Conditions: Primary Sclerosing Cholangitis Compensated Cirrhosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the safety and tolerability of escalating doses of cilofexor (CILO) in participants with primary sclerosing cholangitis (PSC) and compensated cirrhosis.

Detailed description:

Arms:
arm 1: Participants will receive escalating doses of cilofexor 30 mg, 60 mg, and 100 mg.

Interventions: intervention 1: Cilofexor
Intervention descriptions: intervention 1: Tablets administered orally once daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Proof-of-Concept, Open-Label Study Evaluating the Safety and 
Tolerability of Cilofexor in Subjects with Primary Sclerosing 
Cholangitis (PSC) and Compensated Cirrhosis
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
Clinical Trials.gov 
Identifier:
131031
NCT04060147
Indication:
Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis 
Protocol ID:
GS-US-428-5443
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List
Protocol 
Version/Date:
Original:
06 May 2019
Amendment 1:
17 July 2019
Amendment 2:
22 November 2019
Amendment 3:
15 January 2021
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
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The information contained in this document, particularly unpublished data, is the property or under 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.
(rJ GILEAiJ 


Cilofexor (CILO; GS-9674) 
Protocol GS-US-428-5443 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
FINAL 
Amendment3 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXTTABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 15 
I. 
INTRODUCTION .............................................................................................................................................. 19 
1.1. 
Background ............................................................................................................................................ 19 
1.2. 
lnvestigational Medicinal Product Name ............................................................................................... 20 
1.2.1. 
General Information ............................................................................................................. 20 
1.2.2. 
Nonclinical Pharmacology ................................................................................................... 20 
1.2.3. 
Nonclinical Toxicology ........................................................................................................ 2 1 
1.2.4. 
Nonclinical Pharmacokinetics .............................................................................................. 2 1 
1.2.5. 
Clinical Trials ofCILO ........................................................................................................ 22 
1.2.6. 
A Phase I, Open-Label, Parallel-Group, Adaptive, Single-Dose Study to 
Evaluate the Phannacokinetics and Phannacodynamics ofCilofexor in 
Subjects with Normal and Impaired Hepatic Function (Study 
GS-US-402-3 885) ................................................................................................................ 23 
1.2.7. 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy ofCilofexor in Subjects 
with Primmy Sclerosing Cholangitis without Cirrhosis (Study 
GS-US-428-4025) ................................................................................................................ 24 
1.2.8. 
GS-US-428-4025: Preliminary Efficacy Results .................................................................. 27 
1.3. 
Rationale for This Study ........................................................................................................................ 36 
1.4. 
Rationale for Dose Selection of CILO ................................................................................................... 37 
1.5. 
Risk/Benefit Assessment for the Study .................................................................................................. 38 
1.6. 
Compliance ............................................................................................................................................ 39 
2. 
OBJECTIVES ..................................................................................................................................................... 40 
3. 
STUDY DESIGN ................................................................................................................................................ 4 1 
3.1. 
Study Design .......................................................................................................................................... 4 1 
3.2. 
Study Treatments ................................................................................................................................... 4 1 
3.3. 
Duration ofTreatment ............................................................................................................................ 42 
3.4. 
Biomarker Testing .................................................................................................................................. 42 
3.4.1. 
Biomarker Sam les to Address the Stud Ob·ectives: ......................................................... 42 
4. 
SUBJECT POPULATION .................................................................................................................................. 44 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 44 
4.1.1. 
Subject Replacement ............................................................................................................ 44 
4.2. 
Inclusion Criteria .................................................................................................................................... 44 
4.3. 
Exclusion Criteria ................................................................................................................................... 45 
5. 
INVESTIGA TIONAL MEDICINAL PRODUCTS ........................................................................................... 48 
5.1. 
Treatment Codes Access ........................................................................................................................ 48 
5.2. 
Description and Handling of CILO ........................................................................................................ 48 
5.2.1. 
Formulation .......................................................................................................................... 48 
5.2.2. 
Packaging and Labeling ....................................................................................................... 48 
CONFIDENTIAL 
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5.2.3.
Storage and Handling...........................................................................................................48
5.3.
Dosage and Administration of CILO .....................................................................................................49
5.4.
Prior and Concomitant Medications.......................................................................................................49
5.5.
Prohibited Medications ..........................................................................................................................49
5.6.
Accountability for CILO........................................................................................................................51
5.6.1.
Study Drugs Return or Disposal...........................................................................................51
6.
STUDY PROCEDURES ....................................................................................................................................52
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................52
6.2.
Pretreatment Assessments......................................................................................................................52
6.2.1.
Screening Visit .....................................................................................................................52
6.3.
Baseline/Day 1 Assessments..................................................................................................................54
6.4.
Treatment Assessments..........................................................................................................................56
6.4.1.
Week 1, Week 4, Week 8, and Week 12 (± 3 days).............................................................56
6.4.2.
Telephone Follow-Up Visit (weekly; during PI approved study drug dose 
interruption) .........................................................................................................................57
6.4.3.
Early Termination Visit........................................................................................................58
6.4.4.
Follow- Up Visit (± 5 Days).................................................................................................59
6.4.5.
Unscheduled Visit ................................................................................................................60
6.5.
Assessments for Premature Discontinuation from Study.......................................................................61
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................62
6.8.
Procedures and Specifications................................................................................................................63
6.8.1.
Clinical Laboratory Analytes ...............................................................................................63
6.8.2.
Medical History....................................................................................................................64
6.8.3.
Physical Examination...........................................................................................................65
6.8.4.
Vital Signs............................................................................................................................65
6.8.5.
Clinical Liver Assessments ..................................................................................................65
6.8.6.
IBD Symptom Severity Assessment ....................................................................................67
6.8.8.
Electrocardiogram................................................................................................................68
6.9.
End of Study...........................................................................................................................................68
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................69
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................69
7.1.1.
Adverse Events.....................................................................................................................69
7.1.2.
Serious Adverse Events........................................................................................................69
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................70
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................70
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................70
7.2.2.
Assessment of Severity ........................................................................................................71
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................71
7.4.
Gilead Reporting Requirements.............................................................................................................73
7.5.
Toxicity Management ............................................................................................................................73
7.5.1.
Observation for Drug-Induced Liver Injury.........................................................................73
7.5.2.
Close Observation ................................................................................................................74
7.5.3.
Child-Pugh Score .................................................................................................................76
7.5.4.
Pruritus Management ...........................................................................................................76
7.5.5.
Management of Study Drug Dose Interruption Due to AE ..................................................76
7.6.
Special Situations Reports......................................................................................................................77
CCI
CCI
CCI
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Cilofexor (CILO; GS-9674) 
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7 .6.1. 
Definitions of Special Situations .......................................................................................... 77 
7.6.2. 
lnsttuctions for Reporting Special Situations ....................................................................... 78 
8. 
STA TIS TI CAL CONSIDERATIONS ................................................................................................................ 81 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
I 
8.9. 
8.10. 
Analysis Objectives and Endpoints ........................................................................................................ 81 
8.1.1. 
Analysis Objectives .............................................................................................................. 81 
8.1.2. 
Primar End oint ................................................................................................................. 81 
.
ysis Conventions ............................................................................................................................ . 
8.2.1. 
Analysis Sets ........................................................................................................................ 82 
8.2.2. 
Data Handling Conventions ................................................................................................. 83 
Demographic Data and Baseline Characteristics ................................................................................... 83 
Efficacy Analysis ................................................................................................................................... 83 
Safety Analysis ....................................................................................................................................... 84 
8.5.1. 
Extent of Exposure ............................................................................................................... 84 
8.5.2. 
Adverse Events ..................................................................................................................... 84 
8.5.3. 
Laboratory Evaluations ........................................................................................................ 84 
8.5.4. 
Other Safe 
Evaluations ...................................................................................................... 85 
B1omar er Ana ys1s ................................................................................................................................ 5 
Sample Size ............................................................................................................................................ 86 
Data Monitoring Committee .................................................................................................................. 86 
9. 
RESPONSIBILITIES .......................................................................................................................................... 87 
9.1. 
Investigator Responsibilities .................................................................................................................. 87 
9.1.1. 
Good Clinical Practice .......................................................................................................... 87 
9 .1.2. 
Financial Disclosure ............................................................................................................. 87 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
A~row l ............................................................................................................................... 
9 .1 .4. 
Informed Consent ................................................................................................................. 87 
9.1.5. 
Confidentiality ...................................................................................................................... 88 
9.1.6. 
Study Files and Retention of Records .................................................................................. 88 
9.1.7. 
Electronic Case Report Forms .............................................................................................. 89 
9 .1.8. 
lnvestigational Medicinal Product Accountability and Return ............................................. 90 
9.1.9. 
lnspections ............................................................................................................................ 90 
9.1.10. 
ProtocoI Compliance ............................................................................................................ 9 1 
9.2. 
Sponsor Responsibilities ........................................................................................................................ 9 1 
9 .2.1. 
Protocol Modifications ......................................................................................................... 9 1 
9 .2.2. 
Study Report and Publications ............................................................................................. 9 1 
9 .3. 
Joint Investigator/Sponsor Responsibilities ........................................................................................... 9 1 
9.3.1. 
Payment Reporting ............................................................................................................... 9 1 
9.3.2. 
Access to Information for Monitoring .................................................................................. 92 
9.3.3. 
Access to Information for Auditing or Inspections .............................................................. 92 
9.3.4. 
Study Discontinuation .......................................................................................................... 92 
10. REFERENCES ................................................................................................................................................... 93 
11. APPENDICES .................................................................................................................................................... 95 
Appendix I. 
Appendix 2. 
Appendix 3. 
CONFIDENTIAL 
Investigator Signature Page .................................................................................................... 96 
Study Procedures Table .......................................................................................................... 97 
Common Terminology Criteria for Adverse Events (CTCAE) ............................................ 100 
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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................101
Appendix 5.
West Haven Criteria .............................................................................................................104
Appendix 6.
IBD Symptom Severity Assessment.....................................................................................105
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-428-4025: Demographics and Baseline Characteristics (Safety Analysis Set)..........26
Table 1-2.
GS-US-428-4025: Overall Summary of Biochemical and Biomarker Responses 
from Baseline to Week 12 (Evaluable Subjects, Full Analysis Set)*.....................................31
Table 1-3.
GS-US-428-4025: Overall Summary of Treatment-Emergent Adverse Events, 
Double-Blind Phase (Safety Analysis Set).............................................................................33
Table 1-4.
GS-US-428-4025: Treatment-Emergent Adverse Events Reported for at Least 2 
Subjects in Any Treatment Group by Preferred Term, Double-Blind Phase (Safety 
Analysis Set)...........................................................................................................................34
Table 1-5.
GS-US-428-4025: Grade 3 Treatment-Emergent Adverse Events by Preferred Term, 
Double-Blind Phase (Safety Analysis Set).............................................................................35
Table 5-1.
List of Medications Prohibited and to be used with Caution..................................................50
Table 6-1.
Child-Pugh (CP) Classification of the severity of cirrhosis....................................................66
LIST OF IN-TEXT FIGURES
Figure 1-1.
GS-US-428-4025: Median (Q1, Q3) Serum ALP Concentration (U/L) by Visit in 
Double-Blind Phase (Evaluable Subjects, Full Analysis Set) ................................................29
Figure 1-2.
GS-US-428-4025: ALP Response at Week 12 of the Randomized Phase (Evaluable 
Subjects, Full Analysis Set)....................................................................................................30
Figure 7-1.
On-Treatment ALT/AST Monitoring Requiring Close Observation......................................74
Figure 7-2.
On-Treatment Monitoring Requiring Withholding of Study Drugs .......................................75


Cilofexor (CILO; GS-9674) 
Protocol GS-US-428-5443 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
FINAL 
Amendment3 
A Proof-of-Concept Open-Label Study Evaluating the Safety and 
Tolerability of Cilofexor in Subjects with Primary Sclerosing 
Cholangitis (PSC) and Compensated Cirrhosis 
131031 
N CT0406014 7 
Approximately 10 centers in the United States 
The primary objective of this study is as follows: 
• 
To assess the safety and tolerability of escalating doses of 
cilofexor (CILO, previously known as GS-9674) in subjects with 
primary sclerosing cholangitis (PSC) and compensated cirrhosis 
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CONFIDENTIAL
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Study Design:
This is a proof-of-concept, open-label study evaluating the safety 
and tolerability of CILO in subjects with PSC and compensated 
cirrhosis.
Eligible subjects will be enrolled to receive treatment with escalating 
doses of CILO over a 12-week period. The study will consist of a 
4-week Screening period, 12 weeks of treatment (divided into three 
4-week dosing stages at 30 mg, 60 mg, and 100 mg orally once daily 
[QD]), and a follow-up visit 4 weeks after the Week 12 visit.
The overall study design is shown in the figure below:
Number of 
Subjects Planned:
Approximately 20 subjects 
Target Population:
Males and nonpregnant, nonlactating females equal to or greater than 
18 years of age with PSC and compensated cirrhosis
Duration of 
Treatment:
12 weeks scheduled treatment; up to 16 weeks if subject requires 
dose re-challenge after study drug dose interruption
Diagnosis and 
Main Eligibility 
Criteria:
Key Inclusion Criteria
1) Diagnosis of PSC based on cholangiogram (magnetic resonance 
cholangiopancreatography [MRCP], endoscopic retrograde 
cholangiopancreatography [ERCP], or percutaneous transhepatic 
cholangiogram [PTC]) or liver biopsy
2) Subjects have evidence of cirrhosis based on at least one of the 
three following criteria
a) Historical liver biopsy that reveals Ludwig stage F4 fibrosis 
(or equivalent) 
-
-
CILO 
CJLO 
CILO 
·.;; 
Oil 
30mg 
60mg 
100 mg 
> 
C: ·a 
Q. 
" 
One 30 mg tablet ----+ Two 30 mg tablets f-----+ One I 00 mg tablet 
=? ,: 
<.J 
orally once daily 
orally once da ily 
orally once daily 
_g 
VJ 
0 
u.. 
4 weeks 
4 weeks 
4 weeks 
-
-
4 weeks 
12 weeks 
4 weeks 


Cilofexor (CILO; GS-9674)
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b) Abdominal imaging with features consistent with cirrhosis in 
the opinion of the investigator (eg, small nodular liver, 
splenomegaly, evidence of portosystemic collaterals, diffuse 
surface irregularity). Magnetic resonance imaging (MRI), 
computed tomography (CT), and/or ultrasound are acceptable 
modalities to make this determination.
c) Any one of the following completed at the Screening visit:
i)
FibroScan ≥ 14.4 kPA
ii) ELF ≥ 11.3
iii) FibroTest ≥ 0.75
3) Subject has the following laboratory parameters at the Screening 
visit, as determined by the central laboratory:
a) Estimated glomerular filtration rate (eGFR) > 60 mL/min, as 
calculated by the Cockcroft-Gault equation
b) ALT ≤ 5 upper limit of the normal (ULN)
c) Total bilirubin ≤ 2 mg/dL, unless the subject is known to 
have Gilbert’s syndrome or hemolytic anemia
d) INR ≤ 1.4, unless due to therapeutic anticoagulation
e) Platelet count ≥ 75,000/µL. Patients with evidence of 
high-risk esophageal or gastric varices in the opinion of the 
investigator are excluded
f)
Negative anti-mitochondrial antibody
4) For subjects on ursodeoxycholic acid (UDCA), the dose of 
UDCA must have been stable in the opinion of the investigator
for at least 6 months before screening. For subjects not on 
UDCA, no UDCA use for at least 6 months prior to screening.
Key Exclusion Criteria
1) Current or prior history of any of the following
a) Decompensated liver disease, including ascites, hepatic 
encephalopathy (HE), or variceal hemorrhage
b) Liver transplantation
c) Cholangiocarcinoma or hepatocellular carcinoma (HCC). If a 
dominant structure has been identified, cholangiocarcinoma 
must be adequately excluded in the opinion of the 
investigator prior to Day 1


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2) Model for end-stage liver disease (MELD) score > 12 at 
screening, unless due to an alternate etiology such as therapeutic 
anticoagulation 
3) Child-Pugh (CP) score > 6 at screening, unless due to an 
alternative etiology such as Gilbert’s syndrome or therapeutic 
anticoagulation
4) Presence of moderate to severe itch in the opinion of the 
investigator at screening and baseline/Day 1
5) Ascending cholangitis within 30 days of screening
6) Presence of a percutaneous drain or biliary stent
7) Other causes of liver disease including IgG4-related sclerosing 
cholangitis, PSC-autoimmune hepatitis overlap syndrome, 
secondary sclerosing cholangitis, and 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.
8) Current moderate to severely active inflammatory bowel disease 
(IBD) (including ulcerative colitis, Crohn’s disease, and 
indeterminate colitis). See Section 6.8.6.
Note: Subjects with IBD who currently have an external ostomy 
bag and/or proctocolectomy are not subject to this exclusion 
criterion and need not undergo IBD Symptom Severity 
Assessment.
9) Current or prior history of any of the following:
a) Malignancy within 5 years of screening with the following 
exceptions:
i)
Adequately treated carcinoma in situ of the cervix
ii) Adequately treated basal or squamous cell cancer or other 
localized nonmelanoma skin cancer. 
Subjects under evaluation for possible malignancy are not 
eligible. 
b) Unstable cardiovascular disease as defined by any of the 
following:
i)
Unstable angina, myocardial infarction, coronary artery 
bypass graft surgery or coronary angioplasty within 
6 months prior to screening
ii) Transient ischemic attack or cerebrovascular accident 
within 6 months prior to screening


Cilofexor (CILO; GS-9674)
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iii) Symptomatic obstructive valvular heart disease or 
hypertrophic cardiomyopathy
iv) Symptomatic congestive heart failure
v) Uncontrolled or recurrent ventricular tachycardia or other 
arrhythmia requiring an automatic implantable 
cardioverter defibrillator (AICD). Stable, controlled atrial 
fibrillation is allowed.
vi) Hypercoagulable condition or venous or arterial 
thromboembolic disease
vii)Intestinal resection or malabsorptive condition that may 
limit the absorption of CILO. Prior cholecystectomy and 
appendectomy are permitted.
10) HIV infection (HIV antibody [Ab] and HIV ribonucleic acid 
[HIV RNA] positive)
11) Hepatitis B virus (HBV) infection (hepatitis B surface antigen 
[HBsAg] positive) 
12) Hepatitis C virus (HCV) infection (HCV Ab and HCV RNA 
positive). Subjects cured of HCV infection ≥ 2 years prior to 
screening are eligible.
13) Habitual alcohol consumption greater than 21 oz/week for males 
or 14 oz/week for females (1 oz/30 mL of alcohol is present in 
one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, and a 
1 oz/30 mL measure of 40% proof alcohol)
14) Use of antibiotics (eg, vancomycin, metronidazole, minocycline, 
etc.) for the treatment of PSC within 60 days of screening. 
Antibiotic prophylaxis for ascending cholangitis is permitted if 
stable in the opinion of the investigator for at least 6 months 
prior to screening
15) Use of any prohibited concomitant medications (CMs) as 
described in the protocol (refer to Section 5.5)
16) Positive urine screen for amphetamines, cocaine or opiates 
(ie, heroin, morphine) at screening. Subjects on stable methadone 
or buprenorphine maintenance treatment for at least 6 months 
prior to screening may be included. Subjects with a positive urine 
drug screen due to prescription opioid-based mediation are 
eligible if the prescription and diagnosis are reviewed and 
approved by the investigator


