistical analysis for the randomized phase will be presented by treatment groups.  
Safety data from the OLE Phase will be summarized for overall subjects who roll-over into the 
OLE Phase for safety review, supporting regulatory document update or publication purposes. 
An administrative interim analysis will be performed after first 30 subjects finish 12 weeks of
treatment.
8.3.
Data Handling Conventions
Missing data can have an impact on the interpretation of the trial data. In general, values for 
missing data will not be imputed.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summary of adverse events according to the treatment received; otherwise, if the 
subject is not dosed then they will be excluded from the summary. If safety laboratory results for 
a subject are missing for any reason at a time point, the subject will be excluded from the 
calculation of summary statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summary statistics for the pre-dose 
value and the change from pre-dose values.
Values for missing safety laboratory data and vital signs will not be imputed; however, a missing 
baseline result will be replaced with a screening result, if available. If no pre-treatment 
laboratory value is available, the baseline value will be assumed to be normal (ie, no grade 
[Grade 0]) for the summary of graded laboratory abnormalities.  
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment group and 
overall. Demographic summaries will include sex, race/ethnicity, and age.
Baseline characteristics summary will include body weight, height, body mass index, and other 
disease characteristic variables.
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8.5.
Efficacy Analysis
The biological activity of GS-9674 will be evaluated using biomarker variables. Because 
efficacy endpoints will be evaluated for exploratory purpose, formal statistical comparisons will 
not be made for these endpoints. Point estimates and ninety-five percent confidence intervals 
(95% CI) will be provided if applicable.
8.6.
Exploratory Analyses
 
 
8.7.
Safety Analysis
All safety data collected on or after the date that GS-9674 was first dispensed up to the date of 
last dose of GS-9674 plus 30 days will be summarized by treatment group. Data for the 
pretreatment and follow-up periods will be included in data listings.
8.7.1.
Extent of Exposure
Data for a subject’s extent of exposure to GS-9674 will be generated from the study drug 
administration eCRF. Exposure data will be summarized by treatment group. 
8.7.2.
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.
Events will be summarized on the basis of the date of onset for the event. Treatment-emergent 
adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug
Summaries (number and percentage of subjects) of TEAEs by SOC 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.
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All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no).
8.7.3.
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 (Appendix 3). Grading of laboratory abnormalities for analysis purposes will be 
performed by the central laboratory.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to and including the date of last dose 
of study drug plus 30 days will be summarized by treatment group. If baseline data are missing, 
then any graded abnormality (ie, at least a Grade 1) will be considered treatment emergent.
8.7.4.
Other Safety Evaluations
Vital sign measurements and 12-lead ECG data will be summarized by treatment group and 
listed by subject.  
8.8.
Pharmacokinetic Analysis
Plasma concentrations and pharmacokinetic parameters (eg, AUCtau, Cmax and Ctau) will be 
listed and summarized as appropriate for GS-9674 (and its metabolites as applicable) using 
descriptive statistics.
Details of the analysis plan will be provided in the pharmacokinetic reporting and analysis plan.
8.9.
Pharmacodynamics Analysis 
Primary PD parameters (AUCpartial, Cmax, Cmin as applicable) of FGF19 and C4 will be listed and 
summarized as appropriate for GS-9674 using descriptive statistics.
Details of the analysis plan will be provided in the pharmacodynamics reporting and analysis 
plan.
8.10.
Biomarker Analysis
Descriptive statistics of biomarker expression and change from baseline will be provided at each 
sampling time by treatment. Point estimates and 95% confidence intervals may be calculated.
 
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8.11.
Sample Size
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. The number of subjects was chosen based on clinical experience with other similar 
proof of concept studies.
8.12.
Data Monitoring Committee
An independent, external data monitoring committee (DMC) that consists of two hepatologists 
and a PhD statistician will review the progress of the study and perform reviews of safety data. 
The DMC will convene once 20 subjects have been randomized and will meet every 3 to 
4 months thereafter to monitor the study for safety events in Blinded Study Phase and every 
6 months in the OLE Phase. The DMC will meet on an ad hoc basis if there are at least 3 similar 
Grade ≥ 3 serious, treatment-related Common Terminology Criteria for Adverse Events 
(CTCAE) observed in the trial. In the event of two similar treatment related  Grade 4 CTCAE 
events or one treatment related  Grade 5 CTCAE, the DMC will review the data and advise the 
sponsor regarding stopping or continuing the trial. The DMC will provide recommendation to 
Gilead whether the nature, frequency, and severity of adverse effects associated with study 
treatment warrant the early termination of the study in the best interests of the participants, 
whether the study should continue as planned, or the study should continue with modifications. 
The DMC may also provide recommendations as needed regarding study design.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, International Conference on Harmonisation (ICH) guidelines, or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
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/EC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC/EC
local requirements.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC/EC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. NOTE: The investigator must keep a screening log showing 
codes, names, and addresses for all subjects screened and for all subjects randomized in the trial.
Subject data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an electronic case report form (eCRF) will be completed by an 
authorized study staff member whose training for this function is documented according to study 
procedures. eCRF should be completed on the day of the subject visit to enable the sponsor to 
perform central monitoring of safety data.  The Eligibility Criteria eCRF should be completed 
only after all data related to eligibility have been received.  Subsequent to data entry, a study 
monitor will perform source data verification within the EDC system. Original entries as well as 


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any changes to data fields will be stored in the audit trail of the system.  Prior to database lock 
(or any interim time points as described in the clinical data management plan), the investigator 
will use his/her log in credentials to confirm that the forms have been reviewed, and that the 
entries accurately reflect the information in the source documents. The eCRF capture the data 
required per the protocol schedule of events and procedures. System-generated or manual 
queries will be issued to the investigative site staff as data discrepancies are identified by the 
monitor or internal Gilead staff, who routinely review the data for completeness, correctness, and 
consistency. The site coordinator is responsible for responding to the queries in a timely manner, 
within the system, either by confirming the data as correct or updating the original entry, and 
providing the reason for the update (e.g. data entry error). At the conclusion of the trial, Gilead 
will provide the site with a read-only archive copy of the data entered by that site. This archive 
must be stored in accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. 
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead 
QA, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. Refer to the pharmacy binder for study drug disposal/return instructions.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to the IRB/IEC/EC, 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. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met: the results of the study 
in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, 
manuscript, or presentation form or the study has been completed at all study sites for at least 
2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
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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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities, IRBs/ IECs/ECs. In terminating the study, Gilead and the investigator will 
assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and 
primary biliary cirrhosis: a systematic review. J Hepatol 2012;56 (5):1181-8.
Boonstra K, Kunst AE, Stadhouders PH, Tuynman HA, Poen AC, van Nieuwkerk KM, et al. 
Rising incidence and prevalence of primary biliary cirrhosis: a large population-
based study. Liver Int 2014;34 (6):e31-8.
Carbone M, Lleo A, Sandford RN, Invernizzi P. Implications of genome-wide association studies 
in novel therapeutics in primary biliary cirrhosis. European journal of 
immunology 2014;44 (4):945-54.
Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, et al. The UK-PBC risk scores: 
Derivation and validation of a scoring system for long-term prediction of end-
stage liver disease in primary biliary cholangitis. Hepatology 2016;63 (3):930-50.
Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical 
response to ursodeoxycholic acid and long-term prognosis in primary biliary 
cirrhosis. Hepatology 2008;48 (3):871-7.
Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and 
comorbidities in primary biliary cirrhosis: a controlled interview-based study of 
1032 patients. Hepatology 2005;42 (5):1194-202.
Hamlyn AN, Macklon AF, James O. Primary biliary cirrhosis: geographical clustering and 
symptomatic onset seasonality. Gut 1983;24 (10):940-5.
Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of 
obeticholic acid in patients with primary biliary cirrhosis and inadequate response 
to ursodeoxycholic acid. Gastroenterology 2015;148 (4):751-61 e8.
Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth 
factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. 
Cell metabolism 2005;2 (4):217-25.
Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. 
Development and Validation of a Scoring System to Predict Outcomes of Patients 
With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. 
Gastroenterology 2015;149 (7):1804-12 e4.
Metcalf JV, Bhopal RS, Gray J, Howel D, James OF. Incidence and prevalence of primary 
biliary cirrhosis in the city of Newcastle upon Tyne, England. Int J Epidemiol 
1997;26 (4):830-6.