Cilofexor (CILO; GS-9674) 
Protocol GS-US-428-5443 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
FINAL 
Amendment3 
• 
After signing the infonned consent fonn, subjects will complete 
a Screening visit which will include the following assessments: 
complete medical history, review of inclusion and exclusion 
criteria, IBD symptom severity assessment (as appropriate, see 
Section 6.8.6), complete physical examination (PE) including 
assessment for ascites and HE, vital signs, height, weight, 
standard 12-lead ECG, laboratory assessments (including blood 
for biomarkers); serum pregnancy test (for females of 
childbearing potential), urine drug screen, liver stiffness 
measurement by FibroScan, calculation of CP and MELD scores, 
and review of adverse events (AE) related to Screening 
procedures and CMs. 
• 
After the Screening period, in-clinic study visits will occur at 
Baseline/Day 1 and at Weeks 1, 4, 8, and 12. At minimum, vital 
signs, symptom-driven physical examination (PE) including 
assessment for ascites and HE, safety laboratory tests, calculation 
of CP and MELD scores, pruritus assessment (VAS and 
SD-Itch), review for active IBD, for subjects with history of IBD 
(as appropriate, see Section 6.8.6), and review of AEs and CMs 
will be perfonned at every in-clinic visit. 
• 
Eligible subjects will be enrolled in the study with initial starting 
dose of CILO of 30 mg daily. Prior to initial dosing, required 
Baseline/Day 1 assessments will be perfonned and will include 
symptom-driven PE, vital signs, laboratory assessments 
including biomarker assessments (eg, ELF, FibroTest), 
pregnancy tests (for females of child-bearing potential), blood 
collection and stool collection (if available), calculation of CP 
and MELD scores, IBD symptom severity assessment and review 
for active IBD, for subjects with history of IBD (as appropriate, 
see Section 6.8.6), pruritus assessment (SD-Itch score and VAS), 
standard 12 lead ECG, and review of AEs and CMs. 
During the treatment phase of the study, subjects will undergo the 
following procedures and laboratory assessments: 
• 
Pruritus assessments: Pruritus VAS and SD-Itch at 
Baseline/Day 1 and at all subsequent in-clinic study visits 
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• 
For subjects with history of IBD (as appropriate, see 
Section 6.8.6): 
FINAL 
Amendment3 
IBD symptom severity assessment at Weeks 4, 8, and 12 
Any evidence of active IBD seen on routinely perfonned 
colonoscopy will be captured at all in-clinic visits 
I 
• 
Symptom-directed PE, assessments for ascites and HE, vital 
signs, and body weight at Baseline/Day 1 and at all subsequent 
in-clinic study visits 
• 
CP and MELD score calculations at Baseline/Day 1 and at all 
subsequent in-clinic study visits 
• 
Blood chemistry, eGFR, hematology, and coagulation panel at 
Baseline/Day 1 and at all subsequent in-clinic study visits 
• 
Lipid profile at Baseline/Day 1 and Weeks 4, 8, and 12 
• 
C-Peptide, Insulin, and hemoglobin A1c (HbA1c) at 
Baseline/Day 1 and Week 12 
• 
Urine pregnancy testing (females of childbearing potential only) 
at Baseline/Day 1 and Weeks 4, 8, 12 
• 
Biomarker Testing at Baseline/Day 1 and Weeks 1, 4, 8, and 12 
including but not limited to the following biomarkers: 
I 
I 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
-
CONFIDENTIAL 
FINAL 
Amendment3 
• 
Stool collection (biomarker) at Baseline/Day 1 and Week 12 (if 
available) 
• 
Standard 12-lead ECG at Baseline/Day 1 
• 
Liver stiffness measurement by FibroScan at Week 12 
• 
At the posttreatment follow-up visit, subjects will have a 
symptom-driven PE including assessments for ascites, HE, 
calculation of CP and MELD score, lBD symptom severity 
assessment and review for active lBD, for subjects with history 
of lBD (as appropriate, see Section 6.8.6), vital signs, weight, 
laboratory assessments including blood collection for biomarker 
assessments urine 
for females of childbearing 
potential), 
and review of 
AEs and CMs. 
CILO 30 mg (1 x 30 mg tablet), CILO 60 mg (2 x30 mg tablets), or 
CILO 100 mg (1 xl00 mg tablet) administered orally once daily. 
None 
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. 
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Statistical Methods: 
Efficacy Analysis: 
The biological activity of the study drug will be evaluated usin 
biochemist end oints and biomarker variables. 
Safety Analysis: 
All safety data collected will be listed and smmnarized, as 
appropriate, by overall. 
Sample Size: 
Due to the exploratory nature of this study, no fonnal power 
calculations were used to detennine sample size. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
-hCG
beta human chorionic gonadotropin
Ab
antibody
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AhR
aryl hydrocarbon receptor
AICD
automatic implantable cardioverter defibrillator
ALDH
aldehyde dehydrogenase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus 
time curve
BAP
biomarker analysis plan
BCRP
breast cancer resistance protein
BMI
body mass index
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CAR
constitutive androstane receptor
CFR
code of federal regulations
CILO
cilofexor
Clast
last observed quantifiable plasma/serum concentration of the drug
CLDQ
Chronic Liver Disease Questionnaire
CM
concomitant medication
Cmax
maximum observed plasma/serum concentration of drug
CP
Child-Pugh
CPK
creatine phosphokinase
CRF
case report form
CRO
contract (or clinical) research organization 
CRP
C-reactive protein
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C8
cytochrome P4502C8
CYP2C9
cytochrome P4502C9


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CYP3A 
cytochrome P4503A
DDI
drug-drug interaction
DILI
drug induced liver injury
DMC
data monitoring committee
EC
ethics committee 
EC50
concentration of drug that gives half-maximum response
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis
EQ-5D
EuroQol five dimensions
ERCP
endoscopic retrograde cholangiopancreatography
ESA
erythropoiesis-stimulating agent
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle-stimulating hormone
FXR
Farnesoid X Receptor
GCP
Good Clinical Practice
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyltransferase
GLPS
Global Patient Safety
GSI
Gilead Sciences, Inc.
GWAS
genome-wide association studies
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high-density polyethylene
HDL-C
high-density lipoprotein cholesterol
HE
hepatic encephalopathy
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HLGT
high-level group term
HLT
high-level term


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hsCRP
high sensitivity C-reactive protein
IB
investigator’s brochure
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LDH
lactate dehydrogenase
LDL-C
low-density lipoprotein cholesterol
LLT
lower-level term
LPLV
last patient last visit
MATE
multidrug and toxin extruder
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MRCP
magnetic resonance cholangiopancreatography
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
NASH
nonalcoholic steatohepatitis
NOAEL
no observed adverse event level
NOEL
no observed effect level
NTCP
sodium-taurocholate cotransporter protein
OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
OLE
open-label extension
OST
organic solute transporter
PIII-NP
procollagen type III N-terminal propeptide
PBC
primary biliary cholangitis
PD
pharmacodynamic(s)
PE
physical examination
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PRO
patient–reported outcome
PSC
primary sclerosing cholangitis
PSC-PRO
primary sclerosing cholangitis patient-reported outcome


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PT
preferred term
PTC
percutaneous transhepatic cholangiogram
PTT
partial prothrombin time
PXR
pregnane X receptor
Q1
first quartile
Q3
third quartile
QD
once daily
QoL
quality of life
RBC
red blood cell count
RNA
ribonucleic acid
RXR
Retinoid X Receptor
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SIBDQ
Short Inflammatory Bowel Disease Questionnaire
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life 
TEAEs
treatment emergent adverse events
TGR5
bile acid receptor
TIMP
tissue inhibitors of metalloproteinases
TPO
thrombopoietin
UDCA
ursodeoxycholic acid
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of the normal 
US
United States
USPI
United States prescribing information
VAS
visual analog scale
VLDL-C
very low-density lipoprotein cholesterol
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease of unknown etiology 
characterized by persistent inflammation of the bile ducts leading to fibrosis, cholestasis, and 
biliary cirrhosis {Chapman 2010, Hirschfield 2013}. The overall incidence of PSC is 0.77 per 
100,000 person-years, with a median age at diagnosis of 41 years and 2-to-1 male to female 
predominance {Molodecky 2011}. PSC is associated with inflammatory bowel disease (IBD), 
typically ulcerative colitis, in up to 90% of patients. Conversely, PSC develops in approximately 
8% of all patients with IBD {Saich 2008}. There are likely fewer than 50,000 persons with PSC 
in the United States (US), making it a rare disease. In Japan there are an estimated 1,211 patients 
with PSC. PSC affects less than 1.6 in 10,000 people in the European Union (EU), equivalent to 
a total of fewer than 82,000 people {Boonstra 2012, Isayama 2018}.
The clinical presentation of PSC is variable, and ranges from asymptomatic disease with mild 
elevations in serum alkaline phosphatase (ALP) and transaminases to more rapidly progressive, 
symptomatic disease in 15-30% of all patients. In addition to complications related to cirrhosis 
and portal hypertension, patients with PSC are prone to repeated episodes of bacterial 
cholangitis, pruritus, and are at high risk for cholangiocarcinoma. Specifically, the lifetime risk 
of cholangiocarcinoma in patients with PSC is 10-15%, a rate 160-fold that of the general 
population {Saich 2008}. 
There are no approved therapies for PSC. Medical therapy with ursodeoxycholic acid (UDCA)
may improve liver biochemistry, but does not have a beneficial impact on clinical outcomes 
{Triantos 2011}. Immunosuppressive therapy has also been ineffective {Lindor 2015}. Episodes 
of ascending cholangitis are managed supportively with antibiotics in conjunction with 
therapeutic drainage if necessary. Liver transplantation is the only therapeutic option currently 
available to patients with PSC. Outcomes of transplantation are generally favorable (five-year 
survival ~85%), but the disease recurs posttransplant in up to 25% of patients {Graziadei 1999}.
The etiology of PSC is unknown. As noted above, there is a strong association with IBD and 
genome-wide association studies (GWAS) indicate moderate genetic associations with PSC. The 
strongest associations are in the human leukocyte antigen (HLA) complex on chromosome 6p21 
with weaker associations at loci known to be associated with IBD, chromosome 3p21, 2q35 and 
the GPC5/GPC6 region on chromosome 13q31 {Karlsen 2010}. Several hypotheses as to the 
underlying cause of the disease have been proposed including aberrant homing of T cells to the 
bile ducts, autoimmunity, bile acid toxicity, and gut bacterial translocation leading to fibrosing 
cholangitis, and subsequent cholestasis and hepatotoxicity.


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1.2.
Investigational Medicinal Product Name 
1.2.1.
General Information
Cilofexor (CILO, previously known as GS-9674) is a potent and selective small molecule agonist 
of the farnesoid X receptor (FXR) whose activity in intestinal epithelial cells results in the 
release of fibroblast growth factor 19 (FGF19). FGF19 is an endocrine peptide which drives a 
signaling cascade to decrease hepatic lipogenesis, gluconeogenesis, triglyceride accumulation, 
and bile acid synthesis. Please refer to the Investigator’s Brochure (IB) for additional information 
on CILO including:

In vitro FXR agonism

Nonclinical pharmacology and toxicology

Nonclinical pharmacokinetics (PK) and In vitro metabolism
1.2.2.
Nonclinical Pharmacology
CILO interacts with the binding domain of FXR/retinoid X receptor (RXR) consistent with 
agonist activity and induces an agonist response in biochemical and cell-based assays with 
half-maximal effective concentration (EC50) of 16 and 43 nM, respectively. The biochemical 
assay value for CILO was comparable to that of other known FXR agonists and the cell-based 
assay value was more potent than chenodeoxycholic acid (EC50 of 1770 nM), an endogenous 
agonist of FXR. CILO 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.
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in 
plasma FGF19 at a dose of 5 mg/kg. In addition, the oral administration of CILO (30 mg/kg) to 
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). In monkeys, there were no effects on circulating FGF19 levels after 
IV dosing of CILO (resulting in systemic exposures higher than those observed after oral dosing) 
suggesting that FGF19 production is a result of intestinal FXR agonism in response to local 
enteric concentrations of CILO. The low systemic free drug concentrations contributed to the 
lack of effects following IV administration of CILO. CILO reduced liver fibrosis in a 
choline-deficient high fat diet/NaNO2 rat model of liver fibrosis.
There were no CILO-related effects on the central nervous or respiratory systems in mice or the 
cardiovascular system in cynomolgus monkeys administered up to 600 mg/kg (mice) or 
300 mg/kg (monkey) CILO. 
Overall, the results from these pharmacology studies demonstrate that CILO is a potent and 
selective agonist of intestinal FXR with the potential to benefit patients with PSC by inducing 
FGF19 production and reducing bile acid levels.


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1.2.3.
Nonclinical Toxicology
The nonclinical toxicity profile of CILO has been assessed in mice, rats, and cynomolgus 
monkeys administered CILO orally for up to 26, 13, and 39 weeks, respectively. CILO-related 
effects were primarily limited to nonadverse findings in the liver for all species that are likely 
related to the pharmacology of the compound. These findings included mild increases in ALP 
and/or increased liver weight with or without minimal to slight hepatocellular hypertrophy. 
Minor, nonadverse clinical pathology findings included decreased red blood cell parameters, 
increased platelets, shortened activated partial thromboplastin time (APTT), decreased serum 
bile acids, decreased cholesterol and triglycerides, increased albumin, globulin, and total protein, 
increased phosphorus and/or increased urea nitrogen. All findings are expected to reverse with 
cessation of dosing based on the transient nature of the finding, type of finding observed and/or 
evidence of recovery after a 4-week nondosing period in the 26-week mouse and 39-week 
monkey studies. The no observed adverse event levels (NOAELs) from the 26- (mice), 13- (rats) 
and 39-week (monkeys) repeat dose toxicity studies were 60 mg/kg/day in mice, 1500 mg/kg/day 
in rats, and 300 mg/kg/day in monkeys. These doses were associated with exposure margins 8
(male mice), 14(female mice), 27(male rats), 18(female rats), and 20(male and female 
monkeys) higher than the human exposure at the 100 mg once daily (QD) dose.
There were no effects of CILO on fetal development at doses of up to 300 mg/kg/day in mice 
and 200 mg/kg/day in rabbits. There were effects on male and female fertility (reduced 
conception/copulation rates and longer precoital intervals) at a dose of 300 mg/kg/day, which 
was associated with exposure margins 24(male) and 63(female) higher than the human 
exposure at the 100 mg QD dose.
1.2.4.
Nonclinical Pharmacokinetics
The oral bioavailability of CILO was low in the nonclinical species. Low pH-dependent 
solubility and high hepatic extraction have been identified as factors likely contributing to the 
low bioavailability of CILO. In plasma from humans and nonclinical species, CILO was highly 
protein bound (≥ 99.64%), consistent with the low volumes of distribution (approximately equal 
to extracellular water, 0.2 L/kg) observed in nonclinical species. In mice, [14C] CILO-derived 
radioactivity was distributed to most of the tissues, with the highest maximum concentrations of 
radioactivity determined in organs of absorption and excretion. No quantifiable radioactivity was 
detected in brain, suggesting [14C] CILO-derived radioactivity did not cross the blood:brain 
barrier. The primary metabolic pathways for CILO in pooled cryopreserved human hepatocytes 
were observed to be oxidative. Cytochrome P450 enzymes (CYP)2C8, CYP3A4, and CYP2C19 
were shown to metabolize CILO in vitro; in a clinical drug-drug interaction (DDI) study, 
CYP2C8 was shown to be the primary enzyme responsible for CILO metabolism. The primary 
metabolic pathways of CILO in vivo were oxidation and O-dealkylation as observed in mice, 
rats, and monkeys; glutathione conjugation as observed in mice and rats; and dechlorination as 
observed in mice. Two prominent, inactive, circulating metabolites of CILO have been identified 
in humans and nonhuman primates: GS-716070 (dihydrodiol metabolite) and GS-1056756 
(azetidine-ring-opened-CILO-carboxylic acid metabolite). Fecal elimination was the 
predominant route of elimination of [14C] CILO-derived radioactivity in both mice and monkeys. 


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CILO has the potential to affect hepatic uptake of organic anion transporter protein (OATP) 
substrates or metabolism of CYP3A4 substrates and to a lesser extent CYP2C8 or CYP2C9
substrates in vitro, however, in a clinical DDI study it was not a clinically relevant inhibitor of 
CYP3A4 and/or OATP substrates. In vitro, CILO was a substrate for efflux transporters 
P-glycoprotein and breast cancer resistance protein (BCRP), as well as the uptake transporters 
OATP1B1, OATP1B3, OATP2B1, and sodium-taurocholate cotransporter protein (NTCP); 
however, in a clinical DDI study, only OATP1B1 and OATP1B3 played a major role in the 
disposition of CILO. CILO and GS-716070 did not activate nuclear hormone receptors 
associated with the potential for induction of human drug-metabolizing enzymes and transporters 
(eg, PXR, CAR, AhR) in cell-based reporter assays. Thus, the liability of CILO and GS-716070 
to cause DDIs through proteins regulated by these nuclear receptors is low.
GS-1056756 has shown low potential to inhibit CYP enzymes and uridine diphosphate 
glucuronosyltransferase (UGT) in vitro. GS-1056756 did not inhibit P-glycoprotein (P-gp), 
BCRP, OCT2, MATE1, MATE2K, and showed low probability to be clinically relevant inhibitor 
of OAT1, OAT3, OCT1, OATP1B1, OATP1B3 or OATP2B1. No clinical DDI liability of 
GS-1056756 on enzymes and transporters was predicted from in vitro characterizations. 
GS-1056756 has been identified in nonclinical assays as a substrate of OATP1B1/1B3/2B1. In 
vitro, GS-1056756 is formed by oxidative metabolism by CYP3A4 and CYP2C8 with additional 
conversion to enantiomers by dehydrogenases (eg, ALDH), and is subsequently metabolized by 
CYP3A and CYP2C8 and UGTs. Together with available clinical data described in 
Section 1.2.5, the potential clinical DDI liability of GS-1056756 is low.
1.2.5.
Clinical Trials of CILO
As of 17 October 2019, 6 Phase 1 clinical studies are complete, 2 Phase 1 studies are ongoing 
(GS-US-454-5280 and GS-US-402-374), 1 Phase 2 study in subjects with nonalcoholic 
steatohepatitis (NASH) is complete (GS-US-402-1852) 1 Phase 2 study in subjects with Primary 
Biliary Cholangitis (PBC) (GS-US-427-4024) is complete, and 3 Phase 2 studies in subjects with 
NASH (GS-US-384-3914, GS-US-454-4378), and PSC (GS-US-428-4025) are ongoing. These 
Phase 1 and 2 studies are described in the IB. A brief summary of relevant results that are not 
included in the IB from study GS-US-402-3885 and preliminary results from ongoing study 
GS-US-428-4025 are presented below. Clinical PK data for the newly identified major 
circulating CILO metabolite GS-1056756 (the R-enantiomer of M13) is described in Sections 3
and 1.2.8.7. Briefly, GS-1056756 exhibits a plasma half-life of approximately 175 h. Preliminary 
steady-state plasma concentrations of GS-1056756 in PSC patients administered 100 mg CILO
are as expected based on the single dose PK data for GS-1056756 from the ADME study 
(GS-US-402-4287). Additionally, plasma exposures of GS-1056756 are minimally altered in 
subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic 
function (see Section 1.2.6). These data, taken together with the adequate safety margins from 
nonclinical safety studies and the nonclinical understanding of the metabolic formation (CYP3A 
and CYP2C8) and clearance (CYP3A, CYP2C8, and UGTs) mechanisms of GS-1056756
support the concomitant medication (CM) restrictions in Section 5.5.


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1.2.6.
A Phase 1, Open-Label, Parallel-Group, Adaptive, Single-Dose Study to 
Evaluate the Pharmacokinetics and Pharmacodynamics of Cilofexor in 
Subjects with Normal and Impaired Hepatic Function (Study 
GS-US-402-3885)
Study GS-US-402-3885 is a Phase 1, open-label, parallel-group, single dose study evaluating the 
safety, tolerability, PK, and pharmacodynamics (PD) of CILO in subjects with normal hepatic 
function and mild, moderate, or severe hepatic impairment. Up to 60 subjects were planned for 
enrollment in 1 of 3 hepatic impairment cohorts: Cohort 1 (mild hepatic impairment, Child-Pugh 
[CP] A), Cohort 2 (moderate hepatic impairment, CP B), and Cohort 3 (severe hepatic 
impairment, CP C). Within each cohort, each subject with impaired hepatic function (N 10 per 
cohort) was matched for age (± 10 years), sex, race, and body mass index (BMI: ± 15%) with a 
control subject with normal hepatic function (N 10 per cohort). Data from healthy subjects were
used in >1 cohort if a subject was an appropriate match for a subject with hepatic function in 
>1 cohort. All subjects in Cohorts 1 and 2 received a single oral dose of CILO 30 mg in the fed 
state on Day 1 with PD collected on Day -1 and Day 1. All subjects in Cohort 3 received a single 
oral dose of CILO 10 mg in the fed state on Day 1 with PD collected on Day 1 and Day 1.
1.2.6.1.
Subject Disposition
As of 21 August 2019, a total of 57 subjects were enrolled and 56 subjects had received a single 
dose of study drug. One subject prematurely discontinued study treatment due to quality issues at 
the site that justified a suspension in dosing at the site. No subjects prematurely discontinued due 
to an adverse event (AE), withdrew consent, or were lost to follow up.
1.2.6.2.
Safety Results 
No deaths, serious AEs (SAEs) related to study treatment or study procedures, AEs leading to 
discontinuation from the study, or pregnancies were reported during the study. Of the 56 subjects 
in the Safety Analysis Set, 8 subjects (14.3%) each experienced 1 AE (5 Grade 1 [8.9%], 
1 Grade 2 [1.8%], and 2 Grade 3 [3.6%]). Of these, 1 AE (1.8%) was assessed by the investigator 
as related to study drug (Grade 1 headache). A total of 2 subjects (3.6%) experienced SAEs 
during the study. None of the AEs were experienced by more than 1 subject.
A total of 43 of 56 subjects (76.8%) experienced a graded laboratory abnormality during the 
study. Grade 3 laboratory abnormalities were experienced by 7 subjects (12.5%) and a Grade 4 
laboratory abnormality was experienced by 1 subject (1.8%). The Grade 3 and 4 laboratory 
abnormalities were consistent with the underlying hepatic impairment or with abnormalities 
present at baseline. None of the subjects with normal hepatic function in any cohort experienced 
a laboratory abnormality ≥Grade 3. There were no clinically significant trends in vital sign 
measurements. There were no clinically significant electrocardiogram (ECG) assessments.


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PK and PD Results 
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In subjects with mild, moderate, or severe hepatic impairment, CILO AUCinf increased 76%, 
146%, and 525%, respectively, compared with matched subjects with no1mal hepatic function. 
Similarly, GS-716070 AUCinf increased 64%, 94%, and 197% in subjects with mild, moderate, 
or severe hepatic impainnent, respectively, compared with matched subjects with no1mal hepatic 
function. Also, GS-1056756 AUCinfincreased 28%, 16%, and 71% in subjects with mild, 
moderate, or severe hepatic impainnent, respectively, compared with matched subjects with 
n01mal hepatic function. 
Sernm concentrations of the bile acid inte1mediate 7-alpha-hydroxy-4-cholesten-3-one (C4) and 
plasma concentrations ofFGF19 were evaluated in subjects with hepatic impaiiment and in 
subjects with n01mal hepatic function under fed conditions to dete1mine the effect of hepatic 
insufficiency on response to CILO. Response to CILO was similar in the mild and moderate 
hepatic impaiiment groups as compared with matched subjects with n01mal hepatic function. 
However, subjects with severe hepatic impaiiment showed a reduced response to CILO, as 
indicated by smaller changes in FGF19 and C4 levels compared with subjects with nonnal 
hepatic function. These findings are likely related to the elevated FGFl 9 and reduced C4 levels 
observed in subjects with severe hepatic impai1ment at baseline. 
The clinical relevance of the altered exposures and PD responses with increasing hepatic 
impai1ment seen in this study will be evaluated across all studies to dete1mine if dose adjustment 
is wairnnted in patients with hepatic impaiiment. 
1.2.7. 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
the Safety, Tolerability, and Efficacy of Cilofexor in Subjects with Primary 
Sclerosing Cholangitis without Cirrhosis (Study GS-US-428-4025) 
Study GS-US-428-4025 is a Phase 2, multicenter, randomized, double-blind study evaluating the 
safety, tolerability, and efficacy of CILO in subjects with PSC without cinhosis. Subjects with 
PSC and a sernm ALP concentration greater than 1.67-times the upper limit of n01mal (ULN) 
were randomized in a 2:2: 1 ratio to one of 3 treatment groups: 
• 
CILO 100 mg orally once daily (N = 22) 
• 
CILO 30 mg orally once daily (N = 20) 
• 
Placebo orally once daily (N = 10) 
Randomization was stratified by the presence or absence ofUDCA use, which was stable for at 
least 12 months prior to screening. 
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Subjects who completed the 12-week blinded study phase without permanently discontinuing 
study drug were eligible to participate in an open-label extension (OLE) phase of the study to 
receive CILO 100 mg once daily for 96 weeks after a 4-week washout period. During the OLE 
phase, dose reduction to 30 mg once daily was permitted if required due to AEs. The randomized 
phase of Study GS-US-428-4025 has completed, but the OLE phase continues.
1.2.7.1.
Subject Disposition and Demographics
A total of 52 subjects were randomized and treated across 24 sites in North America and Europe 
(16 sites in the US, 3 sites in Canada, 4 sites in the United Kingdom, and 1 site in Austria). A 
total of 47 subjects (90.4%) completed study drug in the double-blind phase, which was 
completed on 29 January 2018. The clinical efficacy data presented herein reflect available 
information from both the randomized and OLE phases of the study (22 Aug 2019 data cut). Of 
the 5 subjects who did not complete study drug treatment during the double-blind phase, 
3 subjects (14%) discontinued CILO 100 mg due to AEs: pruritus (n  1), acute kidney 
injury (n
 1), and elevated ALP (n  1); one subject (5%) discontinued CILO 30 mg following a 
decision to withdraw consent; and one subject (10%) in the placebo arm discontinued due to 
elevated liver biochemistry.
The demographics and baseline characteristics of the study population according to treatment 
group are listed in Table 1-1. Across all treatment groups, 58% of subjects were male, with a 
median (first quartile [Q1], third quartile [Q3]) age of 43 years (35, 52). In total, 60% of subjects 
had intra- and extrahepatic bile duct involvement on magnetic resonance 
cholangiopancreatography (MRCP), 60% had concomitant IBD, and 46% were prescribed 
UDCA at baseline. The median (Q1, Q3) serum ALP and bilirubin at baseline were 348 U/L 
(288, 439) and 0.7 mg/dL (0.5, 1.0), respectively. In general, no clinically relevant differences in 
baseline demographic, laboratory, and imaging parameters were noted across the 3 treatment 
groups. 


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Table 1-1.
GS-US-428-4025: Demographics and Baseline Characteristics 
(Safety Analysis Set)
CILO 100 mg
(N = 22)
CILO 30 mg
(N = 20)
Placebo
(N = 10)
Total
(N = 52)
Demographics
Age (yr)
43 (36, 47)
46 (35, 57)
39 (33, 52)
43 (35, 52)
Male, n (%)
11 (50%)
14 (70%)
5 (50%)
30 (58%)
White, n (%)
17 (77%)
15 (75%)
7 (70%)
39 (75%)
Diabetes, n (%)
6 (27%)
2 (10%)
1 (10%)
9 (17%)
Weight (kg)
73.5 (67.5, 89.1)
79.8 (68.4, 
95.9)
82.2 (63.0, 83.3)
77.9 (67.4, 88.6)
BMI (kg/m2)
25.8 (23.2, 30.3)
25.9 (22.8, 
29.9)
25.8 (23.9, 29.6)
25.8 (23.2, 29.9)
IBD, n (%)
13 (59%)
11 (55%)
7 (70%)
31 (60%)
UDCA, n (%)
10 (46%)
9 (45%)
5 (50%)
24 (46%)
Liver
Biochemistry
ALP (U/L)
350 (312, 387)
344 (271, 460)
380 (265, 547)
348 (288, 439)
GGT (U/L)
305 (192, 542)
564 (255, 910)
377 (224, 622)
423 (203, 628)
Total bilirubin 
(mg/dL)
0.6 (0.5, 1.1)
0.8 (0.6, 1.0)
0.6 (0.5, 0.9)
0.7 (0.5, 1.0)
ALT (U/L)
110 (83, 156)
119 (60, 197)
77 (59, 123)
109 (63, 156)
AST (U/L)
67 (52, 98)
75 (44, 104)
59 (47, 76)
64 (47, 99)
Albumin (g/dL)
4.4 (4.2, 4.5)
4.5 (4.2, 4.7)
4.6 (4.2, 4.7)
4.4 (4.2, 4.7)
Fibrosis and 
Inflammation
ELF
9.26 (8.73, 9.66)
9.77 (9.26, 
10.31)
9.09 (8.87, 9.60)
9.38 (8.91, 9.88)
FibroTest®
0.29 (0.27, 0.44)
0.47 (0.39, 
0.57)
0.34 (0.23, 0.51)
0.40 (0.28, 0.51)
C-reactive 
Protein (g/mL)
0.27 (0.15, 0.51)
0.26 (0.10, 
0.73)
0.19 (0.12, 0.46)
0.25 (0.13, 0.57) 
Markers of 
Bile Acid 
Homeostasis
FGF19 (pg/mL)
102 (66, 171)
118 (61, 174)
115 (107, 156)
112 (66, 168)
C4 (ng/mL)
10.4 (5.1, 23.5)
18.7 (9.8, 30.0)
18.9 (9.3, 27.1)
13.2 (7.3, 27.1)
Total bile acids 
(mol/L)
19.6 (10.3, 33.1)
15.3 (9.4, 32.2)
13.7 (6.4, 17.0)
16.9 (9.6, 30.7)
Primary bile acids 
(ng/ml)
3182.3 
(2329.3, 7535.0)
2646.1 
(1548.7, 
7036.5)
1759.5 
(1359.4, 2380.9)
2806.4 
(1584.3, 5502.5)


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CILO 100 mg
(N = 22)
CILO 30 mg
(N = 20)
Placebo
(N = 10)
Total
(N = 52)
Imaging
Intra- and extra-
hepatic duct 
involvement on 
MRCP
11 (50.0%)
14 (70.0%)
6 (60.0%)
31 (60%)
Liver stiffness by 
FibroScan(kPa)
7.3 (6.2, 10.6)
10.1 (6.9, 12.5)
9.8 (7.9, 10.1)
9.4 (6.8, 10.6)
Metabolism
Glucose (mg/dL)
87 (81, 98)
87 (82, 94)
84 (79, 90)
87 (82, 96)
Cholesterol 
(mg/dL)
209 (178, 256)
240 (200, 274)
219 (188, 258)
218 (184, 263)
LDL-C (mg/dL)
111 (87, 132)
139 (102, 166)
123 (94, 153)
122 (94, 153)
HDL-C (mg/dL)
82 (64, 97)
75 (64, 86)
75 (58, 87)
77 (63, 91)
Triglycerides 
(mg/dL)
80 (58, 93)
99 (80, 120)
105 (83, 123)
90 (69, 118)
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; BMI  body mass index; 
ELF
enhanced liver fibrosis; FGF19  fibroblast growth factor 19; GGT  gamma glutamyl transferase; HDL C  high density 
lipoprotein cholesterol; IBD  inflammatory bowel disease; LDL C  low density lipoprotein cholesterol; MRCP
magnetic 
resonance cholangiopancreatography; UDCA
ursodeoxycholic acid.
All data are median (Q1, Q3) or n (%).
1.2.8.
GS-US-428-4025: Preliminary Efficacy Results
1.2.8.1.
Treatment with CILO Results in a Substantial Improvement in Serum ALP in 
Subjects with PSC
At the completion of Week 12 of the double-blind phase of GS-US-428-4025 (noncirrhotic 
study), significant and dose-dependent reductions in serum ALP concentration versus baseline 
were observed in subjects that received CILO compared with those that received placebo 
(Table 1-2). Specifically, the median (Q1, Q3) absolute difference from baseline to Week 12 in 
serum ALP was 73 U/L ( 106, 14) in the CILO 100 mg group (p  0.026 vs placebo), 
21 U/L ( 60, 40) in the CILO 30 mg group (p
 0.37 vs placebo), and +8 U/L ( 40, 118) in the 
placebo group (Figure 1-1).
Treatment with CILO led to improvements in most efficacy endpoints assessed in subjects with
PSC during both the blinded and OLE phases of the study. Outcomes were independent of
UDCA use. Dose-dependent decreases from baseline in serum ALP were observed with CILO 
treatment in the blinded phase; differences between the CILO 100 mg and placebo groups in 
percentage change in serum ALP were statistically significant (p  0.0294). Decreases in serum 
ALP continued in the combined CILO group in the OLE phase. Although few subjects with 
baseline ALP > ULN or ALP ≥1.67 ULN normalized ALP or reduced ALP to < 1.67 ULN 
and ≥15% in either phase of the study, half of CILO 100 mg group subjects (10 of 20, 50.0%) in 
the blinded phase and more than a third of combined CILO group subjects (11 of 32, 34.4%) in 
the OLE phase had a reduction in ALP of at least 20%. No differences between treatment groups 


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in median decreases in total bilirubin were observed. Among subjects with baseline total 
bilirubin > ULN, most normalized total bilirubin at blinded Week 12 (4 of 4 subjects [100.0%] in 
the CILO 100 mg group, 2 of 3 subjects [66.7%] in the CILO 30 mg group, and 1 of 1 subject 
[100.0%] in the placebo group).
Dose-dependent decreases in markers of liver injury and function were observed with CILO.
Differences between the CILO 100 mg and placebo groups for alanine aminotransferase (ALT)
(p  0.0089), aspartate aminotransferase (AST) (p  0.0186), and gamma glutamyltransferase 
(GGT) (p < 0.0001), and between the CILO 30 mg and placebo groups for GGT (p  0.0027) 
were statistically significant. The decreases in ALT, AST, and GGT continued in the combined 
CILO group in the OLE phase. Although there were no improvements in liver fibrosis based on 
enhanced liver fibrosis (ELF™) score, a trend toward a significant decrease in median value for 
tissue inhibitor of metalloproteinase 1 (TIMP-1) was observed at Week 12 in the CILO 100 mg 
group compared with placebo (p  0.0626). No decrease in ELF score was observed in the 
combined CILO group from OLE baseline to OLE Week 96. A small decrease from baseline 
FibroSURE/FibroTest® score was observed in the CILO 100 mg group at blinded Week 12. 
Little change was observed in FibroSURE/FibroTest score in the combined CILO group from 
OLE baseline to OLE Week 96. Little improvement from baseline in liver fibrosis stage based on 
FibroScan® was observed across treatment groups in the blinded phase. In the OLE phase, no 
improvement from OLE baseline in liver fibrosis stage based on magnetic resonance 
elastography was observed in the combined CILO group. No clinically relevant changes from 
baseline in body weight were observed across treatment groups in the blinded phase. A small 
increase from OLE baseline in body weight was observed at OLE Week 96 in the combined 
CILO group. Small improvements from baseline in inflammation based on C-reactive protein 
(CRP) were observed in the CILO groups at blinded Week 12. Minimal changes in CRP were 
observed from OLE baseline to OLE Week 96.
During the blinded phase, fasting FGF19 decreased from baseline in the CILO 100 mg group and
increased in the CILO 30 mg group, with increases from OLE baseline at OLE Week 96 in the
combined CILO group. Fasting C4 decreased from baseline in both CILO groups in the blinded
phase and in the combined CILO group in the OLE phase; decreases in the blinded phase were
larger in the CILO 30 mg group than the CILO 100 mg group and significantly different from
changes in the placebo group (p  0.0242 for the difference between the CILO 30 mg and
placebo groups in percentage change from baseline in fasting C4 at blinded Week 12). Fasting
total bile acids decreased from baseline in the CILO 100 mg group, with little change in the
CILO 30 mg group during the blinded phase; the decreases continued in the combined CILO
group during the OLE phase.
No pattern of changes from baseline at Week 12 was observed across lipid parameters.
Dose-dependent decreases from baseline in total cholesterol and high-density lipoprotein 
cholesterol (HDL-C) were observed at Week 12, with a statistically significant difference 
between the CILO 100 mg and placebo groups in percentage change in HDL-C (p  0.0403). 
Increases from baseline were observed at Week 12 in the CILO 100 mg group in fasting 
triglycerides, fasting low-density lipoprotein cholesterol (LDL-C), fasting very low-density 
lipoprotein cholesterol (VLDL-C), and fasting non-HDL-C, with small decreases or no change in 


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the CILO 30 mg group. In the OLE phase, decreases from OLE baseline in total cholesterol, 
fasting triglycerides, HDL-C, fasting LDL-C, fasting VLDL-C, and non-HDL-C were observed 
in the combined CILO group at OLE Week 96.
Pooled cohort risk score increased from baseline in the CILO 100 mg group and showed little
change in the CILO 30 mg and placebo groups at blinded Week 12. Pooled cohort risk score
increased from OLE baseline at OLE Week 96 in the combined CILO group. Mayo risk score
decreased from baseline in the CILO 100 mg group and showed little change in the CILO 30 mg
and placebo groups at blinded Week 12. Mayo risk score decreased from OLE baseline at OLE
Week 96 in the combined CILO group.
Figure 1-1.
GS-US-428-4025: Median (Q1, Q3) Serum ALP Concentration (U/L) 
by Visit in Double-Blind Phase (Evaluable Subjects, Full Analysis Set)
Similarly, relative reductions from baseline in serum ALP were greatest in subjects that received 
CILO. Specifically, the median (Q1, Q3) relative difference from baseline to Week 12 in serum 
ALP was 20.5% ( 30.2, 3.5) in the CILO 100 mg group (p  0.029 vs placebo), 6.1% 
( 17.6, 16.8) in the CILO 30 mg group (p  0.32 vs placebo), and +3.4% ( 7.2, 18.6) in the 
placebo group. The relative improvements in serum ALP concentration from baseline to 
Week 12 in the CILO 100 mg group were similar between UDCA-treated (n
 8) and untreated 
(n  12) subjects (median, 18.6% vs 20.5%; p  0.85). 
GS-9674 100 mg (,,..): 
GS-9674 30 mg (n-): 
Placebo (n- ): 
B - Blinded 
700 
650 
600 
550 
Q'. 
400 
• 
., 
350 
JOO 
250 
200 
22 
20 
10 
22 
19 
10 
20 
19 
10 
Basellllt' value was determined by averaging all values between screming and Baseline/Day 1. 
21 
19 
10 
Weeks on Study 
= GS-9674 IO0 mg 
= GS-9674 30 mg 
D = Placebo 
20 
19 
10 
12 
20 
19 
10 
700 
650 
600 
550 
500 
450 
400 
350 
300 
250 
200 
150 