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Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and 
safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 
diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145 (3):574-
82 e1.
Murakami S, Takayama F, Egashira T, Imao M, Mori A. Fermented papaya preparation halts the 
progression of non-alcoholic steatohepatitis in rats. Journal of Biophysical 
Chemisty 2013;4 (2):84-90.
Nakamoto K, Takayama F, Mankura M, Hidaka Y, Egashira T, Ogino T, et al. Beneficial Effects 
of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis. 
Journal of clinical biochemistry and nutrition 2009;44 (3):239-46.
Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6alpha-ethyl-
chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem 2002;45 (17):3569-72.
Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME. Innate immunity and primary biliary 
cirrhosis. Curr Mol Med 2009;9 (1):45-51.
Woolbright BL, Jaeschke H. Novel insight into mechanisms of cholestatic liver injury. World J 
Gastroenterol 2012;18 (36):4985-93.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table for GS-US-427-4024
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Amendment 3 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404, 
USA 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-9674 in Subjects with Primary Biliary Cholangitis Without 
Cirrhosis 
GS-US-427-4024, Amendment 3, 09 February 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
b~a~a~----------------~ 
Medical Monitor 
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. 1 will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 82 
09 February 2017 


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Appendix 2.
Study Procedures Table for GS-US-427-4024
Blinded Study Phase Treatment Weeks (±3 days)
OLE Weeks 
(±3 days weeks 1-12 and ±5 days 
weeks 24-96)
Screening
a
Baseline
(Day 1)
Week 
1
Week 
2
Week 
4
Week 
8
Week 12 /ET b
Blinded Study Phase 
follow-up visit c
(±5 days)
OLE 
Baseline/Day1,Weeks 1,
2, 4, 8, 12, 24, 36, 48, 
60, 72, 84, 96/ET b
OLE 
follow-up
d
Subject Fasting
X
X
X
X
X
X
X
X
Written Informed 
Consent e
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Pruritus VAS &5D-
Itch f
X
X
X
X
X
X
X
X
X
QoL SF-36, & PBC-
40f
X
X
X
X
Symptom-directed PEg
X
X
X
X
X
X
X
X
X
X
Vital Signsh
X
X
X
X
X
X
X
X
X
X
Height and weighti
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Coagulation Panel 
X
X
X
X
X
X
X
X
X
X
Cirrhosis Assessments
X
Lipid Profile
X
X
X
X
X
X
X
X


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Blinded Study Phase Treatment Weeks (±3 days)
OLE Weeks 
(±3 days weeks 1-12 and ±5 days 
weeks 24-96)
Screening
a
Baseline
(Day 1)
Week 
1
Week 
2
Week 
4
Week 
8
Week 12 /ET b
Blinded Study Phase 
follow-up visit c
(±5 days)
OLE 
Baseline/Day1,Weeks 1,
2, 4, 8, 12, 24, 36, 48, 
60, 72, 84, 96/ET b
OLE 
follow-up
d
C-Peptide, 
hemoglobin A1C and 
insulin
X
X
Blood for Biomarkers j
X
X
X
X
X
X
X
Single PK and PD 
Sampling
X k
X
X
X
HIV-1, HBV and 
HCV Serology
X
Pregnancy Testl
X
X
X
X
X
X
X
X
X
Serum FSH m
X
12- lead ECGs
X
X
Fibroscano
X
X
MREp
X
X
Urine drug screening
X
Urine collectionq 
(Biomarkers)
X
X
X
X
X
X
Stool collectionr
(Biomarkers)
X
X
X
X
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Blinded Study Phase Treatment Weeks (±3 days)
OLE Weeks 
(±3 days weeks 1-12 and ±5 days 
weeks 24-96)
Screening
a
Baseline
(Day 1)
Week 
1
Week 
2
Week 
4
Week 
8
Week 12 /ET b
Blinded Study Phase 
follow-up visit c
(±5 days)
OLE 
Baseline/Day1,Weeks 1,
2, 4, 8, 12, 24, 36, 48, 
60, 72, 84, 96/ET b
OLE 
follow-up
d
Dispense GS-9674/ 
PTM GS-9674t
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Take GS-9674/ PTM 
GS-9674 Tablets
X – Daily (Baseline/ Day 1 to Week 12)u
X-Daily (OLE Baseline/ 
Day 1 to Week 96)
a
The visit window may be extended under special circumstances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to an abnormal 
laboratory result may undergo re-testing of the abnormal analyte during the screening window. This will be done at the discretion of the investigator and also with prior 
approval of the Medical Monitor.
b
Blinded Study Phase subjects discontinuing the study at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 12/ Visit AND 
the follow-up visit. OLE Phase subjects discontinuing the study at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 96/ 
Visit AND the follow-up visit if possible.
c
After completing 12 weeks of treatment in the Blinded Study Phase, subjects will return for the follow-up visit 4 weeks post the last dose of the study drug. and at that time 
they can begin their OLE Phase follow-up visit for Blinded Study Phase and Baseline/Day 1 OLE visit can occur on the same day if convenient. If OLE Baseline/Day 1 and 
Blinded study follow-up visit is on the same day subjects should only complete OLE Baseline /Day 1 assessments.
d
Follow-up visit should be completed during the Blinded Study Phase as well as the OLE Phase.
e
Obtain written informed consent before initiation of any screening procedure.
f
QoL questionnaires and pruritus assessments should be completed prior to any study procedures being performed and prior to the subject seeing a health care provider. Refer 
to the Study Reference Binder for guidance on QoL questionnaire administration. During OLE, QoL questionnaires are required at OLE Baseline/Day 1, Weeks 4, 12 and 
every 12 weeks thereafter.
g
Complete PE at screening and symptom-directed PE for other visits. The focus of a symptom-driven physical examination will be determined by the investigator based on 
subject complaint.
h
Vital signs include (heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature)
i
Height should be collected at Screening and Baseline/Day 1 only. Weight should be collected at all visits. Refer to the Study Reference Binder for specific instructions on 
how weight should be measured.
j
Biomarker analyses include, but are not limited to, the tests listed in Section 6.12.1. 
k
PD sampling only at Baseline/Day 1.
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l
Females of childbearing potential only (see Appendix 4). Serum pregnancy test at Screening and Urine pregnancy tests at all Blinded Study Phase visits, except Week 2 and at 
OLE Baseline/Day 1 and every 4 weeks thereafter.
m
Only required for some female subjects – see Appendix 4. 
o
Subject should be in fasted state for FibroScan® collection. Refer to the study reference binder for further details. If FibroScan® is not available at a site the test may be 
omitted. 
p
Subject should be in fasted state for MRE scan. Refer to the study reference binder for further details. If MRE is not available at a site the test may be omitted. MRE scan 
should be performed at Blinded Study Phase Baseline /Day 1 and OLE weeks 48 and 96.
q
Urine Biomarker sample collection at Blinded Study Phase Baseline/Day 1, week 1, weeks 4, 12 and at the Follow up and Early term visits. Urine Biomarker sample 
collection during OLE at OLE Baseline/Day 1, Weeks 24, 48, 72 and 96 only.
r
Stool sample collection at Blinded Study Phase Baseline/Day 1, week 12 and at the Follow up and Early term visits.  Stool sample collection during OLE at OLE 
Baseline/Day 1, Week 48 and Week 96 visit.
t
Study drug will be assigned via the IWRS system every 4 weeks from Baseline/Day 1 through Week 8 in Blind Study Phase and at OLE Baseline/Day 1, Weeks 1, 4, 8, 12 
and every 12 weeks thereafter.
u
Subjects to self-administer the study drug at the investigative site at the conclusion of the Blinded Study Phase Baseline/Day 1 and Week 12 visit.
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Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2. Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9674 has not yet been studied in pregnant women. In the initial dose range-finding studies in 
pregnant mice and rabbits there were no effects on embryofetal development other than a 
decrease in fetal body weights in pregnant rabbits administered 1000 mg/kg/day. The decrease in 
fetal body weights are likely secondary to maternal toxicity rather than a direct effect of 
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 with hormones 
used for contraception.
Please refer to the latest version of the Investigator’s Brochure for additional information.


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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  At minimum, a 
pregnancy test will be performed at all study visits except Blinded Study Phase Week 2 and OLE 
Weeks 1 and 2 and at 30 days after the last dose of the study drug.  Female subjects must also 
agree to one of the following from Screening until 30 days following the last dose of the study 
drug GS-9674.
Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method.
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


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Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of the study drug, GS-9674.
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 (plus spermicide) during treatment and until
90 days after last dose of GS-9674. Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must agree to avoid sperm donation during treatment and until at least 90 days 
after the last dose of study drug, GS-9674.
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 30 days (90 days of partner of male subject) of last 
study drug dose. Subjects who become pregnant or who suspect that they are pregnant during the 
study must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant during the study must 
report the information to the investigator.  Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.6.2.1.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, and Efficacy of 
GS-9674 in Subjects with Primary Biliary Cholangitis Without 
Cirrhosis  
Name of Test Drug:
GS-9674
Study Number:
GS-US-427-4024
Protocol Version (Date):
Protocol Amendment 3, 09 February 2017
Analysis Type:
Interim analysis, Primary analysis and Final analysis 
Analysis Plan Version:
Version 1.1
Analysis Plan Date:
14 August 2018
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS................................................................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
DMC Interim Analyses ..........................................................................................................................12
2.2.
Interim Analyses ....................................................................................................................................12
2.3.
Primary Analysis....................................................................................................................................12
2.4.
Final Analysis ........................................................................................................................................13
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................14
3.1.
Analysis Sets..........................................................................................................................................14
3.1.1.
All Randomized Analysis Set...............................................................................................14
3.1.2.
Full Analysis Set ..................................................................................................................14
3.1.3.
Safety Analysis Set...............................................................................................................14
3.1.4.
OLE Analysis Set.................................................................................................................15
3.1.5.
Pharmacokinetic Analysis Set..............................................................................................15
3.1.6.
Pharmacokinetic Substudy Analysis Set ..............................................................................15
3.2.
Subject Grouping ...................................................................................................................................15
3.3.
Strata and Covariates..............................................................................................................................16
3.4.
Examination of Subject Subgroups........................................................................................................17
3.5.
Multiple Comparisons............................................................................................................................17
3.6.
Missing Data and Outliers......................................................................................................................17
3.6.1.
Missing Data ........................................................................................................................17
3.6.2.
Outliers.................................................................................................................................17
3.7.
Data Handling Conventions and Transformations .................................................................................17
3.8.
Analysis Visit Windows.........................................................................................................................18
3.8.1.
Definition of Study Day .......................................................................................................18
3.8.2.
Analysis Visit Windows.......................................................................................................18
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................24
4.
SUBJECT DISPOSITION ..................................................................................................................................26
4.1.
Subject Enrollment and Disposition.......................................................................................................26
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................27
4.2.1.
Duration of Exposure to Study Drug....................................................................................27
4.2.2.
Adherence to Study Drug.....................................................................................................28
4.3.
Protocol Deviations................................................................................................................................29
5.
BASELINE CHARACTERISTICS....................................................................................................................30
5.1.
Demographics ........................................................................................................................................30
5.2.
Baseline Characteristics .........................................................................................................................30
5.3.
Medical History......................................................................................................................................32


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6.
EFFICACY ANALYSES ...................................................................................................................................33
6.1.
Exploratory Efficacy Endpoints in the BD Phase ..................................................................................33
6.1.1.
Definition of Exploratory Efficacy Endpoints......................................................................33
6.1.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................35
6.2.
Exploratory Efficacy Endpoints in OLE Phase......................................................................................37
6.2.1.
Definition of Exploratory Efficacy Endpoints......................................................................37
6.2.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................39
6.3.
Exploratory Efficacy Endpoints in Long Term Analysis .......................................................................40
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................40
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints in Long Term 
Analysis................................................................................................................................42
6.4.
Subgroup Analysis of the Exploratory Efficacy Endpoints....................................................................43
7.
SAFETY ANALYSES........................................................................................................................................44
7.1.
Adverse Events and Deaths....................................................................................................................44
7.1.1.
Adverse Event Dictionary ....................................................................................................44
7.1.2.
Adverse Event Severity........................................................................................................44
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................44
7.1.4.
Serious Adverse Events........................................................................................................44
7.1.5.
Treatment-Emergent Adverse Events...................................................................................44
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................45
7.2.
Laboratory Evaluations ..........................................................................................................................47
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................47
7.2.2.
Graded Laboratory Values ...................................................................................................48
7.2.3.
Liver-related Laboratory Evaluations...................................................................................49
7.3.
Vital Signs..............................................................................................................................................50
7.4.
Prior and Concomitant Medications.......................................................................................................51
7.4.1.
Prior Medications .................................................................................................................51
7.4.2.
Concomitant Medications.....................................................................................................51
7.5.
Electrocardiogram Results .....................................................................................................................52
7.6.
Other Safety Measures ...........................................................................................................................52
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................52
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................53
8.1.
PK Sample Collection............................................................................................................................53
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................53
8.2.1.
Estimation of PK Parameters ...............................................................................................53
8.2.2.
PK Parameters......................................................................................................................54
8.3.
PK Analyses Related to Sparse PK Sampling........................................................................................55
9.
REFERENCES ...................................................................................................................................................56
10.
SOFTWARE.......................................................................................................................................................57
11.
SAP REVISION..................................................................................................................................................58
12.
APPENDICES ....................................................................................................................................................59
Appendix 1.
Study Procedures Table..........................................................................................................60
Appendix 2.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities .........................................................................................................................63
Appendix 3.
Programming Specifications...................................................................................................64


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows in BD Phase for Vital Signs, Body Weight, Pruritus 
Measures, Chemistry, Hematology, and Coagulation Laboratory, UK-PBC Score, 
and GLOBE PBC Risk Score.................................................................................................19
Table 3-2.
Analysis Visit Windows in BD Phase for Lipid Profiles, and Pooled Cohort Risk 
Score.......................................................................................................................................19
Table 3-3.
Analysis Visit Windows in BD Phase for Fibroscan®, QoL Questionnaires, and 
Electrocardiogram (ECG), HOMA-IR, HbA1c, C-peptide, Insulin, ELF™ Score, 
FibroSURE/FibroTest, High-sensitivity C-reactive Protein (hsCRP) ....................................19
Table 3-4.
Analysis Visit Windows in BD Phase for FGF19, C4 and Total Bile Acids..........................20
Table 3-5.
Analysis Visit Windows in OLE Phase for Vital Signs, Body Weight, Lipid 
Profiles, Pruritus Measures, Chemistry, Hematology and Coagulation Laboratory, 
Pooled Cohort Risk Score, UK-PBC Score, and GLOBE PBC Risk Score ...........................20
Table 3-6.
Analysis Visit Windows in OLE Phase for QoL Questionnaires ...........................................21
Table 3-7.
Analysis Visit Windows in OLE Phase ELF™Score and hsCRP...........................................21
Table 3-8.
Analysis Visit Windows in OLE Phase for FGF19, C4, and Total Bile Acids.......................21
Table 3-9.
Analysis Visit Windows in OLE Phase FibroSURE/FibroTest®............................................22
Table 3-10.
Analysis Visit Windows in OLE Phase for MRE...................................................................22
Table 3-11.
Mapping algorithm from visit windows from BD/OLE Phase to LT Analysis ......................23
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................54
Table 8-2.
PK Parameters for Each Analyte............................................................................................54
LIST OF IN-TEXT FIGURES
Figure 1-1.
Overall Study Design .............................................................................................................10


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ASCVD
atherosclerotic cardiovascular disease 
AST
aspartate aminotransferase
BD Phase
blinded study phase
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
CRF
case report form
CSR
clinical study report
CTCAE
common toxicity criteria for adverse events
DILI
drug-induced liver injury
DMC
data monitoring committee
ELF
enhanced liver fibrosis
ECG
electrocardiogram
ET
early termination
FAS
Full Analysis Set
FGF19
fibroblast growth factor 19
FU
follow-up
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
HA
hyaluronic acid
HbA1c
hemoglobin A1c
HDL-C
high density lipoprotein-cholesterol
HLT
high-level term
HOMA-IR
homeostatic assessment of insulin resistance
hsCRP
high-sensitivity C-reactive protein
ICH
international conference on harmonization (of technical requirements for registration of 
pharmaceuticals for human use)
ID
identification
INR
international normalized ratio
IXRS
interactive voice or web response system
LDL-C
low density lipoprotein-cholesterol
LT
long-term
LTT
lower-level term


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LOCF
last observation carried forward
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MRE
magnetic resonance elastography
Non-HDL-C
non high density lipoprotein cholesterol
OLE
Open Label Extension
PBC
primary biliary cholangitis
PD
pharmacodynamics
PI
principal investigator
PIIINP
procollagen III amino terminal peptide
PK
pharmacokinetics
PP
per protocol
PT
preferred term
PTM
Placebo to match
Q1, Q3
first quartile, third quartile
QoL
quality of life
SAP
statistical analysis plan
SD
standard deviation
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
UDCA
ursodeoxycholic acid
ULN
upper limit of normal
VAS
visual analog scale
VLDL-C
very low density lipoprotein-cholesterol
WHO
World Health Organization


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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 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-427-4024. 
This study consists of two phases, a Blinded Study (BD) Phase followed by an Open Label 
Extension (OLE) Phase. An administrative interim analysis will be performed when a total of at 
least 30 subjects have completed 12 weeks of blinded study treatment or prematurely 
discontinued from the study treatment in the BD Phase. The primary analysis will be performed 
when all subjects have completed the blinded study treatment and the BD follow-up visit, or 
prematurely discontinued from the study in the BD Phase. The final analysis will be performed 
when all the subjects have completed the study or prematurely discontinued from the study.  
This SAP is based on the study protocol amendment 3 dated 09 February 2017 and the electronic 
case report form (eCRF). The SAP will be finalized prior to data unblinding for the interim 
analysis. Any changes made after the finalization of the SAP will be documented in the clinical 
study report (CSR).
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9674 in subjects with primary biliary 
cholangitis (PBC)
The exploratory objectives of this study are as follows:
 
 
 
 
 
 
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1.2.
Study Design
This is a Phase 2 randomized, double-blind, placebo-controlled study evaluating the safety, 
tolerability, and efficacy of GS-9674 in subjects with PBC without cirrhosis.
The study consists of 2 phases, a BD Phase and an OLE Phase. 
BD Phase: Includes a 4-week screening period, 12 weeks of blinded treatment, and a BD Phase
follow-up visit 4 weeks after completion of blinded treatment. 
Subjects who complete the BD Phase treatment will participate in the OLE Phase of the study.
OLE Phase: Includes a 96-week OLE treatment and an OLE Phase follow-up visit 4 weeks after 
completion of open label treatment. 
The overall study design is presented graphically in Figure 1-1.
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Figure 1-1.
Overall Study Design 
Eligible subjects are randomly assigned to 1 of the following 3 treatment groups in a 2:2:1 ratio:

GS-9674 30 mg + PTM GS-9674 100 mg orally once daily (n = 30);

GS-9674 100 mg + PTM GS-9674 30 mg orally once daily (n = 30);

PTM GS-9674 30 mg + PTM GS-9674 100 mg orally once daily (n = 15),
where PTM stands for Placebo to Match.
Central randomization is used. The randomization schedule is stratified by the presence or 
absence of ursodeoxycholic acid (UDCA) use. 
Study drugs are administered for a total of 12 weeks from the Baseline/Day 1 visit during the BD 
Phase and 96 weeks during the OLE Phase. During the OLE Phase, subjects begin with open 
label treatment of GS-9674 (100 mg once daily). The dose of GS-9674 may be reduced from 
100 mg to 30 mg (or subsequently increased back to 100 mg) at the principal investigator’s (PI) 
discretion with the approval of the medical monitor, as required.
Subjects will be unblinded to their BD Phase treatment assignment after the primary analysis has 
been completed, approximately 6 weeks after all subjects have completed the BD Phase or early 
terminated. The schedule of assessments is provided as an appendix to this analysis plan
(Appendix 1).