Cilofexor (CILO; GS-9674) 
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At Week 12, more subjects had a clinically relevant serum ALP response, defined as a~ 25% 
relative reduction from baseline, in the CILO 100 mg group (35%, 7 of 20 subjects with 
evaluable data; p 
0.21 vs placebo) compared with the CILO 30 mg group (5.3%, 1 of 
19 subjects; p 
1.00 vs placebo) and the placebo group (10%, 1 of 10 subjects) (Figure 1-2). 
Figure 1-2. 
GS-US-428-4025: ALP Response at Week 12 of the Randomized 
Phase (Evaluable Subjects, Full Analysis Set) 
Subjects with~ 25% Reduction 
in ALP at 12 weeks 
N 100 
..... 
80 
-
RS 
QI 
Ill 
C: 
60 
0 
Cl. 
(35%) 
Ill 
40 
QI ... 
ll. 
...I 
20 
(10%) 
<( 
(5%) 
0 
0 
100mg 
30mg 
Placebo 
(7/20) 
(1 /19) 
(1 /10) 
GS-9674 
These changes in serum ALP concentration with CILO, particularly at the 100 mg dose, 
represent a significant improvement over placebo on a clinically relevant endpoint reflective of 
the severity of cholestasis in subjects with PSC. 
1.2.8.2. 
Treatment with CILO Results in Significant Improvement in Liver Biochemistry 
and Biomarkers in Subjects with PSC 
In addition to improvements in serum ALP, treatment with CILO was associated with 
dose-dependent reductions in other liver biochemistry tests ( eg, GGT, AST, ALT), PD markers 
of FXR agonism (eg, C4, bile acids), and serum fibrosis markers (eg, TIMP-1) compared with 
placebo at the completion of Week 12 of the double-blind phase (2). 
In summary, these data indicate that treatment with CILO is associated with reductions in 
markers of cholestasis, hepatic inflammation, and potentially fibrosis, in subjects with PSC. 
CONFIDENTIAL 
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15 January 2021 


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Table 1-2.
GS-US-428-4025: Overall Summary of Biochemical and Biomarker 
Responses from Baseline to Week 12 (Evaluable Subjects, Full 
Analysis Set)*
CILO
100 mg
(N = 22)
CILO
30 mg
(N = 20)
Placebo
(N = 10)
P-values
100 mg vs. 
Placebo
30 mg vs 
Placebo
ALP
-20.5 
(-30.2, -3.5)
-6.1 
(-17.6, 16.8)
3.4 (-7.2, 18.6)
0.029
0.32
UDCA use
-18.6 
(-35.2, -3.5)
-7.8 
(-14.3, -1.6)
1.3 (-7.2, 18.6)
0.12
0.27
No UDCA use
-20.5 
(-27.9, 0.5)
0.0 
(-19.2, 21.0)
5.6 (-5.8, 14.7)
0.23
1.00
≥ 25% ALP reduction, 
% (n/N)
35% (7/20)
5.3% (1/19)
10% (1/10)
0.21†
1.00†
Absolute ALP change, 
U/L 
-73 (-106, -14)
-21 (-60, 40)
8 (-40, 118)
0.026
0.37
GGT
-30.3 
(-47.8, -21.8)
-16.3 
(-29.7, -7.2)
1.1 (-6.1, 15.0)
< 0.001
0.003
ALT
-49.4 
(-60.7, -22.5)
-26.2 
(-36.8, 1.7)
-12.9 
(-22.9, -12.1)
0.009
0.24
AST
-42.3 
(-51.1, -10.9)
-22.5 
(-34.7, 20.4)
-10.8 
(-24.6, 10.5)
0.019
0.32
Total bilirubin
0.0 
(-22.1, 29.2)
14.3 
(-11.1, 34.5)
-11.0 
(-27.3, 25.0)
0.58
0.35
Fasting C4
-23.2 
(-71.2, 25.7)
-30.5 
(-50.5, 5.6)
10.0 
(-14.3, 29.7)
0.21
0.024
Total bile acids
-38.6 
(-55.6, 19.5)
0.0 
(-41.5, 57.1)
5.5 
(-12.4, 44.6)
0.17
0.67
Primary bile acids#
-45.1 
(-65.8, 18.3)
-5.3 
(-53.1, 78.3)
4.3 
(-35.3, 32.4)
0.15
0.92
ELF
-0.4 
(-2.9, 3.0)
0.1 (-1.9, 4.7)
1.2 (-1.9, 2.8)
1.00
0.55
TIMP-1
-8.2 
(-13.2, 3.5)
3.8 
(-12.7, 17.7)
0.3 (-5.2, 15.5)
0.063
0.73
Hyaluronic acid
-4.3 
(-20.6, 17.7)
10.0 
(-17.7, 56.5)
9.9 (-2.2, 14.3)
0.69
0.59
PIII-NP
2.2 (-6.0, 18.2)
-5.4 
(-12.8, 22.2)
-6.2 
(-30.8, 15.5)
0.23
0.30
CRP
-12.2 
(-65.7, 40.5)
-28.7 
(-43.8, 14.8)
8.5 
(-23.1, 30.5)
0.56
0.085
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; CRP  C reactive protein; 
ELF
enhanced liver fibrosis; GGT  gamma glutamyltransferase; PIII NP  procollagen type III N terminal propeptide; 
TIMP 1
 tissue inhibitors of metalloproteinase 1; UDCA  ursodeoxycholic acid
*
Unless indicated, all data are median relative (%) changes from baseline and p values were from Wilcoxon rank sum test.
†
P value by Fisher exact test.
#
Primary bile acid species measured by LC/MS.
PIII NP  procollagen III amino terminal peptide


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1.2.8.3.
Preliminary Results from the OLE Phase
As of 22 August 2019, 47 subjects had completed the 12-week randomized phase and entered the 
OLE phase after a 4-week washout period to receive CILO 100 mg once daily. At Week 12 of 
the OLE phase, the median relative change in serum ALP from the OLE baseline was 14.6% in 
the group previously treated with placebo, 15.5% in the CILO 30 mg group, and 16.2% in the 
CILO 100 mg group. Among 42 subjects with ALP > 1.67-times ULN at the beginning of the 
OLE phase, 37 subjects completed Week 12 and 12 of these subjects (32%) had a ≥ 25% relative 
reduction in serum ALP 12 weeks after initiating treatment with CILO 100 mg during the OLE 
phase. The median relative change in serum GGT from the OLE baseline at Week 12 was 
35.3% in the CILO 100 mg group, 38.8% in the CILO 30 mg group, and 34.2% in the 
placebo group. Overall, Grade 2 or 3 pruritus (including pruritus generalized) has been reported 
in 12 subjects (26%), and 4 subjects (9%) have discontinued treatment prematurely due to 
pruritus. Rash (including rash macular and papular) occurred in 4 subjects (9%), none of which 
were Grade 3 or higher, or led to study drug discontinuation. This ALP response in subjects 
previously treated with placebo and CILO 30 mg during the blinded phase provides additional 
evidence to support the therapeutic efficacy of CILO 100 mg. 
1.2.8.4.
Preliminary Safety Results
Treatment with CILO 100 or 30 mg was generally well tolerated in Study GS-US-428-4025. 
Table 1-3 presents an overall summary of AEs during the 12-week double-blind phase. A 
majority of subjects in each treatment group experienced at least 1 AE: CILO 100 mg, 18 of 
22 subjects (81.8%); CILO 30 mg, 13 of 20 subjects (65.0%); and placebo, 10 of 10 subjects 
(100.0%). Most AEs were Grade 1 or 2 in severity. Four subjects discontinued study treatment in 
the double-blind phase due to AEs: 3 subjects (13.6%) in the CILO 100 mg group (due to acute 
kidney injury, pruritus, and increased ALP, respectively) and 1 subject (10.0%) in the placebo 
group (due to increased AST, ALT, and ALP). No deaths were reported during the study.


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Table 1-3.
GS-US-428-4025: Overall Summary of Treatment-Emergent Adverse 
Events, Double-Blind Phase (Safety Analysis Set)
CILO
100 mg
(N = 22)
CILO
30 mg
(N = 20)
CILO
Pooled
(N = 42)
Placebo
(N = 10)
AE
18 (81.8%)
13 (65.0%)
31 (73.8%)
10 (100.0%)
AE with grade of 3 or higher
5 (22.7%)
3 (15.0%)
8 (19.0%)
2 (20.0%)
AE with highest grade of 3
5 (22.7%)
3 (15.0%)
8 (19.0%)
2 (20.0%)
Treatment-related AE
5 (22.7%)
5 (25.0%)
10 (23.8%)
2 (20.0%)
Treatment-related AE with grade 
of 3 or higher
1 (4.5%)
1 (5.0%)
2 (4.8%)
1 (10.0%)
SAE
3 (13.6%)
0
3 (7.1%)
0
Treatment-related SAE
0
0
0
0
AE Leading to Premature 
Discontinuation of Study Drug
3 (13.6%)
0
3 (7.1%)
1 (10.0%)
Death during the Study
0
0
0
0
Adverse events were coded according to MedDRA Version 20.1. Severity grades were defined by the CTCAE Version 4.03.
Treatment emergent events of the Double Blind Phase began on or after the study drug start date of the Double Blind Phase up to 
30 days after permanent discontinuation of study drug in the Double Blind Phase (and before the first dose date in the OLE 
Phase), or led to premature study drug discontinuation.
Death includes any death that occurred during the study.
1.2.8.5.
Adverse Events
Table 1-4 presents the treatment-emergent AEs reported for ≥2 subjects in any treatment group 
during the double-blind phase. The most common AEs in each treatment group during the 
double-blind phase were pruritus, nasopharyngitis, upper abdominal pain, and fatigue (CILO
100 mg); pruritus, nasopharyngitis, and headache (CILO 30 mg); and pruritus and nausea 
(placebo). Most AEs were Grade 1 or 2 in severity and deemed not to be treatment-related by the 
investigator.


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Table 1-4.
GS-US-428-4025: Treatment-Emergent Adverse Events Reported for 
at Least 2 Subjects in Any Treatment Group by Preferred Term, 
Double-Blind Phase (Safety Analysis Set)
Preferred Term
CILO
100 mg
(N = 22)
CILO
30 mg
(N = 20)
CILO
Pooled
(N = 42)
Placebo
(N = 10)
Number (%) of Subjects with 
Any AE
18 (81.8%) 
13 (65.0%)
31 (73.8%) 
10 (100.0%)
Pruritus
8 (36.4%) 
5 (25.0%) 
13 (31.0%) 
6 (60.0%)
Nasopharyngitis
5 (22.7%) 
5 (25.0%) 
10 (23.8%) 
2 (20.0%)
Abdominal pain upper
3 (13.6%) 
2 (10.0%) 
5 (11.9%) 
1 (10.0%)
Fatigue
3 (13.6%) 
2 (10.0%) 
5 (11.9%) 
2 (20.0%)
Abdominal discomfort
2 (9.1%)
0
2 (4.8%)
1 (10.0%)
Abdominal distension
2 (9.1%) 
0 
2 (4.8%) 
1 (10.0%)
Blood alkaline phosphatase 
increased
2 (9.1%) 
0 
2 (4.8%) 
1 (10.0%)
Constipation
2 (9.1%) 
0 
2 (4.8%) 
0
Diarrhoea
2 (9.1%) 
1 (5.0%) 
3 (7.1%) 
0
Dizziness
2 (9.1%) 
1 (5.0%) 
3 (7.1%) 
0
Electrocardiogram abnormal
2 (9.1%) 
0 
2 (4.8%) 
0
Upper respiratory tract infection
2 (9.1%) 
0 
2 (4.8%) 
1 (10.0%)
Viral infection
2 (9.1%) 
0 
2 (4.8%) 
0
Alanine aminotransferase 
increased
1 (4.5%) 
0 
1 (2.4%) 
2 (20.0%)
Back pain
1 (4.5%) 
2 (10.0%) 
3 (7.1%) 
0
Headache
1 (4.5%) 
4 (20.0%) 
5 (11.9%) 
2 (20.0%)
Muscle spasms
1 (4.5%) 
2 (10.0%) 
3 (7.1%) 
0
Pyrexia
1 (4.5%) 
2 (10.0%) 
3 (7.1%) 
0
Aspartate aminotransferase 
increased
0 
0 
0 
2 (20.0%)
Nausea
0 
1 (5.0%) 
1 (2.4%) 
3 (30.0%)
Adverse events (AEs) were coded according to MedDRA Version 20.1.
Treatment emergent events of the Double Blind Phase began on or after the study drug start date of the Double Blind Phase up to 
30 days after permanent discontinuation of study drug in the Double Blind Phase (and before the first dose date in the OLE 
Phase), or led to premature study drug discontinuation.
Multiple AEs were counted only once per subject for each preferred term (PT).
PTs were presented by decreasing frequency in the CILO 100 mg group.


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Table 1-5 presents Grade 3 treatment-emergent AEs. No Grade 4 AEs were reported. Overall, 
Grade 3 AEs were uncommon. A total of 3 Grade 3 AEs were reported in > 1 subject: pruritus 
(2 subjects each in the CILO 100 mg and CILO 30 mg groups and 1 subject in the placebo 
group); increased blood ALP (1 subject each in the CILO 100 mg and placebo groups); and 
muscle spasms (1 subject each in the CILO 100 mg and CILO 30 mg groups).
Table 1-5.
GS-US-428-4025: Grade 3 Treatment-Emergent Adverse Events by 
Preferred Term, Double-Blind Phase (Safety Analysis Set)
Preferred Term
CILO
100 mg
(N = 22)
CILO
30 mg
(N = 20)
CILO
Pooled
(N = 42)
Placebo
(N = 10)
Number (%) of Subjects with 
Any AE of Grade 3 or Higher
5 (22.7%)
3 (15.0%)
8 (19.0%)
2 (20.0%)
Pruritus
2 (9.1%)
2 (10.0%)
4 (9.5%)
1 (10.0%)
Acute kidney injury
1 (4.5%)
0
1 (2.4%)
0
Anal abscess
1 (4.5%)
0
1 (2.4%)
0
Asthenia
1 (4.5%)
0
1 (2.4%)
0
Blood alkaline phosphatase 
increased
1 (4.5%)
0
1 (2.4%)
1 (10.0%)
Dehydration
1 (4.5%)
0
1 (2.4%)
0
Diarrhoea
1 (4.5%)
0
1 (2.4%)
0
Fatigue
1 (4.5%)
0
1 (2.4%)
0
Muscle spasms
1 (4.5%)
1 (5.0%)
2 (4.8%)
0
Rib fracture
1 (4.5%)
0
1 (2.4%)
0
Alanine aminotransferase 
increased
0
0
0
1 (10.0%)
Aspartate aminotransferase 
increased
0
0
0
1 (10.0%)
Gamma-glutamyltransferase 
increased
0
1 (5.0%)
1 (2.4%)
0
Adverse events (AEs) were coded according to MedDRA Version 20.1. Severity grades were defined by the CTCAE 
Version 4.03.
Treatment emergent events of the Double Blind Phase began on or after the study drug start date of the Double Blind Phase up to
30 days after permanent discontinuation of study drug in the Double Blind Phase (and before the first dose date in the OLE
Phase), or led to premature study drug discontinuation.
Multiple AEs were counted only once per subject for each preferred term (PT).
PTs were presented by decreasing frequency in the CILO 100 mg group.


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1.2.8.6.
Serious Adverse Events
Serious AEs were reported in 3 subjects during the double-blind phase, all in the CILO 100 mg
group. No SAEs were reported in subjects in the CILO 30 mg group or placebo group. The SAEs 
were Grade 3 rib fracture (1 subject), Grade 3 acute kidney injury (1 subject), and Grade 3 
diarrhea and dehydration (1 subject). None of these events were considered related to study drug; 
the event of Grade 3 acute kidney injury resulted in premature discontinuation of study drug.
1.2.8.7.
Preliminary PK Results
The average steady-state GS-1056756 plasma concentration in subjects with PSC administered 
100 mg CILO was consistent with predicted exposure based on PK data in Study 
GS-US-402-4287 (ADME Study), in which AUCinf was 8220 hr*ng/mL, Cmax was 35.5 ng/mL, 
and t1/2 was approximately 175 hr.
1.3.
Rationale for This Study
PSC is a chronic disease of unknown etiology characterized by inflammation and fibrosis of the 
intrahepatic and/or extrahepatic bile ducts that result in the impairment of bile flow (cholestasis). 
Accumulation of excess bile acids causes hepatocellular cytotoxicity that leads to progressive 
injury characterized by biliary strictures, liver fibrosis, and eventually cirrhosis. CILO is a potent 
and selective, small molecule agonist of the nuclear hormone receptor FXR. FXR is the master 
regulator of bile acid homeostasis and modulates the transcription of genes controlling the 
synthesis, conjugation, transport, and absorption of bile acids {Inagaki 2005, Mudaliar 2013, 
Pellicciari 2002}. This homeostatic balance is disturbed in patients with PSC in whom bile acids 
are markedly elevated compared with unaffected individuals. By agonizing FXR in the intestine 
and stimulating the release of FGF19 and suppression of CYP7A1-mediated bile acid synthesis, 
CILO is expected to reduce hepatic bile acid accumulation in PSC patients, and thereby decrease 
hepatocellular and cholangiocyte cell death, inflammation, and progressive fibrosis characteristic 
of this condition. Indeed, data from animal models of liver fibrosis have demonstrated that oral 
administration of CILO increased FGF19 synthesis, reduced hepatic CYP7A1 expression and 
bile acid levels, and led to improvements in markers of hepatic inflammation and fibrosis. 
Moreover, in a rodent model of advanced fibrosis, CILO administration resulted in a reduction in 
elevated portal pressure, which accounts for the majority of complications in patients with 
cirrhosis due to PSC.
Finally, in a Phase 2 study (GS-US-428-4025) of 52 subjects with noncirrhotic PSC and elevated 
serum ALP (> 1.67ULN) at baseline, treatment with CILO for 12 weeks led to dose-dependent 
improvements in serum ALP compared with placebo treatment. The decrease in serum ALP was 
evident by 4 weeks of CILO treatment, which supports the design of the current study to evaluate 
each dose for 4 weeks before escalating to a higher dose. This endpoint is clinically relevant and 
has been associated with a reduced risk of liver-related complications in prior studies. Consistent 
with improvement in serum ALP, compared with placebo-treated subjects, those treated with 
CILO 100 mg had greater reductions in other markers of cholestasis (eg, serum GGT, bile acids, 
C4), hepatic inflammation (eg, ALT, AST), and fibrosis (eg, TIMP-1). Based on these Phase 2 