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1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. The number of subjects was chosen based on clinical experience with other similar 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Interim Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will 
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination (ET) of the study, the continuation of the 
study, or the continuation of the study with modifications.
The initial review will be conducted after first 20 subjects have been randomized. Additional 
meetings will be scheduled approximately every 3 to 4 months in BD Phase and every 6 months 
in OLE Phase.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination due to a negative safety signal, Gilead retains final 
decision-making authority on all aspects of the study.
2.2.
Interim Analyses
There will be 1 planned administrative interim analysis when approximately 30 subjects have 
completed Week 12 assessments or discontinued from the study treatment in the BD phase.
Safety data of all randomized subjects will be included in this interim analysis, while the efficacy 
analysis will focus on the subjects who completed Week 12 assessments or discontinued from 
the study treatment in the BD Phase. Data will be summarized and/or analyzed for the BD Phase, 
as well as the OLE Phase (if applicable). 
There will be no interim assessment of superiority or futility.
2.3.
Primary Analysis
After all subjects have completed the blinded study treatment and the follow-up visit for the BD 
Phase or discontinued from the study in the BD Phase, outstanding data queries have been 
resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the study 
blind will be broken and the primary analysis of the data will be performed.


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2.4.
Final Analysis
After all subjects have completed the open label treatment and the follow-up visit for the OLE 
Phase, or discontinued from study, and data have been cleaned and finalized, 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 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.
This study is not designed to formally test statistical hypotheses. Efficacy endpoints will be 
evaluated for exploratory purposes. 
By-subject listings will be presented for all subjects in the corresponding analysis sets in 
accordance with tables, and sorted by subject identification (ID) number, visit date, and time (if 
applicable). Data collected on log forms, such as AEs, will be presented in chronological order 
within subject. Age, sex at birth, race, and ethnicity will be included in the listings, as space 
permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set in BD Phase will be 
determined before the study blind is broken for analysis. The analysis set will be identified and 
included as a subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized. The denominator for percentage calculation will be the total number of subjects 
in the All Randomized Analysis Set by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized into the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized into the study and took
at least 1 dose of study drug. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.


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3.1.4.
OLE Analysis Set
The OLE Analysis Set includes all subjects who took at least 1 dose of study drug in the OLE 
Phase. This is the primary analysis set for safety and efficacy analyses during the OLE Phase.
3.1.5.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all randomized subjects who took at least 
1 dose of study drug and have at least 1 nonmissing postdose concentration data of analytes 
GS-9674 (and its metabolites as applicable) reported by the PK laboratory. This is the primary 
analysis set for all PK analyses. 
3.1.6.
Pharmacokinetic Substudy Analysis Set
 
 
 
3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were randomized. For analyses based on the Safety Analysis Set and PK Analysis Set, 
subjects will be grouped according to 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 duration in the BD Phase.  
For analyses in the BD Phase, subjects will be grouped into the following groups, and only the 
BD Phase data will be summarized:
1) BD Phase GS-9674 100 mg: This group includes all subjects who received GS-9674 100 mg
in the BD Phase;
2) BD Phase GS-9674 30 mg: This group includes all subjects who received GS-9674 30 mg in 
the BD Phase;
3) BD Phase GS-9674 Pooled: This group includes all subjects who received GS-9674 100 mg 
or GS-9674 30 mg in the BD Phase;
4) BD Phase Placebo: This group includes all subjects who received Placebo in the BD Phase. 
Treatment groups 1, 2 and 4 will be presented in efficacy tables in BD Phase. Treatment 
groups 1 - 4 will be presented in all tables other than efficacy tables in BD Phase.
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For analyses in the OLE Phase, subjects will be grouped into the following groups, and only the 
OLE Phase data will be summarized:
5) OLE Phase GS-9674 - Previously in 100 mg: This group includes all subjects who received
the OLE study drug and previously received GS-9674 100 mg in the BD Phase;
6) OLE Phase GS-9674 - Previously in 30 mg: This group includes all subjects who received
the OLE study drug and previously received GS-9674 30 mg in the BD Phase;
7) OLE Phase GS-9674 - Previously in Placebo: This group includes all subjects who received 
the OLE study drug and previously received placebo in the BD Phase;
8) OLE Phase GS-9674 Total: This group includes all subjects who received the OLE study 
drug.
For long-term (LT) analyses, subjects will be grouped into the following groups, and data from 
both BD Phase and OLE Phase will be summarized:
9) LT GS-9674 initially in 100 mg: This group includes all subjects who received GS-9674 
100 mg in the BD Phase and may or may not enter the OLE Phase;
10) LT GS-9674 initially in 30 mg: This group includes all subjects who received GS-9674 
30 mg in the BD Phase and may or may not enter the OLE Phase.
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive voice or web response 
system (IXRS) in a 2:2:1 ratio using a stratified randomization schedule. Randomization will be 
stratified by the presence or absence of UDCA use as below:

Presence of UDCA use at baseline in BD Phase
or

Absence of UDCA use at baseline in BD Phase
If there are discrepancies in stratification factor values between the IXRS and concomitant 
medication records from the clinical database, the values recorded in the clinical database will be 
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3.4.
Examination of Subject Subgroups
Subgrouping of subjects based on randomization stratification factors will be explored for 
subgroup analyses. The subgroups are as follows:

Subjects with UDCA use at baseline in BD Phase

Subjects without UDCA use at baseline in BD Phase
See Section 6.4 for details.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.  P-values, when presented, are for exploratory purposes only.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen failures, 
the date the informed consent was signed will be used for age calculation. If only the birth year is 
collected on the case report form (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.


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.
The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤x” or “≥ x” (where x is considered the LOQ).
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day/OLE study day will be calculated from the first dosing date of study drug in the BD 
Phase/OLE Phase and derived as follows:

For postdose study days: Assessment Date – First Dosing Date of the study phase + 1

For days prior to the first dose: Assessment Date – First Dosing Date of the study phase 
Therefore, study day 1/ OLE study day 1 is the day of first dose of study drug administration in 
the corresponding phase.
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.
The analysis windows to be applied to the BD Phase are provided in Table 3-1, Table 3-2, 
Table 3-3 and Table 3-4, except that the algorithm for assigning baseline analysis window does 
not apply to the liver tests (ALP, ALT, AST, and total bilirubin). For these 4 parameters, the 
baseline values will be determined by averaging the values obtained at screening and 
Baseline/Day 1, and no specific study day is associated with the average values.


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Table 3-1.
Analysis Visit Windows in BD Phase for Vital Signs, Body Weight, 
Pruritus Measures, Chemistry, Hematology, and Coagulation 
Laboratory, UK-PBC Score, and GLOBE PBC Risk Score
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
NA
1
Week 1
8
2
11
Week 2
15
12
21
Week 4
29
22
42
Week 8
57
43
70
Week 12
85
71
≥ 85
NA = not applicable 
Table 3-2.
Analysis Visit Windows in BD Phase for Lipid Profiles, and Pooled 
Cohort Risk Score
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
NA
1
Week 1
8
2
18
Week 4
29
19
42
Week 8
57
43
70
Week 12
85
71
≥ 85
NA = not applicable 
Table 3-3.
Analysis Visit Windows in BD Phase for Fibroscan®, QoL 
Questionnaires, and Electrocardiogram (ECG), HOMA-IR, HbA1c, 
C-peptide, Insulin, ELF™ Score, FibroSURE/FibroTest, 
High-sensitivity C-reactive Protein (hsCRP)
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
NA
1
Week 12
85
2
≥ 85
NA = not applicable 


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Table 3-4.
Analysis Visit Windows in BD Phase for FGF19, C4 and Total Bile 
Acids
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
NA
1
Week 1
8
2
18
Week 4
29
19
56
Week 12
85
57
≥ 85
NA = not applicable 
The analysis windows to be applied to the OLE Phases are provided in Table 3-6, Table 3-7, 
Table 3-8, Table 3-9 and Table 3-10.
Table 3-5.
Analysis Visit Windows in OLE Phase for Vital Signs, Body Weight, 
Lipid Profiles, Pruritus Measures, Chemistry, Hematology and 
Coagulation Laboratory, Pooled Cohort Risk Score, UK-PBC Score, 
and GLOBE PBC Risk Score
Analysis Visit
OLE Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 1
8
2
11
OLE Week 2
15
12
21
OLE Week 4
29
22
42
OLE Week 8
57
43
70
OLE Week 12
85
71
126
OLE Week 24
169
127
210
OLE Week 36
253
211
294
OLE Week 48
337
295
378
OLE Week 60
421
379
462
OLE Week 72
505
463
546
OLE Week 84
589
547
630
OLE Week 96
673
631
≥ 673
NA = not applicable 


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Table 3-6.
Analysis Visit Windows in OLE Phase for QoL Questionnaires
Analysis Visit
Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 4
29
2
56
OLE Week 12
85
57
126
OLE Week 24
169
127
210
OLE Week 36
253
211
294
OLE Week 48
337
295
378
OLE Week 60
421
379
462
OLE Week 72
505
463
546
OLE Week 84
589
547
630
OLE Week 96
673
631
≥ 673
NA = not applicable 
Table 3-7.
Analysis Visit Windows in OLE Phase ELF™Score and hsCRP 
Analysis Visit
OLE Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 24
169
2
252
OLE Week 48
337
253
420
OLE Week 72
505
421
588
OLE Week 96
673
589
≥ 673
NA = not applicable 
Table 3-8.
Analysis Visit Windows in OLE Phase for FGF19, C4, and Total Bile 
Acids
Analysis Visit
Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 4
29
2
56
OLE Week 12
85
57
126
OLE Week 24
169
127
252
OLE Week 48
337
253
420
OLE Week 72
505
421
588
OLE Week 96
673
589
≥ 673
NA = not applicable 


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Table 3-9.
Analysis Visit Windows in OLE Phase FibroSURE/FibroTest®
Analysis Visit
OLE Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 48
337
2
420
OLE Week 72
505
421
588
OLE Week 96
673
589
≥ 673
NA = not applicable 
Table 3-10.
Analysis Visit Windows in OLE Phase for MRE
Analysis Visit
OLE Study Day
Lower Limit
Upper Limit
OLE Baseline
1
NA
1
OLE Week 48
337
2
505
OLE Week 96
673
506
≥ 673
NA = not applicable
Note: MRE values are collected at baseline in BD Phase, OLE Week 48, and Week 96 in OLE Phase, and will be analyzed in 
OLE phase only.
For the safety and efficacy endpoints listed above where visit windows are to be assigned by 
study phase, data collected up to and including the last dosing date + 30 days of the 
corresponding phase (and before the first dose of OLE phase for Week 12 visit in BD Phase) will 
be mapped according to the specified analysis windows unless the nominal visit is ET or 
follow-up (FU) in BD/OLE phase.  For derived risks and scores, not all windowed visits are to 
be summarized or listed in the tables, figures and listings. Refer to Section 6.1.1, 6.2.1, and 6.3.1
for the analysis visits to be presented.
In LT analysis, the above endpoints will first be mapped to visit windows in the BD Phase and 
the OLE Phase (if applicable), respectively.  The LT analysis window will be mapped from their 
BD Phase window and OLE Phase window:

The baseline visit of BD Phase is to be mapped to LT Baseline

The on-treatment visits of BD Phase is to be mapped to the same Week number in LT 
analysis, ie, Week 1, 2, 4, 8, 12 will be mapped to LT Week 1, 2, 4, 8, 12 accordingly

The baseline visit of OLE Phase is to be mapped to LT OLE Baseline

For visits in OLE phase, the on-treatment analysis visits will be mapped to 12 weeks after 
their originally assigned OLE week numbers, eg, data from OLE Week 1, 2, 4 will be 
mapped as LT Week 13, 14, 16 accordingly. 
The mapping algorithm is provided in Table 3-11.


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Table 3-11.
Mapping algorithm from visit windows from BD/OLE Phase to LT 
Analysis
BD/OLE Analysis Visit
LT Analysis Visit
Study Day
Baseline 
LT Baseline
1
Week 1
LT Week 1
8
Week 2
LT Week 2
15
Week 4
LT Week 4 
29
Week 8
LT Week 8 
57
Week 12
LT Week 12 
85
OLE Baseline
LT OLE Baseline
85
(OLE Week 1)
(LT Week 13)
92
(OLE Week 2)
(LT Week 14)
99
OLE Week 4
LT Week 16 
113
OLE Week 8
LT Week 20 
141
OLE Week 12
LT Week 24 
169
OLE Week 24
LT Week 36 
253
OLE Week 36
LT Week 48 
337
OLE Week 48
LT Week 60 
421
OLE Week 60
LT Week 72 
505
OLE Week 72
LT Week 84 
589
OLE Week 84
LT Week 96 
673
OLE Week 96
LT Week 108 
757
Note: Only map applicable visits per endpoint. LT OLE Baseline visit is not an on-treatment visit, which is included in the LT 
summary for reference, and carried the target study day as LT Week 12. Summary statistics from LT Week 13 and 14 will not be 
included in the tables and figures of LT analysis. 
Data relating to unscheduled visits may be assigned to a particular visit or time point. The 
following conventions will be followed:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who prematurely discontinue from the study, ET data will be summarized as a 
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
Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
“Follow-up Visit” of each phase.

In LT analysis, the ET and FU visits from BD/OLE Phase will be considered as “LTET” and 
“LTFU” visits.  However, the LTET and LTFU visits will not be summarized in LT 
summary tables or figures. 
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 rules 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 drug in the corresponding study phase, unless specified differently. If multiple 
measurements occur on the same day, the last nonmissing value prior to the time of 
first dosing of study drug 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. 

Baseline values of the liver tests (ALP, ALT, AST, and total bilirubin) in the BD Phase will 
be determined by averaging the values obtained at Screening and Baseline/Day 1. For the 
calculated baseline 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. 

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, unless 
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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 enrollment will be provided for each country and investigator within a 
country, by treatment group and overall. The summary will present the number and percentage of 
subjects enrolled. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of subjects in the stratum will be the total number of randomized subjects. If there are 
discrepancies in the value used for stratification assignment between the IXRS and the clinical 
database, the value collected in the clinical database will be used for the summary. A listing of 
subjects with discrepancies in the value used for stratification assignment between the IXRS and 
the clinical database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and study phase. This 
summary will present the number of subjects screened, the number of subjects randomized, and 
the number of subjects in each of the categories listed below:

Safety Analysis Set; 

Continuing study drug in the BD Phase (for interim analysis); 

Completed study drug in the BD Phase; 

Did not complete study drug with reasons for premature discontinuation of study drug in BD
Phase,

OLE Analysis Set 

Continuing study drug in the OLE Phase (for interim/primary analysis);

Completed study drug in the OLE Phase;

Did not complete study drug with reasons for premature discontinuation of study drug in the 
OLE Phase.

Continuing study (for interim/primary analysis); 

Completed study; 

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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/OLE 
Analysis Set corresponding to that column in that study phase. In addition, a flowchart will be 
provided to depict the disposition.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study drug discontinuation in each study phase or study 
discontinuation

Reasons for screen failure will be provided by screening ID number in ascending order

Lot number and kit ID
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
For each study phase, total duration of exposure to study drug will be defined as last dose date 
minus first dose date plus 1 of the reporting phase, 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). When summarizing cumulative exposure in LT analysis, the sum of exposure in 
the BD Phase and OLE Phase is used.  If the last study drug dose date is missing, the latest date 
among the study drug end date, clinical visit date, laboratory sample collection date, and vital 
signs assessment date that occurred during the on-treatment period will be used.
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: 1 day, 4 weeks, 8 weeks, and 12 weeks in the BD Phase; 1 day, 4 weeks, 
12 weeks, 24 weeks, and every 12 weeks thereafter in the OLE Phase. Summaries will be 
provided by treatment group 1 – 4 for the Safety Analysis Set in the BD Phase, 5 – 8 for the OLE 
Analysis Set in the OLE Phase, and 9 – 10 for the LT analysis, as defined in Section 3.1 and 
Section 3.2.
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:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















4.2.2.1.
Adherence in the BD Phase
Prescribed adherence rate will be calculated for the BD Phase and will be provided by treatment 
group 1, 2 and 4 by type of tablet for the Safety Analysis Set in the BD Phase. The level of 
prescribed adherence to the study drug regimen will be determinehd 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 BD Phase.
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






Total amount of study drug specified by protocol for the BD Phase is 84 for each type of tablet. 
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.
4.2.2.2.
Adherence in the OLE Phase
On-treatment adherence rate will be calculated for the OLE Phase and will be provided by 
treatment group 5 - 8 for the OLE Analysis Set in the OLE Phase. The level of on-treatment
adherence to the study drug regimen will be determined by the total amount of study drug 
administered relative to the total amount of study drug expected to be administered during a 
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The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






On-Treatment adherence will be calculated based on overall tablets administered, regardless of 
the type of the tablets in OLE Phase. Descriptive statistics for the level of on-treatment
adherence with the number and percentage of subjects belonging to adherence categories 
(< 75%, ≥ 75 to < 90%, ≥ 90%) will be provided.
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number and percentage of subjects who did not meet specific criteria by treatment group 
based on the All Randomized Analysis Set. A by-subject listing will be provided for those 
subjects who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will 
present the eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and 
related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the All Randomized Analysis Set/OLE Analysis Set 
per study phase. 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 for the BD phase.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Baseline Characteristics
Other baseline characteristics include 

Body weight 

Height 

Body mass index (BMI) as a continuous variable and by categories (< 18.5 kg/m2, 18.5 to 
< 25 kg/m2, 25 to < 30 kg/m2  and ≥30 kg/m2)

UDCA use (Yes or No, based on concomitant medication page)

ALP as a continuous variable and by categories (< 1.67 ULN or ≥ 1.67 ULN) 

Total bilirubin as a continuous variable and as categories (≤ ULN or > ULN)

Direct bilirubin

ALT as a continuous variable and by categories (< ULN and ≥ ULN)

AST as a continuous variable and by categories (< ULN and ≥ ULN)

GGT

Fasting serum glucose 

Fasting insulin

Homeostatic assessment of insulin resistance (HOMA-IR)

Hemoglobin A1c (HbA1c)

Fasting triglycerides

Total cholesterol


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
High density lipoprotein-cholesterol (HDL-C)

Calculated fasting low density lipoprotein-cholesterol (LDL-C)

Calculated fasting very low density lipoprotein-cholesterol (VLDL-C)

Calculated fasting non high density lipoprotein-cholesterol (Non-HDL-C)

ELF™ score and components (hyaluronic acid [HA], procollagen III amino terminal peptide 
[PIIINP], tissue inhibitor of metalloproteinase 1 [TIMP-1])

FibroSURE/FibroTest®

FibroScan

hsCRP

Fasting total bile acids

Albumin

INR

Platelets

Creatinine

Smoking status at baseline

Diabetes mellitus diagnosis at baseline (yes or no, based on medical history page)

Taking hypertension treatment at baseline (yes or no, based on prior and concomitant 
medication page)
These baseline characteristics will be summarized by treatment group 1 - 4 and overall 
(Section 3.2) 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. In addition, baseline characteristics will be summarized by 
baseline UDCA use in a separate table. No formal statistical testing is planned.
The tables will be repeated for the OLE Phase by treatment group 5 - 8 (Section 3.2), except for 
height, fasting insulin, HOMA-IR, HbA1c, FibroScan, smoking status and diabetes diagnosis, 
which are not collected in the OLE Phase.
A by-subject listing of 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.