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data, CILO is hypothesized to be beneficial in subjects with PSC however to date, these 
observations have been limited to subjects with noncirrhotic disease. 
PSC is a progressive disorder with frequent progression to cirrhosis which confers an increased 
risk of complications including ascites, variceal hemorrhage, hepatic encephalopathy, 
malignancy, as well as decreased survival {Tischendorf 2008}. As no available therapies have 
been shown to improve clinical outcomes in patients with cirrhosis due to PSC, aside from liver 
transplantation, there is a large unmet medical need in this patient population. 
In an effort to expand our understanding of the safety, tolerability, and efficacy of CILO to 
cirrhotic patients with PSC, inclusion criteria for this study were developed in order to identify 
subjects with PSC and cirrhosis. Only subjects who meet clinical, histologic, or noninvasive 
criteria consistent with cirrhosis and have preserved liver function will be included. In this open-
label study design, the aim will be to evaluate safety, efficacy, 
 properties of 
CILO in the setting of PSC-related cirrhosis. 
1.4.
Rationale for Dose Selection of CILO
In this study we aim to evaluate the safety and tolerability of escalating daily doses of CILO 
from 30 to 100 mg once daily in a PSC population with compensated cirrhosis. 
A dose of CILO 100 mg daily provided greater therapeutic benefit than a dose of CILO 30 mg in 
a Phase 2 study in subjects with PSC without cirrhosis (Study GS-US-428-4025). Subjects with 
compensated cirrhosis are expected to have approximately 1.8-fold higher CILO plasma 
exposure compared to those without cirrhosis (GS-US-402-3885; Section 1.2.6). CILO is a 
hepatic OATP substrate, and the higher CILO plasma exposure observed in subjects with 
compensated cirrhosis is attributable to decreases in hepatic uptake by OATP, and not expected 
to alter the hepatic exposure of CILO. Thus, a similar dose of CILO 100 mg is expected to be 
needed for efficacy in subjects with PSC and compensated cirrhosis. Adequate exposure margins 
(5- to 11-fold relative to preclinical NOAEL exposures) are expected after 100 mg CILO 
administration in subjects with PSC and compensated cirrhosis.
The current study is designed to assess the safety of increasing daily doses of CILO from 30 to 
100 mg daily in subjects with PSC and compensated cirrhosis. The starting dose, CILO 30 mg 
once daily, was well tolerated following 12 weeks of treatment in subjects with compensated 
cirrhosis due to NASH (GS-US-384-3914) and conferred improvements in liver biochemistry 
(eg, GGT) and markers of cholestasis (eg, C4) in patients with noncirrhotic PSC 
(GS-US-428-4025). After 4 weeks of dosing with CILO 30 mg, the dose will escalate to 60 mg 
and then to 100 mg over 4-week intervals, to evaluate the safety, tolerability and improvements 
in ALP and other liver biochemistry tests at each dose level in subjects with PSC and 
compensated cirrhosis.
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Dosing of CILO in this study will be without regard to food based on PK, PD, safety and 
efficacy data from Phase 1 studies in healthy subjects and subjects with hepatic impairment 
(GS-US-402-1851, GS-US-454-4315, and GS-US-402-3885) and Phase 2 studies in subjects 
with NASH with or without cirrhosis (GS-US-402-1852 and GS-US-384-3914).
1.5.
Risk/Benefit Assessment for the Study
This study will provide information on the safety and potential efficacy of CILO for the 
treatment of patients with PSC who also have compensated cirrhosis. The results from this study 
may inform the potential of nonsteroidal FXR agonists such as CILO to be tolerated in patients 
with hepatic impairment, and their future potential to improve biochemical parameters of 
cholestasis and/or regression of liver fibrosis in patients with PSC and cirrhosis.
The potential benefits of CILO for the treatment of PSC with cirrhosis include improvements in 
hepatic injury due to reduced bile acid synthesis attributable to FXR agonism. Based on these 
effects, improvements in liver biochemistry, hepatic fibrogenesis, and potentially health-related 
quality of life (QoL) would be expected to ensue.
Cilofexor is a new chemical entity, and as such, its long-term safety profile has yet to be 
established in this patient population. However, available data from the Phase 1 and 2 studies 
indicate that CILO is safe and generally well tolerated. The primary risk of CILO treatment 
across different diseases studied, especially in subjects with more advanced fibrosis at baseline, 
is the potential for pruritus, a symptom commonly associated with cholestatic liver
diseases - particularly PSC and PBC - and a known complication of FXR agonist therapy. During
the 12-week double-blind period of the Phase 2 PSC study (GS-US-428-4025), the overall
incidence of treatment-emergent pruritus was lower in CILO-treated PSC subjects (31%, 13 of 
42 subjects treated with 100 mg or 30 mg) compared with those administered placebo (60%, 6 of 
10 subjects). Grade 2 or 3 pruritus was also lower with CILO 100 mg (14%, 3 of 22 subjects) 
and 30 mg (20%, 4 of 20 subjects) compared with placebo (40%, 4 of 10 subjects). Only one 
subject treated with CILO 100 mg discontinued treatment due to pruritus. In the ongoing OLE 
phase of this study, Grade 2-3 pruritus has thus far been reported in 8 of 46 PSC subjects (17%) 
treated with CILO 100 mg and 3 subjects (7%) have discontinued treatment prematurely due to 
pruritus.
In this study, we will further evaluate the frequency of pruritus in a population of subjects with 
PSC and cirrhosis taking CILO. The study is designed to dose escalate every 4 weeks based on 
investigator assessment of tolerability of CILO (particularly with respect to pruritus), with 
additional quantitative measures of pruritus (eg, the 5D-Itch and visual analog scale [VAS]
questionnaires) performed every 4 weeks. For subjects who develop significant pruritus, a formal 
pruritus management plan has been included in this study which includes, temporary study drug
dose interruption of CILO dosing, dose reduction, and supportive management with
antihistamines and bile acid sequestrants.


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Another potential risk of CILO treatment is drug-related hepatotoxicity. In nonclinical studies, 
effects on the liver have been limited to nonadverse mild increases in ALP 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) to suggest direct cellular damage. During the randomized phases of the 
Phase 2 NASH (GS-US-402-1852) and PSC studies (GS-US-428-4025), similar rates of 
treatment-emergent elevations in liver biochemistry tests were observed in CILO versus 
placebo-treated subjects. Specifically, Grade 3 or 4 ALT elevation was observed in 3.9% of 
subjects (6 of 154) treated with CILO and 2.6% of subjects (1 of 38) treated with placebo in 
these studies. Grade 3 or 4 AST elevations occurred in 4.5% (7 of 154) and 5.3% (2 of 38) of 
subjects, respectively. In the majority of these cases, an alternative etiology was identified 
including natural fluctuations in underlying disease activity and biliary obstruction in a subject 
with PSC that resolved following endoscopic intervention. To mitigate the potential risk of liver 
injury in this study, subjects will be monitored closely and defined rules for close observation 
and drug cessation due to elevated liver tests have been specified in the protocol (see Section 7.5.
Toxicity Management: Observation for Drug-Induced Liver Injury).
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 drug due to 
AEs and nonhepatic laboratory abnormalities are also defined and will be closely followed.
As PSC is a serious, life-threatening condition with no available therapies, the potential benefits
of treatment with CILO, as described above, outweigh the known risks. The available data in 
noncirrhotic PSC subjects treated for 12 weeks, as well as the favorable safety profile seen across
ongoing and completed studies provide strong support for furthering the evaluation of CILO in 
subjects with PSC and compensated cirrhosis as an additional step in its evaluation as a potential 
therapy for this patient population. 
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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OBJECTIVES 
The primary objective of this study is: 
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To assess the safety and tolerability of escalating doses of CILO in subjects with PSC and 
compensated cirrhosis 
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3.
STUDY DESIGN
3.1.
Study Design
This is a proof of concept, open-label study evaluating the safety and tolerability of CILO in 
subjects with PSC and compensated cirrhosis.
Eligible subjects will be enrolled and receive treatment with escalating doses of CILO over 
12 weeks. Subjects will dose escalate at Week 4 (from 30 mg to 60 mg once daily) and Week 8 
(from 60 mg to 100 mg once daily) if in the opinion of the principal investigator (PI) study drug 
is being tolerated. 
Individual subject participation in the study can last up to 20 weeks, which includes a 4-week
screening period, a 12-week treatment period (divided into three 4-week dosing stages at 30 mg
QD, 60 mg QD, and 100 mg QD), and a follow-up visit 4 weeks after the Week 12 visit. 
Study drug dosing may be interrupted for up to 4 consecutive weeks at the discretion of the PI if 
a subject experiences an AE (eg, intolerable pruritus) thought to be related to the study drug. 
During the period of study drug dose interruption, subjects are not required to attend in-clinic 
visits per the Study Procedures Table (Appendix 2) but will be monitored via weekly telephone 
follow-up visits (refer to Section 7.5.5). If a study drug dose interruption requires reinitiation of a 
dosing stage, participation in the study could be extended from up to 20 weeks to up to 28 weeks
to complete 4 consecutive weeks of dosing at each dose stage.
The overall study design is shown in the figure below:
3.2.
Study Treatments
Individual subjects will receive escalating doses of CILO 30 mg (1 30 mg tablet), 60 mg
(2 30 mg tablets), then 100 mg (1 100 mg tablet), administered orally once daily. If tolerated, 
subjects will dose escalate after 4 weeks on each dose. 
CILO 
CILO 
CILO 
·;;; 
00 
30 mg 
60mg 
100 mg 
> 
.5 
0. 
C 
. 
-
" e 
One 30 mg tablet 
Two 30 mg tablets 
One J 00 mg tablet 
u 
orally once daily 
orally once daily 
orally once daily 
.3 
Cl'.} 
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4 weeks 
4 weeks 
4 weeks 
4 weeks 
12 weeks 
4 weeks 


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3.3. 
Duration of Treatment 
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Subject will be treated with study drug for 12 weeks; up to 16 weeks if subject requires dose re-
challenge after study drug dose interruption. 
3.4. 
3.4.1. 
Biomarker Testing 
Biomarker Samples to Address the Study Objectives: 
Biological specimens will be collected from all subjects who have provided consent to 
participate in this study and may be used to evaluate the association of systemic based 
biomarkers with study drug response, including efficacy and/or AEs and to better m1derstand the 
biological pathways, biology of PSC or related diseases such as PBC and/or the validation of a 
companion diagnostic for PSC. The specific analyses will include, but will not be limited to, the 
biomarkers and assays listed below. Because biomarker science is a rapidly evolving area of 
investigation, and AEs in particular are difficult to predict, it may not be possible to specify 
prospectively all tests that may be perfonn ed on the specimens provided. As such, the testing 
outlined below is based upon the current state of scientific knowledge. It may be modified during 
or after the end of the study to remove tests no longer indicated and/or to add new tests based 
upon new state of art knowledge. 
Biomarker testing may include biomarkers in blood and stool, that monitor hepatic fibrosis 
( collagen synthesis and degradation such as ProC3 and ProC5), cell apoptosis and necrosis 
(CKl 8 M30 and M65), and other biochemicals, biological macromolecules, and naturally 
occurring metabolites that ma indicate disease ro ession or response to therapy. In addition, 
biomarkers of FXR activity 
may also be detennined. Biomarkers 
that may be useful in predictmg t e occurrence o prur1tus, such as serum autotaxin 
-
may also be assessed. Stool samples (if available) will be collected for 
, and 
potentially microbiome analyses, and stool calprotectin may be analyzed to assess mtestinal 
infla1mnation. 
The specimen storage 
period will be in accordance with the Institutional Review Board (IRB)/ Independent Ethics 
Co1mnittee (IEC)-approved Infonn ed ConsentFonn (ICF) and applicable laws (eg, health 
requirements). 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will target approximately 20 subjects for enrollment who are equal to or greater than 
18 years of age with PSC and compensated cirrhosis.
4.1.1.
Subject Replacement
Subjects who discontinue prior to the end of the study will not be replaced. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to give informed consent prior to any study-specific procedures being 
performed
2) Males and nonpregnant, nonlactating females equal to or greater than 18 years of age; 
inclusive based on date of the Screening visit
3) Diagnosis of PSC based on cholangiogram (MRCP, endoscopic retrograde 
cholangiopancreatography [ERCP], or percutaneous transhepatic cholangiogram [PTC]) or 
liver biopsy
4) Subjects have evidence of cirrhosis based on at least one of the three following criteria
a) Historical liver biopsy that reveals Ludwig stage F4 fibrosis (or equivalent)
b) Abdominal imaging with features consistent with cirrhosis in the opinion of the 
investigator (eg, small nodular liver, splenomegaly, evidence of portosystemic collaterals, 
diffuse surface irregularity). magnetic resonance imaging (MRI), computed tomography 
(CT), and/or ultrasound are acceptable modalities to make this determination. 
c) Any one of the following completed at Screening visit:
i)
FibroScan ≥ 14.4 kPA
ii) ELF ≥ 11.3 
iii) FibroTest ≥ 0.75 


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5) Subject has the following laboratory parameters at the Screening visit, as determined by the 
central laboratory:
a) Estimated glomerular filtration rate (eGFR) > 60 mL/min, as calculated by the 
Cockcroft-Gault equation
b) ALT ≤ 5 ULN
c) Total bilirubin ≤ 2 mg/dL, unless the subject is known to have Gilbert’s syndrome or 
hemolytic anemia
d) INR ≤ 1.4, unless due to therapeutic anticoagulation
e) Platelet count ≥ 75,000/μL. Patients with evidence of high-risk esophageal or gastric 
varices in the opinion of the investigator are excluded
f)
Negative anti-mitochondrial antibody
6) For subjects on UDCA, the dose of UDCA must have been stable in the opinion of the 
investigator for at least 6 months before screening. For subjects not on UDCA, no UDCA use 
for at least 6 months prior to screening.
7) For subjects being administered biologic treatments (eg, anti-tumor necrosis factor or 
anti-integrin monoclonal antibodies), immunosuppressants, or systemic corticosteroids, the 
dose must have been stable in the opinion of the investigator for at least 3 months prior to 
screening and anticipated to remain stable throughout the study. 
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.
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use specified method(s) of contraception as described in 
Appendix 4.
10) Subjects must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following
a) Decompensated liver disease, including ascites, hepatic encephalopathy (HE), or variceal 
hemorrhage


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b) Liver transplantation
c) Cholangiocarcinoma or hepatocellular carcinoma (HCC). If a dominant structure has
been identified, cholangiocarcinoma must be adequately excluded in the opinion of the
investigator prior to Day 1
2) Model for end-stage liver disease (MELD) score > 12 at screening, unless due to an alternate
etiology such as therapeutic anticoagulation
3) CP score > 6 at screening, unless due to an alternative etiology such as Gilbert’s syndrome or
therapeutic anticoagulation
4) Presence of moderate to severe itch in the opinion of the investigator at screening and
Baseline/Day 1
5) Ascending cholangitis within 30 days of screening
6) Presence of a percutaneous drain or biliary stent
7) Other causes of liver disease including IgG4-related sclerosing cholangitis, PSC-autoimmune
hepatitis overlap syndrome, secondary sclerosing cholangitis, and viral, metabolic, alcoholic,
and other autoimmune conditions. Subjects with hepatic steatosis may be included if there is
no evidence of NASH in the opinion of the investigator.
8) Current moderate to severely active IBD (including ulcerative colitis, Crohn’s disease, and
indeterminate colitis). See Section 6.8.6.
Note: Subjects with IBD who currently have an external ostomy bag and/or 
proctocolectomy are not subject to this exclusion criterion and need not undergo IBD 
Symptom Severity Assessment.
9) Current or prior history of any of the following:
a) Malignancy within 5 years of screening with the following exceptions:
i)
Adequately treated carcinoma in situ of the cervix
ii) Adequately treated basal or squamous cell cancer or other localized nonmelanoma
skin cancer.
Subjects under evaluation for possible malignancy are not eligible. 
b) Unstable cardiovascular disease as defined by any of the following:
i)
Unstable angina, myocardial infarction, coronary artery bypass graft surgery or
coronary angioplasty within 6 months prior to screening
ii) Transient ischemic attack or cerebrovascular accident within 6 months prior to
screening


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iii) Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy
iv) Symptomatic congestive heart failure
v) Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an 
automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial 
fibrillation is allowed.
c) Hypercoagulable condition or venous or arterial thromboembolic disease
d) Intestinal resection or malabsorptive condition that may limit the absorption of CILO. 
Prior cholecystectomy and appendectomy are permitted.
10) HIV infection (HIV antibody [Ab] and HIV ribonucleic acid [HIV RNA] positive)
11) Hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive) 
12) Hepatitis C virus (HCV) infection (HCV Ab and HCV RNA positive). Subjects cured of 
HCV infection ≥2 years prior to screening are eligible.
13) Habitual alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, 
and a 1 oz/30 mL measure of 40% proof alcohol)
14) Use of antibiotics (eg, vancomycin, metronidazole, minocycline, etc.) for the treatment of 
PSC within 60 days of screening. Antibiotic prophylaxis for ascending cholangitis is 
permitted if stable in the opinion of the investigator for at least 6 months prior to screening. 
15) Use of any prohibited CMs as described in the protocol (refer to Section 5.5).
16) Positive urine screen for amphetamines, cocaine or opiates (ie, heroin, morphine) at 
screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 
6 months prior to screening may be included. Subjects with a positive urine drug screen due 
to prescription opioid-based mediation are eligible if the prescription and diagnosis are 
reviewed and approved by the investigator
17) Participation in another investigational study of a drug or device within 28 days prior to or 
within 5 half-lives of the prior investigational agent (whichever is longer) prior to screening.
18) Concurrent participation in another therapeutic clinical study
19) Known hypersensitivity to CILO, its metabolites, or formulation excipient
20) Presence of any concomitant medical condition that could, in the opinion of the investigator, 
compromise the subject’s ability to participate in the study
21) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their 
psychiatric illness within the last 2 years


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Treatment Codes Access 
An interactive web response system (IWRS) will be used for treatment assignment. Investigative 
site personnel will obtain the subject’s identification number and study drug assignment from the 
IWRS. Study drug will be dispensed by the study pharmacist, or designee.
5.2.
Description and Handling of CILO
5.2.1.
Formulation
CILO is supplied as 30 mg and 100 mg strength (as free form equivalent) tablets. The tablets 
contain cilofexor tromethamine and inactive ingredients mannitol, microcrystalline cellulose, 
crospovidone, magnesium stearate and film-coating material comprised of polyvinyl alcohol, 
polyethylene glycol, titanium dioxide, talc, yellow iron oxide and black iron oxide. CILO tablets, 
30 mg, are round, film-coated green tablets debossed with “30” on one side and “GSI” on the 
other side. CILO tablets, 100 mg, are capsule-shaped, film-coated green tablets debossed with 
“100” on one side and “GSI” on the other side. 
5.2.2.
Packaging and Labeling
CILO tablets, 30 mg and 100 mg, 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 US Food and Drug Administration (FDA), and/or 
other local regulations.
5.2.3.
Storage and Handling
Study drug CILO tablets should be stored below 30 °C (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 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 study drug contact with the body. Appropriate precautions should be followed to 
avoid direct eye contact or exposure when handling CILO tablets.