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6.
EFFICACY ANALYSES
Efficacy data will be summarized and analyzed based on the FAS for the BD Phase using 
treatment group 1, 2, and 4.  Data from the OLE Phase will be summarized based on the OLE 
Analysis Set using treatment group 5-8.  For the LT analysis data will be summarized using 
treatment group 9-10. Refer to Section 3.2 for the detailed grouping of subjects.
6.1.
Exploratory Efficacy Endpoints in the BD Phase
6.1.1.
Definition of Exploratory Efficacy Endpoints
 
 
 
 
PPD
PPD


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PPD
PPD
I 


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6.1.2.
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD


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A Wilcoxon Rank Sum test will be used to compare change from baseline in ALP at Week 12 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
PPD
PPD
PPD


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6.2.
Exploratory Efficacy Endpoints in OLE Phase
6.2.1.
Definition of Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD


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PPD
PPD


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6.2.2.
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
  
 
 
 
 
 
PPD
PPD


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6.3.
Exploratory Efficacy Endpoints in Long Term Analysis
6.3.1.
Definition of Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


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PPD
PPD


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6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints in Long Term 
Analysis
 
 
  
 
 
 
 
PPD
PPD
PPD


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6.4.
Subgroup Analysis of the Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
PPD
PPD
PPD


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7.
SAFETY ANALYSES
Safety data will be summarized based on the Safety Analysis Set for the BD Phase using 
treatment group 1 − 4 in Section 3.2, and the LT analysis using treatment group 9 − 10. Data 
from OLE Phase will be summarized based on the OLE Analysis Set using treatment group 5 - 8.  
Refer to Section 3.2 for the detailed grouping of subjects.
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.
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 Drug Safety and 
Public Health 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 in the BD Phase (and before the first dosing 
date in the OLE Phase)/OLE Phase.

Any AEs leading to premature discontinuation of study drug in the BD/OLE phase.


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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 (TE) AEs will be summarized based on the Safety Analysis Set for the BD 
Phase, and the LT analysis. TEAEs in the OLE Phase will be summarized based on the OLE 
Analysis Set.  In LT analysis, TEAEs will be those included in BD Phase/OLE Phase summary.  
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and treatment group. For other AEs described below, summaries will 
be provided by SOC, PT, and treatment group:

TEAEs of Grade 3 or higher 

TEAEs by severity

All TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher 

TE Treatment-related AEs by severity

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to death (ie, outcome of death)


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
All TEAEs leading to dose interruption of study drug

All TEAEs leading to dose reduction of study drug (OLE Phase only)

All AEs recorded between screening and prior to first dose of study drug
A brief, high-level summary of TEAEs, TEAEs with Grade 3 or Higher, TEAEs Related to 
Study Drug, TEAEs Related to Study Drug with Grade 3 or Higher, TE Serious AEs, TE Serious 
AEs Related to Study Drug, and TEAEs Leading to Premature Discontinuation of Study Drug 
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 
frequency of BD GS-9674 100 mg group within each SOC in the BD Phase/ total frequency 
within each SOC for the OLE Phase/ frequency of LT GS-9674 initially in 100 mg group in the 
long-term summary. 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 frequency in the GS-9674 100 mg group in the BD Phase/total frequency for 
the OLE phase/ frequency of LT GS-9674 initially in 100 mg group in the long-term summary:

All TEAEs

TEAEs of Grade 3 or higher 

TE treatment-related AEs

TE treatment-related AEs of Grade 3 or higher

All TE SAEs 

All TE treatment-related SAEs
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment-emergent

All AEs of Grade 3 or higher

SAEs

All TEAEs leading to Death


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
AEs leading to premature discontinuation of study drug

AEs leading to dose interruption of study drug

AEs leading to dose reduction of study drug (OLE Phase only)
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set/ OLE Analysis Set and will include data collected up to the last dose of 
study drug plus 30 days in the BD Phase (and on or before the first dose date in the OLE Phase)/ 
OLE Phase for subjects who have permanently discontinued study drug, or all available data at 
the time of the database snapshot for subjects who were ongoing at the time of an interim 
analysis. Data obtained at the ET or FU visit will be included in the by-visit summaries by their 
nominal visit ID in BD/OLE Phase, regardless of the relevant number of days to the last dose 
date.  LT analysis will include data summarized in BD Phase/OLE Phase. Data obtained after the 
last dose of study drug plus 30 days in the BD (and prior to first dose date of OLE Phase)/OLE 
Phase will not be included in the evaluation of the TE laboratory abnormalities in the LT 
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. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
CTCAE severity grade will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for HOMA-IR, HbA1c, albumin, 
creatinine, fasting insulin, fasting glucose, prothrombin time, INR, WBC, neutrophils, 
lymphocytes, hemoglobin, platelets as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) of the observed values for HOMA-IR, HbA1c, albumin, creatinine, fasting 
insulin, fasting glucose, prothrombin time, INR, WBC, neutrophils, lymphocytes, hemoglobin, 
platelets will be plotted using a line plot 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.
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.
For the baseline ALP, ALT, AST, total bilirubin toxicity grades at the BD Phase, the CTCAE 
version 4.03 will be used to assign grades to the derived average values. See Appendix 2 for the 
link to CTCAE 4.03. 
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 in the BD Phase (and on or before the first dose of the OLE 
Phase)/ OLE Phase 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. LT analysis will include data summarized in BD Phase/OLE Phase. Data obtained after 
the last dose of study drug plus 30 days in the BD (and prior to first dose date of OLE 
Phase)/OLE Phase will not be included in the evaluation of the TE laboratory abnormalities in 
the LT 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 in BD Phase (and on or before the first dose of OLE 
Phase)/ OLE Phase 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. LT analysis will include data summarized in BD Phase/OLE Phase. Data obtained after 
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Phase)/OLE Phase will not be included in the evaluation of the TE laboratory abnormalities in 
the LT analysis.  If the relevant baseline laboratory value is missing, any Grade 3 or 4 values 
observed within the timeframe specified above will be considered treatment-emergent marked 
abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group for the BD Phase, the OLE Phase, 
and the LT analysis, separately; subjects will be categorized according to the most severe
postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose date in the study phase reported.
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 or abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:
Subjects meet criteria for liver-related events:

For subjects with normal baseline ALT (AST):
ALT (AST) > 3 ULN
Total bilirubin > 2 ULN
INR >1.5 (except for subjects on anticoagulant therapy)
For subjects with elevated ALT (AST) (≥upper limit of normal [ULN]) at study start: 
ALT (AST) > 2 baseline 
Total bilirubin > 2 ULN
INR >1.5 (except for subjects on anticoagulant therapy) 


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Subjects meet criteria for drug withheld

ALT (AST) > 5 baseline

ALT (AST) >10 ULN

ALT (AST) >3 baseline with total bilirubin > 2 ULN

ALT (AST) >3 baseline with total bilirubin > 1.5 baseline 

ALT (AST) >3 baseline with INR >1.5 (except for subjects on anticoagulant therapy)

ALT (AST) > baseline with total bilirubin > 2 ULN, and INR >1.5 (except for subjects on 
anticoagulant therapy)

ALT (AST) > baseline with total bilirubin > 1.5 baseline, and INR >1.5 (except for 
subjects on anticoagulant therapy)
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug in the BD Phase (and on or before the first dose of the OLE Phase)/ OLE Phase. LT 
analysis will include data summarized in BD Phase/OLE Phase. For individual laboratory tests, 
subjects will be counted once based on the most severe postbaseline values. For the criteria of 
ALT (AST) and total bilirubin, 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/ OLE Analysis Set who have nonmissing postbaseline values of all relevant tests at 
the same postbaseline visit date in the corresponding baseline group. A listing of subjects who 
met at least 1 of the above criteria will be provided.
7.3.
Vital Signs
Descriptive statistics will be provided for vital signs (systolic and diastolic blood pressure 
[mmHg], pulse [beats/min], respiratory rate [breath/min] and temperature [°C]) in the BD Phase, 
the OLE Phase and the LT analysis according to treatment groups in Section 3.2 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 in the reporting phase. 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.


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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. 
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall in BD Phase. A subject reporting the same 
medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered by preferred 
term in order of descending overall frequency. For drugs with the same frequency, sorting will 
be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dose date of study 
drug will be included in the prior medication summary regardless of when the stop date is. If a 
partial start date is entered the medication will be considered prior unless the month and year (if 
day is missing) or year (if day and month are missing) of the start date are after the first dose
date. Medications with a completely missing start date will be included in the prior medication 
summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in descending 
frequency in the GS-9674 100 mg group (BD Phase/LT analysis), and in the “GS-9674 Total” 
group (OLE Phase). For drugs with the same frequency, sorting will be done alphabetically.


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For the purposes of analysis, any medications with a start date prior to or on the first dose date of 
study drug of the study phase and continued to be taken after the first dose date, or started after 
the first dose date but prior to or on the last dose date of study drug of the study phase will be 
considered concomitant medications. Medications started and stopped on the same day as the 
first dose date or the last dose date of study drug will also be considered concomitant. 
Medications with a stop date prior to the date of first dose date of study drug or a start date after 
the last dose date of study drug will be excluded from the concomitant medication summary. If a 
partial stop date is entered, any medication with the month and year (if day is missing) or year (if 
day and month are missing) prior to the date of first study drug administration will be excluded 
from the concomitant medication summary. If a partial start date is entered, any medication with 
the month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will be excluded from the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. Summaries will be based on the Safety Analysis Set/ OLE 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
ECG analysis results are intended to identify meaningful abnormalities. If potential abnormalities 
of interest are identified, further analyses may be conducted. 
A shift table of the investigators’ assessment of ECG results at Week 12 of the BD Phase 
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.
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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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
A single predose PK blood sample (Sparse PK Sampling) will be collected at Week 1, 2, 4, 8, 
and 12 in BD Phase for all subjects.
 
 
 
 
 
8.2.
PK Analyses Related to Intensive PK Sampling
 
8.2.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear up/log down rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to 0.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing 
interval (τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
PPD
PPD


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8.2.2.
PK Parameters
 
The analytes and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The primary PK parameters are AUClast, AUCtau, and Cmax of GS-9674. The PK 
parameters to be estimated in this study are listed and defined in the PK Abbreviations section.
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-9674
AUClast, AUCtau, Cmax, Tmax, Clast, Tlast, Ctau, λz, CLss/F, and t1/2
GS-716070
AUClast, AUCtau, Cmax, Tmax, Clast, Tlast, Ctau, λz, and t1/2
Individual subject concentration data and individual subject PK parameters for GS-9674 and its
metabolites (as appropriate), will be listed and summarized using descriptive statistics by 
treatment. Summary statistics (n, mean, SD, coefficient of variation [%CV], median, min, max, 
Q1, and Q3) will be presented for both individual subject concentration data by time point and 
individual subject PK parameters by treatment. Moreover, the geometric mean, 95% CI, and the 
mean and SD of the natural log-transformed values will be presented for individual subject PK 
parameter data. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated 
as 0 at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points. 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by treatment:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
PPD
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The following figures may be provided for each analyte by treatment:

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)
Mean, postdose concentration values that are ≤LLOQ will not be displayed in the figures and 
remaining points connected.
The following listings will be provided:

PK sampling details by subject including actual dosing time, actual draw time, calculated 
time postdose of sample collection, differences in scheduled and actual draw times, sample 
age, and sample concentration

Individual data on determination of plasma half-life and corresponding correlation coefficient
8.3.
PK Analyses Related to Sparse PK Sampling
Single PK concentration data along with the actual collection time and dosing time, and 
calculated time postdose of sample collection will be included in the corresponding PK data 
listing described in Section 8.2.2.


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9.
REFERENCES
Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, et al. The UK-PBC risk scores: 
Derivation and validation of a scoring system for long-term prediction of end-
stage liver disease in primary biliary cholangitis. Hepatology 2016;63 (3):930-50.
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J 
Dermatol 2010;162 (3):587-93.
Goff DC, Jr., Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. 2013 
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the 
American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines. Circulation 2014;129 (25 Suppl 2):S49-73.
Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, et al. Development, validation, 
and evaluation of the PBC-40, a disease specific health related quality of life 
measure for primary biliary cirrhosis. Gut 2005;54 (11):1622-9.
Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. 
Development and Validation of a Scoring System to Predict Outcomes of Patients 
With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. 
Gastroenterology 2015;149 (7):1804-12 e4.


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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
14 Aug 2018
7.2, 7.4 and 
appendix 3
Clarified the calculation of TE lab 
abnormality, the updated format to 
report for prior and concomitant 
medications, and the algorithm for 
computing overall 5-D itch score. 
To provide a clear guide for 
programming team to produce 
the relevant TFLs in 
DMC/Primary Analysis. 


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 3.
Programming Specifications


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Appendix 1.
Study Procedures Table
Blinded Study Phase Treatment Weeks (±3 days)
OLE Weeks
(±3 days weeks 1-12 and ±5 days
weeks 24-96)
Screening a
Baseline
(Day 1)
Week 
1
Week 
2
Week 
4
Week 
8
Week 12/ET b
Blinded Study Phase 
follow-up visit 
(±5 days) c
OLE 
Baseline/Day 1, 
Weeks 1, 2, 4, 8, 
12, 24, 36, 48, 60, 
72, 84, 96/ET b
OLE 
follow-up d
Subject Fasting
X
X
X
X
X
X
X
Written Informed 
Consente
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Pruritus VAS &5D- Itch f
X
X
X
X
X
X
X
X
X
QoL SF-36, & PBC-
40 f
X
X
X
X
Symptom-directed PEg
X
X
X
X
X
X
X
X
X
X
Vital Signsh
X
X
X
X
X
X
X
X
X
X
Height and weighti
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X
X
X
X
X
X
X
X
X
X
Cirrhosis Assessments
X
Lipid Profile
X
X
X
X
X
X
X
X
C-Peptide, Hemoglobin 
A1C and Insulin
X
X
Blood for Biomarkers j
X
X
X
X
X
X
X


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Blinded Study Phase Treatment Weeks (±3 days)
OLE Weeks
(±3 days weeks 1-12 and ±5 days
weeks 24-96)
Screening a
Baseline
(Day 1)
Week 
1
Week 
2
Week 
4
Week 
8
Week 12/ET b
Blinded Study Phase 
follow-up visit 
(±5 days) c
OLE 
Baseline/Day 1, 
Weeks 1, 2, 4, 8, 
12, 24, 36, 48, 60, 
72, 84, 96/ET b
OLE 
follow-up d
Single PK and PD 
Sampling
X l
X
X
X
X
X
HIV-1, HBV and HCV 
Serology
X
Pregnancy Testl
X
X
X
X
X
X
X
X
X
Serum FSHm
X
12- lead ECGs
X
X
Fibroscano
X
X
MREp
X
X
Urine drug screening
X
Urine collection 
(Biomarkers)q
X
X
X
X
X
X
Stool collection 
(Biomarkers)r
X
X
X
X
Dispense GS-9674/ PTM 
GS-9674t
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Take GS-9674/ PTM 
GS-9674 Tablets
X – Daily (Baseline/ Day 1 to Week 12)u
X-Daily (OLE 
Baseline/ Day 1 to 
Week 96)
PPD
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a
The visit window may be extended under special circumstances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to an abnormal 
laboratory result may undergo re-testing of the abnormal analyte during the screening window. This will be done at the discretion of the investigator and also with prior 
approval of the Medical Monitor.
b
Blinded Study Phase subjects discontinuing the study at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 12/ Visit AND 
the follow-up visit. OLE Phase subjects discontinuing the study at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 96/ 
Visit AND the follow-up visit if possible.
c
After completing 12 weeks of treatment in the Blinded Study Phase, subjects will return for the follow-up visit 4 weeks post the last dose of the study drug and at that time 
they can begin their OLE Phase. Follow-up visit for Blinded Study Phase and Baseline/Day 1 OLE visit can occur on the same day if convenient. If OLE Baseline/Day 1 and 
Blinded study follow-Up visit is on the same day subjects should only complete OLE Baseline /Day 1 assessments.
d
Follow-up visit should be completed during the Blinded Study Phase as well as the OLE Phase.
e
Obtain written informed consent before initiation of any screening procedure.
f
QoL questionnaires and Pruritus assessments should be completed prior to any study procedures being performed and prior to the subject seeing a health care provider. Refer 
to the Study Reference Binder for guidance on QoL questionnaire administration. During OLE, QoL questionnaires are required at OLE Baseline/Day 1, Weeks 4, 12 and 
every 12 weeks thereafter. 
g
Complete PE at screening and symptom-directed PE for other visits. The focus of a symptom-driven physical examination will be determined by the investigator based on 
subject complaint.
h
Vital signs include (heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature)
i
Height should be collected at Screening and Baseline/Day 1 only. Weight should be collected at all visits. Refer to the Study Reference Binder for specific instructions on 
how weight should be measured.
j
Biomarker analyses include, but are not limited to, the tests listed in Section 6.12.1 of the protocol. 
 