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5.3.
Dosage and Administration of CILO
CILO tablets will be provided by Gilead Sciences, Inc. During the treatment phase of the study, 
each subject will be supplied with open-label bottles of CILO tablets. 
Enrolled subjects will start with 1 bottle containing 30 CILO tablets and will be instructed to take 
one (30 mg tablet) orally once daily for 4 weeks. Upon dose escalating, subjects will be provided 
with 2 bottles of CILO, each containing 30 tablets, and will be instructed to take two (30 mg) 
tablets orally once daily for 4 weeks. Upon final dose escalation, subjects will be provided with 
1 bottle of CILO containing thirty 100 mg tablets and will be instructed to take one (100 mg) 
tablet orally once daily for 4 weeks.
The study drug should be taken at approximately the same time each day. 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 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).
CILO increased atorvastatin exposure (39%) which does not necessitate a priori dose 
modification based on the LIPITOR United States prescribing information (USPI). Subjects 
taking atorvastatin with CILO 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:

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents [ESAs]; granulocyte 
colony stimulating factor [GCSF]; thrombopoietin [TPO] mimetics)

Investigational agents or devices for any indication 

Concomitant use of certain medications or herbal/natural supplements (potent inhibitors of 
OATP or potent or moderate inducers of OATP, CYP2C8, P-gp, or CYP3A) with study 
drug(s) may result in PK interactions resulting in increases or decreases in exposure of study 
drug(s) or CMs. 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.


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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 Antagonistsa
Antacidsb
Anticonvulsantsc
Carbamazepine, Phenobarbital, Phenytoin
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Endothelin Receptor 
Antagonists
Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinacea. Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Bile Acid Sequestrantsd
Cholestyramine, Colesevelam, 
Colestipol, Colestilan
Otherc
Modafinil
a
H2 Receptor Antagonists can be taken up to 3 days prior to study drug dosing.
b
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours (before 
or after) study drug administration.
c
May result in a decrease in the concentrations of study drugs.
d 
Bile acid sequestrants are permitted but must not be taken within 4 hours (before or after) of study drug administrations.
Use of obeticholic acid or norursodeoxycholic acid is prohibited within 3 months prior to
screening through the end of treatment. 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. For subjects on UDCA, the 
dose of UDCA must have been stable in the opinion of the investigator for at least 6 months 
before screening and anticipated to remain stable throughout the study. For subjects not on 
UDCA at screening, UDCA should not be administered during the treatment period.


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5.6.
Accountability for CILO
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits 

Record the date, subject number and the study drug kit 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.
Study Drugs Return or Disposal
Refer to Section 9.1.8 for instructions regarding study drug return or disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the Site Operations Manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the Screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened to determine eligibility for participation in the study, with screening 
visit occurring no more than 4 weeks prior to treatment. 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 re-screened once if there is a reasonable 
expectation that the subject will meet eligibility after repeat screening. 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.
The following will be performed and documented at screening:

Obtain written informed consent before initiation of any Screening procedures

Obtain Screening number from IWRS

Obtain medical history 


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
Review and record whether the subject meets inclusion and exclusion criteria

For subjects with history of IBD (as appropriate, see Section 6.8.6):
IBD symptom severity assessment

Complete physical examination including ascites and HE assessments

Record vital signs, body weight, and height

Conduct standard 12-lead ECG

Obtain blood samples for 
Chemistry
eGFR
Hematology 
Coagulation Panel
Biomarkers 
HIV-1, HBV and HCV Serology
Serum pregnancy test (female subjects of child bearing potential only)
Serum follicle-stimulating hormone (FSH) (only for women of any age with amenorrhea 
of ≥ 12 months, see Appendix 4) 

Urine drug screen

Perform FibroScan 

CP and MELD scores 

Record any SAEs and all AEs related to protocol-mandated procedures occurring after 
signing of the consent form.

Record all 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 treatment.


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From the time of obtaining infonned consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the AEs case report fonn (CRF). All other m1toward medical occurrences observed during the 
Screening period, including exacerbation or changes in medical history are to be captured on the 
medical history CRF/eCRF. See Section 7: Adverse Events and Toxicity Management, for 
additional details. 
After the Screening Period, in-clinic study visits will occur at Baseline/Day 1 and at Weeks 1, 4, 
8, and 12. At minimmn, vital signs, symptom-driven physical examination (PE) including ascites 
and HE, safety laboratory tests, pruritus assessment (VAS and 5-ltch), review for active IBD, for 
subjects with history of IBD (as appropriate, see Section 6.8.6), and review of AEs and CMs will 
be perfonned at every in-clinic visit. 
6.3. 
Baseline/Day 1 Assessments 
Subjects returning to the clinic Baseline/Day 1 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 
Baseline/Day 1 visit to ensure an approximate 8-hour fast prior to the fasted blood sample 
collection the next morning. 
After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will be 
assigned study drug and receive their Subject Identification Nmnber via the IWRS prior to their 
first dose of study drugs. 
The following will be perfonned and documented at the Baseline/Day 1 visit prior to dosing: 
I 
I 
• 
For subjects with history of IBD (as appropriate, see Section 6.8.6): 
IBD symptom severity assessment 
any evidence of active IBD seen on routinely perfonned colonoscopy will be captured 
• 
Symptom-driven physical examination including ascites and HE assessments 
• 
Record vital signs and body weight 
• 
Conduct standard 12-lead ECG 
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• 
Obtain blood samples for: 
Chemistry 
eGFR 
Hematology 
Coagulation Panel 
Lipid Profile 
C-peptide, Insulin and Hemoglobin A1c (HbA1c) 
Biomarkers 
• 
CP and MELD scores 
• 
Collect urine samples for: 
Urine pregnancy test for females of child bearing potential only 
• 
Collect stool sample (if available) 
• 
Record all CMs that the subject has taken since the previous visit 
FINAL 
Amendment3 
• 
Record any SAEs and all AEs related to protocol-mandated procedures occurring since the 
Screening visit 
• 
Dispense study drug, and provide subject with instruction on appropriate dosing and 
administration 
• 
Once all visit procedures have been completed, subjects will take their Baseline/Day 1 dose 
of study drug while at the investigative site. 
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6.4. 
6.4.1. 
Treatment Assessments 
Week 1, Week 4, Week 8, and Week 12 (± 3 days) 
FINAL 
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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 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 blood sample collections have been completed. 
The following treatment procedures/assessments are to be completed and docmnented at these 
in-clinic visits: 
I 
I 
• 
For subjects with history of IBD (as appropriate, see Section 6.8.6): 
IBD symptom severity assessment (Week 4, Week 8, and Week 12) 
any evidence of active IBD seen on routinely perfonned colonoscopy will be captured at 
all in-clinic visits 
• 
Symptom-driven physical examination including ascites and HE assessments 
• 
Record vital signs and body weight 
• 
Obtain blood samples for: 
Chemistry 
eGFR 
Hematology 
Coagulation Panel 
Lipid Profile (Week 4, Week 8, and Week 12) 
C-peptide, Insulin and HbA1c (Week 12) 
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Biomarkers (Week 1, Week 4, Week 8, and Week 12) 
I 
I 
The date and time of the previous study drug dose will need to be docmnented 
I 
• 
CP and MELD scores 
• 
Obtain urine samples for: 
FINAL 
Amendment3 
Urine pregnancy testing for females of childbearing potential only at Week 4, 8, and 12 
• 
Collect stool sample (Week 12) for bile acids by mass spectrometry (if available) 
• 
Perfonn FibroScan at Week 12 
• 
Record all CMs that the subject has taken since the previous visit 
• 
Record any SAEs and all AEs occurring since the previous visit 
• 
Dispense the study drug as directed by IWRS (Week 4 and Week 8) 
• 
Review study drug compliance and study drug administration instructions with subject 
Reconcile study drug administration using pill com1ts 
In the case of a PI approved study drug dose interruption, subjects will have weekly telephone 
follow-up assessments as detailed in Section 6.4.2. During the study drug dose interruption, 
subjects are otherwise not required to complete in-clinic assessments unless deemed necessary 
given the rationale for their study drug dose interruption ( eg, Close Observation for drug-induced 
liver injury [DILi], follow up of non-DILi laboratory abnonnalities). 
6.4.2. 
Telephone Follow-Up Visit (weekly; during PI approved study drug dose 
interruption) 
A telephone follow-up visit will occur only if a subject is on a PI approved study drug dose 
interruption. 
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Cilofexor (CILO; GS-9674) 
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Gilead Sciences, Inc. 
The telephone follow up will occur once a week and will document the following: 
• 
Record all CMs that the subject has taken since the previous visit 
• 
Record any SAEs and all AEs occurring since the previous visit 
• 
Record home urine pregnancy test for females of childbearing potential only 
FINAL 
Amendment3 
Urine pregnancy test to be taken at home every 2 weeks during PI approved study drug 
dose interruption. 
• 
At the discretion of the investigator, an unscheduled visit may be completed if the subject 
reports abnonnal or concerning symptoms, or if the subject requires additional fo llow up of 
laboratory abnonnalities 
6.4.3. 
Early Termination Visit 
Subjects prematurely discontinuing from the study should complete an early tennination (ET) 
visit within 30 days of last dose. 
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perfonn the required study-related 
procedures per the Study Procedures Table (see Appendix 2). If a subject who discontinues study 
dosing and continues to perfonn the required study-related procedures decides to prematurely 
discontinue from the study, an ET visit should be completed within 30 days of last study visit. 
Subjects should be instructed to fast (no food or drink, except water), starting from 1nidnight 
(00:00) or earlier, as appropriate, on the evening prior to the ET visit 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 and documented at this 
visit. 
I 
I 
• 
For subjects with history of IBD (as appropriate, see Section 6.8.6): 
IBD symptom severity assessment 
any evidence of active IBD seen on routinely perfonned colonoscopy will be captured 
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
Symptom-driven physical examination including ascites and HE assessments

Record vital signs body weight

Obtain blood samples for:
Chemistry
eGFR
Hematology
Coagulation Panel
Lipid Profile
C-peptide, Insulin and HbA1c
Biomarkers 
 

Obtain urine samples for:
Urine pregnancy test for females of child bearing potential only 

Perform FibroScan 

CP and MELD scores

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
6.4.4.
Follow- Up Visit (± 5 Days)
Subjects will return for a follow-up visit 4 weeks after the Week 12 or 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.
CCI


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The following will be performed and documented at this visit.

Pruritus assessments (Pruritus VAS and 5D-Itch)

For subjects with history of IBD (as appropriate, see Section 6.8.6):
IBD symptom severity assessment
any evidence of active IBD seen on routinely performed colonoscopy will be captured

Symptom-driven physical examination including ascites and HE assessments

Record vital signs, body weight

Obtain blood samples for:
Chemistry
eGFR
Hematology
Coagulation Panel
Lipid Profile 
C-peptide, Insulin and HbA1c
Biomarkers 

CP and MELD scores

Obtain urine samples for:
Urine pregnancy testing for females of childbearing 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
6.4.5.
Unscheduled Visit
Additional unscheduled assessments may be performed at the discretion of the investigator.


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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 fasted blood sample collection 
the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of an 
unscheduled visit until all blood samples have been completed. Unscheduled visits may also 
occur while on a PI approved study drug dose interruption as detailed in Section 6.4.2.
At a minimum, the following will be performed and documented.

For subjects with history of IBD (as appropriate, see Section 6.8.6):
IBD symptom severity assessment
any evidence of active IBD seen on routinely performed colonoscopy will be captured

Symptom-driven physical examination including ascites and HE assessments

Record vital signs and body weight

Obtain blood samples for:
Chemistry
Hematology
eGFR

Record all CMs that the subject has taken since the previous visit

Record any SAEs and all AEs occurring since the previous visit
If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the 
assessments noted above do not need to be performed.
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE thought to be related to 
study drug), every attempt should be made to keep the subject in the study and continue to 
perform the required study-related procedures per the Study Procedures Table (see Appendix 2).
If a subject who discontinues study dosing and continues to perform the required study-related 
procedures decides to prematurely discontinue from the study, an ET visit should be completed 
within 30 days of last study visit. If this is not possible or acceptable to the subject or 
investigator, the subject may be withdrawn from the study. 


Cilofexor (CILO; GS-9674) 
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Gilead Sciences, Inc. 
6.6. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
FINAL 
Amendment3 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator. 
• 
Unacceptable toxicity (Section 7.5), 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 
• 
Any subject without a history of IBD who develops new onset IBD while participating in the 
study, or any subject with a history of IBD who experiences a clinically significant 
worsening in IBD symptoms ( eg, stool frequency, bleeding) or endoscopic evidence of 
disease worsening in the opinion of the PI. 
• 
CP score~ 7 on two consecutive occasions at least two weeks apart unless due to an alternate 
etiology ( eg, therapeutic anticoagulation), refer to Section 7.5 
• 
Any subject who experiences a hepatic decompensation event, including ascites, HE, or 
portal hypertension-related upper gastrointestinal bleeding ( eg, bleeding from esophageal 
varices, gastric varices, or portal hypertensive gastropathy) 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Significant protocol deviation that impacts subject safety 
• 
Pregnancy during the study; refer to Appendix 4 
• 
Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB or IEC 
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6.8. 
Procedures and Specifications 
6.8.1. 
Clinical Laboratory Analytes 
Chemistry: 
FINAL 
Amendment3 
Alanine aminotransferase, AST, albumin, ALP, bicarbonate, blood urea nitrogen (BUN), 
calcimn, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, 
potassium, sodimn, total and direct bilirubin, total protein, uric acid, GGT 
eGFR: 
eGFR is estimated by creatinine clearance calculated by the Cockcroft-Gault equation 
{Cockcroft 1976}. 
Male: eGFR (mL/min) 
[140 
age (years)] x BW(kg) 
72 X Ser 
Female: 
eGFR(mL/min) 
[140 
age (years)] x BW(kg) x 0.85 
72 X Ser 
BW 
body weight; Ser 
sermn creatinine (mg/dL) 
Actual body weight will be used for the eGFR. 
Hematology: 
Hematocrit, hemoglobin (Hb ), platelet count, red blood cell count (RBC), white blood cell count 
(WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and reticulocyte count and mean corpuscular volume. 
Coagulation Panel: 
Prothrombin time, partial thromboplastin time (PTT), and INR. 
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Pregnancy Tests: 
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Serum beta human chorionic gonadotropin (P-hCG) or urine P-hCG (if positive, requires 
immediate confirmation with serum P-hCG), and serum FSH. 
Additional Tests: 
C-peptide, insulin and HbA1c, Lipid Profile, HIV-1 (reflex to HIV-1 RNA), HBV (HBsAg) and 
HCV (reflex to HCV RNA) serology, eGFR as calculated by modification of diet in renal disease 
(MDRD), urine drug screen (for amphetamines, cocaine, opiates), stool collection (if available), 
genomic sample collection, and creatine phosphokinase (CPK) testing (for Close Observation as 
needed per Section 7.5.2). 
Biomarker tests: 
• 
Inflammation high sensitivity C-reactive protein (hsCRP) 
I 
I 
I 
I 
6.8.2. 
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. 
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6.8.3.
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 and neurological, and assessments for ascites & HE.
The focus of a symptom-driven physical examination should include assessments for ascites and 
HE and will be determined by the investigator based on subject complaint. For example, if a 
subject complains of a cough a respiratory exam should be performed. If consistent with 
pneumonia (eg, rales or crackles are identified) then an AE would be documented.
Height and body weight will be collected at specified time points.
6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥ 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 millimeter of mercury (mmHg) mark 
on the manometer or to the nearest whole number on an automatic device.
6.8.5.
Clinical Liver Assessments
The MELD and CP scores will be calculated from the central laboratory values attained at each 
visit. CP will be calculated by the site at screening to assess eligibility; MELD may also be 
calculated by the sites at screening to determine eligibility if the central laboratory is unable to 
perform the calculation. MELD will be monitored by site at each visit for safety. Assessment of 
ascites and HE will be determined by the site at all visits as in the Table 6-1 and will be entered 
into the eCRF. Dialysis in the preceding week will also be determined by the site at each visit. 
HE will also be assessed using the West Haven Criteria (Appendix 5). 


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Table 6-1.
Child-Pugh (CP) Classification of the severity of cirrhosis
1
2
3
Hepatic 
Encephalopathy 
(HE) 
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject is receiving medical 
therapy for HE 
Medication-Refractory
Marked confusion/incoherent, 
rousable but sleeping or 
comatose
Ascites
None
No ascites and not on 
treatment for ascites
Mild/Moderate
Cross sectional imaging 
showing ascites
Abdominal distension 
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3
CP score is obtained by adding the score for each parameter.
CP class:
A  5-6 points
B  7-9 points
C  10-15 points
The MELD score will be calculated by using the following formula:
10 ((0.378 ln (Total Bilirubin (mg/dL)) + (1.12 ln (INR)) + (0.957 ln (Serum Creatinine 
(mg/dL)) + 0.643). 
Serum creatinine in mol/L will be converted to mg/dL by multiplying by 0.01131. Total 
bilirubin in mol/L will be converted to mg/dL by multiplying by 0.05848. Round total bilirubin 
to 1 decimal place and serum creatinine to 2 decimal places prior to using values in formula or 
calculation criteria. 
If the serum creatinine is < 1.00 mg/dL, the calculation will use 1.00 as the serum creatinine 
value. If the serum creatinine is > 4.00 mg/dL or if “For subjects on dialysis, did the subjects 
have 2 or more dialysis treatments within the prior week?” is answered as “Yes”, the calculation 
will use 4.00 as the serum creatinine value. If the total bilirubin is < 1.0 mg/dL, the calculation 
will use 1.0 as the total bilirubin value. If the INR is < 1.0, the calculation will use 1.0 as the INR 
value. If the creatinine is resulted as “Icteric Test Not Performed”, the calculation will use 
serum enzymatic creatinine.


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The online calculator https:/ /www.mdcalc.com/meld-score-original-pre-2016-model-end-stage-
liver-disease may also be used. 
6.8.6. 
IBD Symptom Severity Assessment 
IBD (includes ulcerative colitis, Crohn's disease, and indetenninate colitis) Symptom Severity 
Assessment is a survey for the assessment of IBD that considers stool frequency, rectal bleeding, 
and physician assessment of IBD for disease severity assessment. Evaluation of any changes in 
symptoms related to IBD including stool frequency and bleeding, as detailed in Appendix 6. Any 
subject who experiences worsening IBD symptoms should be instructed to contact the site. IBD 
Symptom Severity Assessment does not need to be evaluated in subjects who currently use an 
external ostomy bag and/or subjects who have undergone proctocolectomy, even if they have 
history of IBD. IBD Symptom Severity Assessment should be evaluated in any subject whose 
external ostomy is reversed while on the study. 
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6.8.8. 
Electrocardiogram 
FINAL 
Amendment3 
Standard 12-lead ECG assessments will be perfonned. The investigator will review the ECGs for 
any clinically significant abnonnalities to ensure subject safety. Abnonnal 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. 
- -
6.9. 
End of Study 
End of study is defined as the last patient last visit (LPLV) when the last subject's follow-up visit 
(4 weeks after completing Week 12 visit) occurs or the ET follow-up visit, whichever occurs 
later. 
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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 AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.
AEs may also include pre- or posttreatment complications that occur as a result of protocol 
specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an AE and must be reported.

Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (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 preexisting and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
An 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 7.6.1.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to 
study drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, or CM).


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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 AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 according to the Common 
Terminology Criteria for Adverse Events (CTCAE). Refer to the Site Operations Manual for 
additional CTCAE information.
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 AE 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 CRF/eCRF: all SAEs and AEs related to protocol-mandated 
procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study drug must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead 
Sciences may request that certain AEs be followed beyond the protocol-defined follow-up 
period.


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All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the infonned consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Global Patient Safety (GLPS) as instructed. This also includes 
any SAEs resulting from protocol-associated procedures perfonned after infonned consent is 
signed. 
Any SAEs and deaths that occur after the posttreatment follow-up visit but 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 study drug, he/she should promptly document and 
report the event to Gilead GLPS. 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined in 
the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process 
• 
Site perso1mel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead GLPS within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electronically, because the 
eCRF database cannot be accessed or is not available (including at study start), record the 
SAE on the paper SAE report fonn and submit by e-mail or fax within 24 hours of the 
investigator's knowledge of the event to: 
Gilead GLPS: 
Fax: 
E-mail: 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper fonn because the eCRF database has been locked, no 
further action is necessary 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a docmnent to the subject identifiers. 
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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 CM section 
of the subject’s CRF/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, which may be in the form of line listings, 
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 IB 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. 
7.5.
Toxicity Management 
7.5.1.
Observation for Drug-Induced Liver Injury 
At baseline, some subjects may have liver biochemistry levels above the ULN. Baseline values 
for liver tests 
 will be determined by averaging the values 
obtained between and including screening and Day 1. Please refer to the Covance Laboratory 
Manual or individual subject Covance laboratory report for gender and age specific reference 
ranges.
On-treatment elevations 
 should be confirmed with repeat testing within 
48-72 hours of results. If the results are confirmed, and if no other cause of the laboratory 
abnormalities is immediately apparent, notify the medical monitor. Subjects with 
 
elevations as per Figure 7-1 must be placed into close observation (as described below).
CCI
CCI
CCI


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Figure 7-1. 
On-Treatment- Monitoring Requiring Close Observation 
7.5.2. 
Baseline-
(average of all Screening & Day 1 values} 
Note: 
Normal 
(~ ULN) 
meet this criterion: 
• 
> 3 x ULN 
Yes 
i 
are evaluated independently 
Elevated 
(> ULN) 
meet any one of these criteria: 
• 
> 2 x Baseline 
• 
> 300 U/L 
Yes 
i 
Enter Subject into Close Observation 
Close Observation 
Close observation includes: 
• 
Repeating liver biochemistries 
) and obtaining a 
CPK level within 48-72 hours of confinnatory results collected prior to entering close 
observation. 
• 
Obtaining a more detailed history of symptoms and prior or concurrent disease 
• 
Obtaining a history of CM use (including nonprescription medications and herbal and dietary 
supplement preparations), alcohol use, recreational drug use, and special diets 
• 
Obtaining a history of exposure to enviromnental chemical agents 
• 
Ruling out other causes of liver disease as needed ( obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the investigator) 
• 
Continue to monitor liver biochemistries at least twice weekly. Frequency can decrease to 
once a week or less if abnonnalities stabilize or study drugs have been discontinued and the 
subject is asymptomatic. 
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During a period of close observation for DILI, study drugs can be continued, if desired, at the 
discretion of both the medical monitor and investigator.
If on-treatment elevations of ALT and/or AST exceed the values shown in Figure 7-2, are 
confirmed on repeat testing within 48-72 hours of results, and no alternative cause is 
immediately apparent, the subject must be placed into close observation and study drug must be 
withheld. 
Figure 7-2.
On-Treatment Monitoring Requiring Withholding of Study Drugs 
If study drugs are withheld, they may be reintroduced with approval from the Gilead medical 
monitor. In instances where study drug is withheld in the context of DILI, up to a 4-week study 
drug dose interruption is permitted. Upon resuming study drug, the subject should restart at prior 
dose as outlined in Section 3.
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. 
Baseline ALT and AST 
(average of all Screening & Day 1 values) 
Note: ALT ond AST are evaluated independently 
I 
Normal 
(:<> ULN) 
i 
While on-treatment, does the subject meet 
any one of these criteria: 
• 
Symptoms of drug-related hepatotoxicity 
• 
ALTorAST>SxULN 
• 
AL Tor AST> 5 x ULN for 2 weeks 
• 
ALT or AST>3 x ULN and [TB>2 x ULN* 
or INR > 1.5**) 
I 
Yes 
I 
I 
Elevated 
(> ULN) 
i 
While on-treatment, does the subject meet 
any one of these criteria: 
• 
Symptoms of drug-related hepatotoxicity 
• 
ALT or AST> 8 x Baseline 
• 
ALT or AST> 500 U/L 
• 
[ALT or AST > 3 x Baseline or 300 U/L) and 
[TB> 2x ULN* or INR > 1.5**) 
I 
Yes 
Withhold Study Drugs and Enter Subject into Close Observation 
.. Unless. subject has Gilbert's syndrome, in which case a direct bilirubin > 2 x baseline (average of Screening & Day 1 values) will be us.ed instead of total bilirubin. 
**If not on therapeutic anticoagulation (e.g. warfarin). If on therapeutic anticoagulation, INR criteria is. disregarded . 
Abbreviations: 
ULN - Upper limit of normal range 
TB - Total Bilirubin 


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Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laboratory abnormalities should be confirmed by repeat testing within 48-72 hours of results, and 
preferably within 3 calendar days of receipt of the original test results. For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality. 
Any questions regarding toxicity management should be directed to the medical monitor.
7.5.3.
Child-Pugh Score
If a subject has an increase in their CP score to ≥ 7, this should be confirmed with repeat testing 
within 48-72 hours of receipt of results. If confirmed, the medical monitor should be notified,
and the subject should be placed into close observation as described above, unless an alternate 
etiology (eg, therapeutic anticoagulation) is identified. If the CP remains ≥ 7 for at least 2 
consecutive weeks, and an alternate etiology has not been identified, study drug must be 
discontinued.
7.5.4.
Pruritus Management
The development or worsening of pruritus during the study is a consideration for patients with 
PSC. Management of pruritus may include nonpharmacologic interventions (eg, skin 
moisturization, minimized heat exposure, avoidance of skin irritants, scratch reduction), topical 
corticosteroids, oral antihistamines, and/or bile acid sequestrants (eg, cholestyramine). Bile acid 
sequestrants must be taken more than 4 hours before or after the study drug dosing, as described 
in Table 5-1. Rifampin may not be used for management of pruritus. 
7.5.5.
Management of Study Drug Dose Interruption Due to AE
If subject experiences an AE (eg, intolerable pruritus) which in the opinion of the investigator 
may be related to the study drug, the subject may temporarily hold study drug at the 
investigator’s discretion. If study drug dosing is held for longer than 5 days, this is considered a 
PI approved study drug dose interruption which may not last longer than 4 consecutive weeks.
During this period, subjects are not required to attend in-clinic visits per Study Procedures 
Table (Appendix 2); however, will be monitored via weekly telephone follow-up visits. Female 
subjects of childbearing potential will be required to perform at home pregnancy tests every 
2 weeks during a PI approved study drug dose interruption.
Following the PI approved study drug dose interruption (ie, the AE has resolved or in the case of 
pruritus, has returned to baseline severity), the subject may initiate a 4-week re-challenge of the 
most recent dose. In-clinic visits and associated assessments per Appendix 2 will also resume, 
beginning with a repeat of the initial visit for that dose stage (ie, Day 1 for 30 mg, Week 4 for 
60 mg, and Week 8 for 100 mg). If resumption of study drug is tolerated in the opinion of the 
investigator for 4 consecutive weeks, the study drug dose can be escalated (ie, subject must 
complete 4 consecutive weeks at 30 mg and 60 mg before escalating to 60 mg and 100 mg, 
respectively). 


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If after resumption of study drug the subject experiences another AE thought to be related to 
study drug (eg pruritus) that necessitates study drug interruption, the study drug should be 
stopped, and the medical monitor should be notified. Only a single study drug dose interruption 
period of up to 4 consecutive weeks is permitted.
For study drug dose interruptions due to AEs that are deemed unrelated to study drug in the 
opinion of the PI, the aforementioned approach should also be followed (ie, only 5-day drug 
interruption permitted before requirement to repeat 4 week dosing stage).
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Medication errors may be classified as a medication error without an AE, which includes 
situations of missed dose; medication error with an AE; intercepted medication error; or potential 
medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 


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Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead investigational product. 
Counterfeit or falsified medicine: Any investigational product with a false representation of: 
a) Its identity 
b) Its source, or 
c) Its history 
7.6.2. 
Instructions for Reporting Special Situations 
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the post-treatment follow-up period, must be reported to Gilead GLPS. Adverse 
events and SAEs resulting from SSRs must be reported in accordance to the AE and SAE 
reporting guidance (Section 7.3). 
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 study drug follow-up 
period, to Gilead GLPS using the pregnancy report fonn within 24 hours of becoming aware of 
the pre~ancy. Reports should be sent directly to Gilead GLPS at fax numberPPD 
or email PPD 
------
Refer to Section 7.3 and the CRF/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 tenninate a 
pregnancy without medical reasons. 
Any premature tennination 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 tenn. 
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. Furthennore, any SAE occurring as an adverse pregnancy outcome 
after study completion must be reported to Gilead GLPS. 
The subject should receive appropriate monitoring and care m1til the conclusion of the 
pregnancy. The outcome should be reported to Gilead GLPS using the pregnancy outcome report 
fonn. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directl to Gilead GLPS. Gilead GLPS contact infonnation is as follows: 
Email: PPD 
and Fax: PD 
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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead GLPS using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead GLPS, 
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
Site personnel must record all other special situations data in the eCRF database and from there 
transmit the special situations information to Gilead GLPS within 24 hours of the investigator’s 
knowledge of the event. Detailed instructions can be found in the eCRF completion guidelines. 
All special situations data will be recorded in the eCRF database within the timelines outlined in 
the eCRF completion guidelines. These reports must consist of situations that involve study drug 
and/or Gilead CMs, but do not apply to non-Gilead CMs. 
If it is not possible to record and submit the special situations information electronically, because 
the eCRF database cannot be accessed or is not available (including at study start), record the 
information on the paper special situations report form and submit by e-mail or fax within 
24 hours of the investigator’s knowledge of the event to Gilead GLPS. Gilead GLPS contact 
information is as follows: 
Email: 
 and Fax: 
As soon as it is possible to do so, any special situations reported via paper must be transcribed 
into the eCRF database according to instructions in the eCRF completion guidelines. If any 
special situations have been reported via a paper form because the eCRF database has been 
locked, no further action is necessary.
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
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 posttreatment follow-up period, 
must be reported to Gilead GLPS utilizing the paper SSR form.
Special situations involving non-Gilead CMs do not need to be reported on the SSR form; 
however, for special situations that result in AEs due to a non-Gilead CM, the AE should be 
reported on the AE form. 
Any inappropriate use of CMs 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 CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
PPD
PPD
PPD
PPD


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All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
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 as follows: 
FINAL 
Amendment3 
• 
To assess the safety and tolerability of escalating doses of CILO in subjects with PSC and 
compensated cirrhosis 
I 
I 
I 
I 
I 
8.1.2. 
Primary Endpoint 
The primary endpoint is the safety and tolerability of CILO in subjects with PSC and cirrhosis. 
The safety and tolerability of CILO will be evaluated by examining treatment-emergent adverse 
events (TEAEs), including SAEs, clinical laboratory tests, and vital signs assessments at various 
time points during the study. 
I 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
FINAL 
Amendment3 
The primary analysis set for efficacy analyses will be the Safety Analysis Set, which includes all 
subjects who were enrolled into the study and received at least 1 dose of study drug. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses will include all subjects who received at least 1 dose 
of study drug. 
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8.2.1.5. 
Biomarkers 
FINAL 
Amendment3 
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. 
Data Handling Conventions 
Missing data can have an impact on the interpretation of the study 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 
smmnary statistics. For example, if a subject received study medication, the subject will be 
included in a smmnary of AEs according to the treatment received; otherwise, if the subject is 
not dosed then they will be excluded from the smmnary. If safety laboratory results for a subject 
are missing for any reason at a time point, the subject will be excluded from the calculation of 
smmnary statistics for that time point. If the subject is missing a predose value, then the subject 
will be excluded from the calculation of smmnary statistics for the predose value and the change 
from predose 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 pretreatment laboratory 
value is available, the baseline value will be assmned to be nonnal (ie, no grade [Grade O]) for 
the smmnary of graded laboratory abnonnalities. 
8.3. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be smmnarized using standard descriptive 
methods (n, mean, SD, median, Q 1, Q3, minimum, and maximum) by overall. Demographic 
smmnaries will include sex, race/ethnicity, and age. 
Baseline characteristics smmnary will include body weight, height, body mass index, and other 
disease characteristics. 
8.4. 
Efficacy Analysis 
oint estimates and 95% CI will be provided if applicable. 
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For all continuous endpoints, descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) will be provided. For categorical variables, descriptive statistics will be calculated 
with count and percentage of subjects in each category.
8.5.
Safety Analysis
All safety data collected on or after the date that CILO was first dispensed up to the date of last 
dose of CILO plus 30 days will be summarized by overall. Data for the pretreatment and follow-
up periods will be included in data listings.
8.5.1.
Extent of Exposure
Data for a subject’s extent of exposure to CILO will be generated from the study drug 
administration eCRF. Exposure data will be summarized by overall. 
8.5.2.
Adverse Events
Clinical and laboratory AEs 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 5.0.
Events will be summarized on the basis of the date of onset for the event. Treatment-emergent 
AEs 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.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no).
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by study visit along with the corresponding change from baseline values. 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 5.0 (see Appendix 3). Grading of laboratory abnormalities for analysis purposes will be 
performed by the central laboratory.


Cilofexor (CILO; GS-9674) 
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Incidence of treatment-emergent laboratory abnonnalities, defined as values that increase at least 
1 toxicity grade from baseline at any time from baseline up to and including the date of last dose 
of study drug plus 30 days will be smmnarized by overall. If baseline data are missing, then any 
graded abnonnality (ie, at least a Grade 1) will be considered treatment emergent. 
Laboratory abnonnalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in a data listing. 
8.5.4. 
Other Safety Evaluations 
Vital sign measurements and 12-lead ECG data will be smmnarized by overall and listed by 
subject. 
8.8. 
Biomarker Analysis 
Descriptive statistics of biomarker expression and change from baseline will be provided at each 
sampling time by overall. Point estimates and 95% confidence intervals may be calculated. 
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8.9.
Sample Size
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. 
8.10.
Data Monitoring Committee
An internal multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data. DMC meeting may be held after approximately
10 subjects enrolled have completed 4 weeks of 30 mg treatment. Subsequent meetings will be 
held on an ad hoc basis.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct, and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) E6 
(R2) GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and sub-investigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. This 
documentation must be provided prior to the investigator’s (and any sub-investigator’s)
participation in the study. The investigator and sub-investigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) to an IRB/IEC/EC. The investigator will not begin any study subject activities until 
approval from the IRB/IEC/EC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after IRB/IEC/EC initial approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB/IEC/EC approved consent form for documenting 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 local IRB/IEC/EC 
requirements. The consent form will inform subjects about genomic testing and/or planned
sample retention. 
 
CCI


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Gilead Sciences, Inc. 
9.1.5. 
Confidentiality 
FINAL 
Amendment3 
The investigator must assure that subjects' anonymity will be strictly maintained and that their 
identities are protected from m1authorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any fonn 
or biological sample submitted to the sponsor, IRB/IEC/EC or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the study. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all infonnation received from Gilead, including but not limited to the 
IB, this protocol, CRF/eCRF, the study drug, and any other study infonnation, remain the sole 
and exclusive property of Gilead during the conduct of the study and thereafter. This infonnation 
is not to be disclosed to any third party ( except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator's study file, and 
(2) subject clinical source docmnents. 
The investigator's study file will contain the protocol/amendments, CRF and query fonns, 
IRB/IEC/EC and governmental approval with correspondence, infonned consent, drug records, 
staff curriculum vitae and authorization fonns, and other appropriate documents and 
correspondence. 
The required source data should include sequential notes containing at least the following 
infonnation for each subject: 
• 
Subject identification (name, date of birth, gender) 
• 
Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confinnation of diagnosis (to support inclusion and exclusion criteria) 
• 
Documentation of the reason(s) a consented subject is not enrolled 
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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 AEs and other safety parameters (start and end date, and including causality 
and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, 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.
9.1.7.
Electronic Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is completed in electronic data capture (EDC). The eCRF should 
be completed in a timely manner to enable the sponsor to perform central monitoring of safety 
data. The Eligibility Criteria and Enrollment 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 any changes to data 


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fields will be stored in the audit trail of the system. Prior to database lock (or any interim time 
points, and as instructed by Gilead), 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 will 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 (eg, data entry 
error). At the conclusion of the study, Gilead will provide the site with a read-only archive copy 
of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.6.
9.1.8.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. If the site has an appropriate standard 
operating procedure (SOP) for drug destruction as determined by Gilead, the site may destroy 
used (empty or partially empty) and unused study drug supplies in accordance with that site’s 
approved SOP. A copy of the site’s approved SOP will be obtained for central files. If study drug 
is destroyed on site, the investigator must maintain accurate records for all study drugs 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the study drug. Upon study completion, copies of 
the study drug accountability records must be filed at the site. Another copy will be returned to 
Gilead.
If the site does not have an appropriate SOP for drug destruction, used and unused study drug
supplies are to be sent to the designated disposal facility for eventual destruction. The study
monitor will provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability
during an on-site monitoring visit. However, study drug may be disposed prior to review of the
accountability records by the study monitor for the following situations, provided appropriate
documentation is available at the site:

study sites do not have the storage capacity for saving empty drug product containers;

institutional and/or pharmacy SOP requires the study drug that is classified as hazardous to 
be destroyed immediately following subject use.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRB/IEC/EC, or to regulatory authority or health authority 
inspectors.


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9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/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 agency. 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 9.1.5).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at investigator's meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 


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expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered in them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/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.
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and 
management of primary sclerosing cholangitis. Hepatology 2010;51 (2):660-78.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Graziadei IW, Wiesner RH, Marotta PJ, Porayko MK, Hay JE, Charlton MR, et al. Long-term 
results of patients undergoing liver transplantation for primary sclerosing 
cholangitis. Hepatology 1999;30 (5):1121-7.
Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet 
2013:1587-99.
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.
Isayama H, Tazuma S, Kokudo N, Tanaka A, Tsuyuguchi T, Nakazawa T, et al. Clinical 
Guidelines for Primary Sclerosing Cholangitis 2017. J Gastroenterol 
2018;53:1006-34.
Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, et al. Genome-wide association 
analysis in primary sclerosing cholangitis. Gastroenterology 2010;138 (3):1102-
11.
Lindor KD, Kowdley KV, Harrison ME, American College of G. ACG Clinical Guideline: 
Primary Sclerosing Cholangitis. Am J Gastroenterol 2015;110 (5):646-59; quiz 
60.
Molodecky NA, Kareemi H, Parab R, Barkema HW, Quan H, Myers RP, et al. Incidence of 
primary sclerosing cholangitis: a systematic review and meta-analysis. 
Hepatology 2011;53 (5):1590-9.
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.