k
PD sampling only at Baseline/Day 1.
l
Females of childbearing potential only (see Appendix 4 of the protocol). Serum pregnancy tests at Screening. Urine pregnancy test at all other visits, except Blinded Study 
Phase Week 2 and OLE Weeks 1, and 2.
m
Only required for some female subjects – see Appendix 4 of the protocol. 
o
Subject should be in fasted state for FibroScan® collection. Refer to the study reference binder for further details. If FibroScan® is not available at a site the test may be 
omitted.
p
Should be in a fasted state for MRE scan. Refer to study reference binder for further details.  If MRE is not available at a site the test may be omitted. MRE scan should be 
performed at Blinded Study Phase Baseline/Day 1 and OLE Weeks 48 and 96.
q
Urine Biomarker sample collection at Blinded Study Phase Baseline/Day 1, week 1, weeks 4, 12 and at the Follow up and Early term visits. Urine Biomarker sample 
collection during OLE at OLE Baseline/Day 1, Weeks 24, 48, 72 and 96 only.
r
Stool sample collection at Blinded Study Phase Baseline/Day 1, Week 12 and at the Follow up and Early term visits.  Stool sample collection during OLE at OLE 
Baseline/Day 1, Week 48 and Week 96 visit
t
Study drug will be assigned via the IWRS system every 4 weeks from Baseline/Day 1 through Week 8 in Blinded Study Phase and at OLE Baseline/Day 1, Weeks 1, 4, 8 12 
and every 12 weeks thereafter.
u
Subjects to self-administer the study drug at the investigative site at the conclusion of the Blinded Study Phase Baseline/Day 1 and Week 12 visit.
PPD
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Appendix 2.
CTCAE Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


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Appendix 3.
Programming Specifications
FibroSURE/FibroTest® Calculation:
Step-1 formula
f5 = 4.467 Log[α2-macroglobulin(g/L)] – 1.357 Log[Haptoglobin (g/L)] + 1.017 
Log[GGT(U/L)] + 0.028 [Age (year)] + 1.737 Log [Total Bilirubin (umol/L)] – 1.184 
[ApoA1 (g/L)] + 0.301 Sex (female = 0, male = 1) – 5.540
Step-2 formula
FibroSURE/FibroTest® Score = 1/(1+exp^(-f5))
Note
In the formula, SI value and units should be applied.
The Log function in the formula is with base 10.
FibroSURE/FibroTest® score should be calculated from the parameters from the same blood 
draw
Age is when the blood draw was taken 
For subject with Gilbert’s syndrome or hemolysis according to the medical history page at 
screening, the FibroSURE/FibroTest® score will be calculated using Direct Bilirubin instead of 
Total Bilirubin in above formula throughout the study. 
HOMA-IR Calculation:
HOMA-IR = fasting glucose (mg/dL) fasting insulin (muIU/mL) / 405. Keep 2 decimal 
places. The lab parameters need to be measured from the same blood draw.


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Pooled Cohort Risk Score:
No.
Parameters
Coefficient
Female
Male
White or 
Other
African 
America
White or 
Other
African 
America
1
ln Age (y)
–29.799
17.114
12.344
2.469
2
ln Age, Squared
4.884
N/A
N/A
N/A
3
ln Total Cholesterol (mg/dL)
13.540
0.940
11.853
0.302
4
ln Age × ln Total Cholesterol
–3.114
N/A
–2.664
N/A
5
ln HDL-C (mg/dL)
–13.578
–18.920
–7.990
–0.307
6
ln Age × ln HDL-C
3.149
4.475
1.769
N/A
7
ln Treated Systolic BP (mm Hg)
2.019
29.291
1.797
1.916
8
ln Age × ln Treated Systolic BP
N/A
–6.432
N/A
N/A
9
ln Untreated Systolic BP (mm Hg)
1.957
27.820
1.764
1.809
10
ln Age × ln Untreated Systolic BP
N/A
–6.087
N/A
N/A
11
Current Smoker (1=Yes, 0=No)
7.574
0.691
7.837
0.549
12
ln Age × Current Smoker
–1.665
N/A
–1.795
N/A
13
Diabetes (1=Yes, 0=No)
0.661
0.874
0.658
0.645
A
Baseline Survival
0.9665
0.9533
0.9144
0.8954
B
Individual Sum = 
∑(coefficient*parameter) 
For each individual patient, individual sum is summation of 
product of each parameter and its corresponding coefficient for 
that sex-race group for all parameters listed above (#1 -#13).
Note: N/A indicates that the specific coefficient is not available 
thus the corresponding parameter will not be included in 
calculation.
C
Population Mean
–29.18
86.61
61.18
19.54
D
Pooled Cohort Risk Score  
= B – C
= Individual Sum - Population Mean
E
Pooled Cohort Risk = Estimated 
probability of a first hard ASCVD 
event within 10 years*
= 1 – A ^ exp(B-C), ie,
= 1 − Baseline Survival ^ exp (individual Sum- Overall mean 
sum)

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; ln = 
natural logarithm. Age is the actual age when the lab parameters are collected for the visit. Total Cholesterol and HDL-C, 
Systolic BP are assessed at a same visit when risk score are to be reported, where total cholesterol and HDL-C should be 
obtained on the same day. Smoker, and diagnosis of Diabetes are collected at Screening/Baseline on the page of Medical 
History. Status of hypertension treatment is determined based on prior and concomitant medications taken at baseline of the 
BD Phase for analysis for the visits in BD Phase, and on the date when the blood pressure is collected for the visit analyzed
in the OLE Phase. Round Pooled Cohort Risk Score and estimated risk of ASCVD events to 0.001. 


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GLOBE PBC Risk Score calculation is as below:
GLOBE score = 0.044378 Age at first dose of study drug (in years) 
+ 0.93982 ln[Total Bilirubin (ULN)]
+ 0.335648 ln[ALP (ULN)]
− 2.266708 Albumin (lower limit normal [LLN] )
− 0.002581 platelet (10^9/L]
+ 1.216865.
Keep 3 decimal places. Age is at first dose of study drug in BD Phase. The lab parameters need 
to be measured from the same day.
Using GLOBE risk score to predict long term risk:
Estimated probability of liver transplant or all-cause of death at year t is denoted as R(t) below, 
and will be rounded to 0.001:

R(3) = 1 −0.9652 ^ exp(GLOBE score)

R(5) = 1 −0.9385 ^ exp(GLOBE score)

R(10) = 1 −0.8429 ^ exp(GLOBE score) 

R(15) = 1 −0.7361 ^ exp(GLOBE score)
UK-PBC Risk Score calculation is as below:
UK-PBC Risk Score exponent = 0.0287854 [ALP (ULN) − 1.722136304]
− 0.0422873 {{[ALT (ULN) /10] ^ −1} − 8.675729006}
+ 1.4199 {ln[Bilirubin (ULN)/10] + 2.709607778}
−1.960303 [Baseline Albumin (LLN) − 1.17673001]
−0.4161954 [Baseline platelet (LLN) − 1.873564875]. 
Keep 3 decimal places. The lab parameters need to be measured from the same blood draw, 
except for baseline albumin and baseline platelet which are from the same day at baseline of the 
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Estimated probability of end-stage liver disease (liver transplant or liver-related death or 
bilirubin first reach ≥ 100 μmol/L without liver transplant) at year t is denoted as R(t) below, and 
will be rounded to 0.001:

R(5) = 1−0.982 ^ exp(UK-PBC Risk Score exponent)

R(10) = 1− 0.941 ^ exp(UK-PBC Risk Score exponent)

R(15) = 1−0.893 ^ exp(UK-PBC Risk Score exponent) 
5D-Itch Score:
5D-Itch contains a total of 5 questions with each ranging from 1 to 5. It includes 16 potential 
locations of itch, including 15 body part items and one point of contact with clothing or 
bandages. Single-item domain scores (duration, degree and direction) are equal to the value 
indicated below the response choice (range 1–5). The score for the disability domain is achieved 
by taking the highest score on any of the four items (Sleep, leisure/social, housework/errands, 
and work/school). For the distribution domain, the number of affected body parts is tallied 
(potential sum 0–16, where body parts with missing responses are considered not affected and 
assigned a value of zero for summation) and the sum is sorted into five scoring bins: sum of 
0-2 = score of 1, sum of 3–5 = score of 2, sum of 6–10 = score of 3, sum of 11–13 = score of 4, 
and sum of 14–16 = score of 5.  The scores of each of the five domains are achieved. For 
subjects who have entered into OLE phase, the missing value on OLE day 1 for a domain is 
imputed using the corresponding last non-missing value in BD phase. The 5D-Itch total score is 
then the summation of the five domain scores. 5D-Itch scores can potentially range between 5 
(no pruritus) and 25 (most severe pruritus) {Elman 2010}.
PBC-40:
PBC-40 scores are calculated using subject responses to 40 questions in the questionnaire. There 
are a total of 6 domains in the following across the 40 questions. 

Fatigue

Emotion

Social function

Cognitive function

General symptoms 

Itching
Analysis is by domain, with the scoring explained in the coded-PBC-40. Data should be 
considered by domain rather than in terms of a cumulative PBC-40 score. If data are missing 
from a domain (typically missed or duplicated answers) the whole domain should be discarded if 


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≥ 50% of items are missing. If >50% of responses are present then the median value for the 
completed items in the domain should be ascribed to the missing item {Jacoby 2005}.
Due to data coding issue in EDC, the scores of 1, 2, 3, 4, 5 for Question #40 were replaced with 
5, 4, 3, 2, 1, respectively, by the clinical programming team.