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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.
Saich R, Chapman R. Primary sclerosing cholangitis, autoimmune hepatitis and overlap 
syndromes in inflammatory bowel disease. World J Gastroenterol 2008;14 
(3):331-7.
The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16 (3):199-208.
Tischendorf JJ, Geier A, Trautwein C. Current diagnosis and management of primary sclerosing 
cholangitis. Liver Transpl 2008;14 (6):735-46.
Triantos CK, Koukias NM, Nikolopoulou VN, Burroughs AK. Meta-analysis: ursodeoxycholic 
acid for primary sclerosing cholangitis. Aliment Pharmacol Ther 2011;34 (8):901-
10.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy 
in chronic liver disease: 2014 Practice Guideline by the American Association for 
the Study of Liver Diseases and the European Association for the Study of the 
Liver. Hepatology 2014;60 (2):715-35.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE)
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
West Haven Criteria
Appendix 6.
IBD Symptom Severity Assessment


Cilofe?(or (CILO; GS-9674) 
Protocol GS-US-428-5443 
Gilead Sciences, Inc. 
AppJndix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404, USA 
STUDY ACKNOWLEDGEMENT 
FINAL 
Amendment 3 
A roof-of-Concept Open-Label Study Evaluating the Safety and Tolerability of Cilofexor in 
Subjects with Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis 
GS-US-428-5443, Amendment 3, 15 January 2021 
This ~rotocol has been approved by Gilead Sciences, Inc. The following signature documents 
rn:_:~ro::L 
pp D 
PPD 
~- ---
~ ~----=---~-
(Printed) 
Signature 
-------
LC 
Date 
INVESTIGATOR ST A TEMENT 
I hav~ read the protocol, including all appendices, and I agree that it contains all necessary 
detailf for me and my staff to conduct this study as described. I will conduct this study as 
outlinrd herein and will make a reasonable effort to complete the study within the time 
desi~ated. 
I will !Provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fllY informed about the drugs and the study. 
Prin 
Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONF DENTlAL 
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Appendix 2. 
Study Procedures Table 
Study Procedures Table - Screening to Follow-Up Visit 
Treatment Visits (± 3 days)h c d 
Baseline/ 
Week 
Follow-Up 
Assessments 
Screening• 
Day I 
Week I 
Week 4 
Week8 
12 
ET' 
(± 5 days) 
Subject Fasting 
X 
X 
X 
X 
X 
X 
X 
Written Informed Consent 
X 
Medical History 
X 
Review 
Inclusion/Exclusion 
X 
X 
Criteria 
Physical Examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
Assess ascites and HE 
X 
X 
X 
X 
X 
X 
X 
X 
CP and MELD Scores 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsg and Body 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Height 
X 
IBO Symptom Severity 
X 
X 
X 
X 
X 
X 
X 
Assessmenth 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
X 
X 
X 
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Assessments 
Review Study Drug 
Compliance 
Chemistry, eGFR, 
Hematology, Coagulation 
Panel 
Lipid Profile 
C-Peptide, Insulin and 
HbA1c 
HIV-I, HBV and HCY 
Serology 
Urine Drug Screen 
Pregnancy Testing 
Serum FSHm 
Baseline/ 
Screening• 
Day I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Visits (± 3 days)h c d 
Week I 
Week 4 
Week8 
X 
X 
X 
Laboratory Assessments 
X 
X 
X 
X 
X 
X 
X 
Week 
12 
ET' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FINAL 
Amendment3 
Follow-Up 
(± 5 days) 
X 
X 
X 
X 
AE adverse event; CLDQ 
Chronic Liver Disease Questionnaire; CP 
Child Pugh; ECG 
electrocardiogram; EDC 
electronic data capture; eGFR estimated glomemlar 
filtration rate; EQ 50 
EuroQol five dimensions; ET 
early tem1ination; FSI-I 
follicle stimulating hom1one; HBV hepatitis B vims; l-lbA1c 
hemoglobin A1c; 
I-ICY 
hepatitis C vims; HE hepatic encephalopathy; HIV I 
human immunodeficiency virus type 1; IBO 
inflammatory bowel disease; IWRS 
interactive web response 
system; MELD 
model for end stage liver disease; PD 
pham1ac.odynamic{s); PE physical examination; Pl 
principal investigator; PK pham1ac.okinetic{s); 
CONFI DENTIAL 
Page 98 
15 January 2021 


Cilofexor (CILO; GS-9674) 
Protocol GS-US-428-5443 
Gilead Sciences, Inc. 
FINAL 
Amendment3 
PRO 
patient reported outcome; PSC primary sderosing cholangitis; QoL quality of life; SIBDQ 
short inflammatory bowel disease questionnaire; VAS 
visual analog 
scale 
a. 
Subjects will be screened up to 4 weeks prior to treatment. The screening period may be extended under special circumstances with the explicit approval of the medical 
monitor. 
b. 
At the discretion of the PI, study dmg dosing may be temporarily intem1pted if subject experiences an AE thought to be related to study dmg, including pmritus. In the event 
this occurs, the PI should notify the medical monitor and the subject should hold study dmg until the AE has resolved or pmritus has returned to baseline levels. When 
resuming study dmg, the subject should resume dosing at the prior dose and restart a 4 week challenge on this dose. If subject tolerates study dmg for the subsequent 4 weeks, 
the subject may dose escalate at the discretion of the PI (refer to Section 7.5.5). The same in clinic visits and associated study assessments during regular visits would be 
perfomied when re challenging a dose (referenced as postintem1ption visit in IWRS and EDC). Ifreinitiating dose stage of30 mg study dmg, subjects are not required to redo 
Baseline/Day I QoLs. 
c. 
Telephone follow up visit will occur only for subjects on PI approved study dmg dose intem1ption. During the period of study dmg dose intem1ption, subjects will be 
contacted on a weekly basis for up to 4 consecutive weeks (refer to Section 6.4.2). 
d. 
Treatment visits windows are ±3 days unless otherwise stated (see Section 6.4.). 
e. 
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of last study visit. 
f. 
Symptom directed PE. The focus of a symptom driven physical examination will be detem1ined by the investigator based on subject complaint. A complete PE will be 
completed at screening. 
g. 
Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature. 
h. 
For subjects with histo 
of IBO. Assessment of Bleed in Histo 
and Dail Bowel Movement Count as detailed in A 
I 
j. I 
I. 
Females of childbeanng potential only (see Appendix 4). Semm pregnancy tests at screening and unne pregnancy tests at Day I, Weeks 4, 8, 12 while on treat111ent. Urine 
pregnancy test to be taken at home every 2 weeks during PI approved study dmg dose intem1ption. 
m. 
Women of an a e with amenorrhea of::: 12 months (see Appendix 4). 
I 
i 
I 
CONFIDENTIAL 
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Cilofexor (CILO; GS-9674)
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Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 100
15 January 2021
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE)
Refer to the Site Operations Manual for additional CTCAE information.


Cilofexor (CILO; GS-9674)
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Amendment 3
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15 January 2021
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 postmenopausal, 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
CILO has not yet been studied in pregnant women. 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 is considered secondary to maternal toxicity 
rather than a direct effect of CILO. The no observed effect level (NOEL) for embryofetal 
development is 300 mg/kg/day in mice and 200 mg/kg/day in rabbits. These doses were 
associated with exposures that are ≥ 38-fold higher than the estimated human exposure at the 
100 mg once daily dose. DDI data do not suggest a potential for interaction with hormones used 
for contraception. Please refer to the latest version of the IB for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to enrollment. Pregnancy tests will be 
performed at monthly intervals at study visits including the follow-up visit; follow-up telephone 
assessments will confirm home pregnancy tests are negative as needed. In the event of a delayed 
menstrual period (over one month between menstruations), a pregnancy tests must be performed 
to rule out pregnancy. This is true for women of childbearing potential with infrequent or 
irregular periods. 


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Amendment 3
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Female subjects must agree to one of the following from screening until 30 days following the 
last dose of the study drug CILO.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
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


Cilofexor (CILO; GS-9674)
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Amendment 3
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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 CILO.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential. 
Male subjects must agree to avoid sperm donation during the study.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (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 of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.6.2.1.


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Appendix 5.
West Haven Criteria
http://www.mdcalc.com/hepatic-encephalopathy-grades-stages/ 
Grade of Hepatic 
Encephalopathy
Description
Suggested Operative Criteria
Grade I

Trivial lack of awareness

Euphoria or anxiety

Shortened attention span

Impairment of addition or subtraction

Altered sleep rhythm
Despite oriented in time and space 
(see below), the patient appears to have some 
cognitive/ behavioral decay with respect to 
his or her standard on clinical examination or 
to the caregivers
Grade II

Lethargy or apathy

Disorientation for time

Obvious personality change

Inappropriate behavior

Dyspraxia

Asterixis
Disoriented for time (at least three of the 
followings are wrong: day of the month, day 
of the week, month, season, or year) ± the 
other mentioned symptoms
Grade III

Somnolence to semistupor

Responsive to stimuli

Confused

Gross disorientation

Bizarre behavior
Disoriented also for space (at least three of 
the following wrongly reported: country, 
state [or region], city, or place) ± the other 
mentioned symptoms
Grade IV

Coma
Does not respond even to painful stimuli
Adapted from {Vilstrup 2014}


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Appendix 6.
IBD Symptom Severity Assessment
Bleeding History 1
0 no recent bleeding
1 rare, minimal blood
2 blood in some stools
3 blood in most stools, or blood alone in any stool
Daily Bowel Movement 
Count
0 no change from a typical day
1 < 3 more stools than on a typical day
2 3-5 more stools than on a typical day
3 > 5 more stools than on a typical day
1
Does not include history of perianal bleeding

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Proof-of-Concept, Open-Label Study Evaluating the 
Safety and Tolerability of Cilofexor in Subjects with Primary 
Sclerosing Cholangitis (PSC) and Compensated Cirrhosis
Study Phase:
1b
Name of Test Drug:
Cilofexor (CILO; GS-9674) 
Study Number:
GS-US-428-5443
Protocol Version (Date):
Amendment 3 (15 January 2021)
Analysis Type:
Final Analysis 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
15 December 2021
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................8
1.2.
Study Design .............................................................................................................................................8
1.3.
Sample Size and Power .............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................10
2.1.
Interim Analyses......................................................................................................................................10
2.1.1.
Data Monitoring Committee Analyses..................................................................................10
2.2.
Final Analysis..........................................................................................................................................10
2.3.
Changes from Protocol-Specified Analysis.............................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................11
3.1.
Analysis Sets ...........................................................................................................................................11
3.1.1.
All Enrolled Analysis Set ......................................................................................................11
3.1.2.
Safety Analysis Set................................................................................................................11
3.1.3.
Pharmacokinetic Analysis Sets..............................................................................................11
3.1.5.
Pharmacodynamic Analysis Sets...........................................................................................12
3.2.
Strata and Covariates...............................................................................................................................12
3.3.
Examination of Subject Subgroups .........................................................................................................12
3.4.
Multiple Comparisons .............................................................................................................................12
3.5.
Missing Data and Outliers.......................................................................................................................12
3.5.1.
Missing Data..........................................................................................................................12
3.5.2.
Outliers ..................................................................................................................................12
3.6.
Data Handling Conventions and Transformations ..................................................................................12
3.7.
Analysis Visit Windows..........................................................................................................................14
3.7.1.
Definition of Study Day ........................................................................................................14
3.7.2.
Analysis Visit Windows........................................................................................................14
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................16
4.
SUBJECT DISPOSITION ...................................................................................................................................18
4.1.
Subject Enrollment and Disposition........................................................................................................18
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................18
4.2.1.
Duration of Exposure to Study Drug.....................................................................................19
4.2.2.
Adherence to Study Drug ......................................................................................................19
4.2.2.1.
Prescribed Adherence ......................................................................................19
4.3.
Protocol Deviations .................................................................................................................................20
4.4.
Assessment of COVID-19 Impact...........................................................................................................20
4.4.1.
Protocol Deviations Due to COVID-19 ................................................................................20
5.
BASELINE CHARACTERISTICS .....................................................................................................................21
5.1.
Demographics and Baseline Characteristics ...........................................................................................21
5.2.
Other Baseline Characteristics ................................................................................................................21
5.3.
Medical History.......................................................................................................................................22
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I 
7. 
SAFETY ANALYSES ......................................................................................................................................... 25 
7.1. 
Adverse Events and Deaths ..................................................................................................................... 25 
7.1. 1. 
Adverse Event Dictiona1y ..................................................................................................... 25 
7.1.2. 
Adverse Event Severity ......................................................................................................... 25 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 25 
7.1.4. 
Serious Adverse Events ......................................................................................................... 25 
7.1.5. 
Treattnent-Emergent Adverse Events .................................................................................... 25 
7.1.5.1. 
Definition of Treattnent-Emergent Adverse Events ........................................ 25 
7. 1.5.2. 
Inco1nplete Dates ............................................................................................. 26 
7.1.6. 
Summaries of Adverse Events and Dea.ths ............................................................................ 26 
7 .2. 
Laborato1y Evaluations ........................................................................................................................... 27 
7.2.1. 
Summaries of Numeric Laborat01y Results .......................................................................... 28 
7.2.2. 
Graded Laborato1y Values .................................................................................................... 28 
7.2.2.1. 
Treattnent-Emergent Laborato1y Abnonnalities ............................................. 28 
7 .2.2.2. 
Summaries of Laborat01y Abnonnalities ........................................................ 28 
7.2.3. 
Liver-related Laborat01y Evaluations .................................................................................... 29 
7 .3. 
Body Weight and Vital Signs .................................................................................................................. 30 
7.4. 
Prior and Concolllitant Medications ........................................................................................................ 30 
7.5. 
Electrocardiogra1n Results ....................................................................................................................... 30 
7.6. 
Other Safety Measures ............................................................................................................................ 30 
I 
I 
10. REFERENCES ..................................................................................................................................................... 34 
11. SOFTWARE ......................................................................................................................................................... 35 
12. SAP REVISION ................................................................................................................................................... 36 
13. APPENDIX .......................................................................................................................................................... 37 
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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Chemistry, eGFR, Hematology, Coagulation, Child-
Pugh (CP)/ Model for End-stage Liver Disease (MELD) Scores, Pruritus VAS, 5D-
Itch and Biomarkers, Including hsCRP, ELF™ Score and Components, 
FibroSURE/FibroTest® and Selected Components, Bile Acids, FGF19, C4. .........................15
Table 3-2.
Analysis Visit Windows for IBD Symptoms ..........................................................................15
Table 3-3.
Analysis Visit Windows for QoL Questionnaires and FibroScan...........................................16
Table 8-1.
PK Parameters for Each Analyte.............................................................................................32


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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CILO
cilofexor
CLDQ
Chronic Liver Disease Questionnaire 
CP
Child-Pugh
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELF™
enhanced liver fibrosis
EQ-5D
EuroQol five dimensions
ET
early termination
FGF19
fibroblast growth factor 19
GGT
gamma glutamyl transferase
HLGT
high-level group term
HLT
high-level term
IBD
inflammatory bowel disease
ID
identification
INR
international normalized ratio
IXRS
interactive voice or web response system
LLN
lower limit of normal
LLT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
PD
pharmacodynamic
PI
principle investigator
PIIINP
procollagen III N-terminal propeptide
PK
pharmacokinetic
PRO
patient-reported outcome
PSC
primary sclerosing cholangitis
PT
preferred term


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Q1, Q3
first quartile, third quartile
QoL
quality of life
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SIBDQ
Short Inflammatory Bowel Disease Questionnaire
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TIMP1
tissue inhibitor of metalloproteinase 1
UC
ulcerative colitus
ULN
upper limit of normal
VAS
visual analog scale
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 of the concentration of drug versus time curve


Cilofexor (CILO; GS-9674) 
GS-US-428-5443 Statistical Analysis Plan - Final Analysis 
Version 1.0 
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 repo1t (CSR) 
for Study GS-US-428-5443. This SAP is based on the study protocol amendment 3 dated 
15 Januaiy 2021 and the electronic case repo1t f01m (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
The study emollment was te1minated eai·ly by the sponsor on 30 July 2021 due to recrnitment 
challenges in a rai·e disease population. 
1.1. 
Study Objectives 
The prima1y objective of this study is as follows: 
• 
To assess the safety and tolerability of escalating doses of cilofexor (CILO, previously 
known as GS-9674) in subjects with primaiy sclerosing cholangitis (PSC) and compensated 
cinhosis 
I 
I 
I 
I 
I 
I 
1.2. 
Study Design 
This is a proof of concept, open-label study evaluating the safety and tolerability of CILO in 
subjects with PSC and compensated ciIThosis. 
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Eligible subjects were enrolled and received treatment with escalating doses of CILO over 
12 weeks. Subjects dose escalated at Week 4 (from 30 mg to 60 mg once daily) and Week 8 
(from 60 mg to 100 mg once daily) if in the opinion of the Principal Investigator (PI) study drug 
had been tolerated. 
The overall study design is presented graphically in the figure below.
Individual subject participation in the study can last up to 20 weeks, which includes a 4-week 
screening period, a 12-week treatment period (divided into three 4-week dosing stages at 30 mg 
QD, 60 mg QD, and 100 mg QD), and a Follow-Up visit 4 weeks after the Week 12 visit. 
Study drug dosing may be interrupted for up to 4 consecutive weeks at the discretion of the PI if 
a subject experienced an adverse event (AE) (eg, intolerable pruritus) thought to be related to the 
study drug. During the period of study drug dose interruption, subjects were not required to 
attend in-clinic visits per the Study Procedures Table (Appendix 1) but were monitored via 
weekly telephone follow-up visits (refer to Section 7.5.5 of study protocol). If a study drug dose 
interruption required reinitiation of a dosing stage, participation in the study could be extended 
from up to 20 weeks to up to 28 weeks to complete 4 consecutive weeks of dosing at each dose 
stage.  
1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. 
CILO 
CILO 
CILO 
·;;; 
00 
30 mg 
60mg 
100mg 
> 
C 
'i: 
0.. 
" 
f--Jo 
-
;:::) 
One 30 mg tablet 
Two 30 mg tablets 
One 100 mg tablet 
i 
u 
orally once daily 
orally once daily 
orally once daily 
..9 
en 
0 
"'" 
4 weeks 
4 weeks 
4 weeks 
4 weeks 
12 weeks 
4 weeks 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
No interim analysis for efficacy was planned.
2.1.1.
Data Monitoring Committee Analyses
This study had an internal multidisciplinary Data Monitoring Committee (DMC) to review the 
progress of the study and safety of the study after 10 subjects completed 4 weeks of CILO 30 mg 
treatment.
The DMC’s role and responsibilities and the scope of analysis provided to the DMC were 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Final Analysis
The final analysis will be performed after all subjects have completed the study, outstanding data 
queries have been resolved or adjudicated as unresolvable, and the data have been cleaned and 
finalized. 
2.3.
Changes from Protocol-Specified Analysis
Due to limited subject enrollment in the study, part of safety summaries and listings (body 
weight, vital signs, prior and concominant medications, electrocardiogram [ECG], and 
pharmacodynamic parameters) planned in the protocol will not be provided. 
PSC Patient-Reported Outcome (PRO) is a novel endpoint. 
 
CCI


Cilofexor (CILO; GS-9674) 
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Version 1.0 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each catego1y will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard eITor (SE), median, first 
quaiiile (QI), third quaiiile (Q3), minimum, and maximum will be presented. 
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set, and so1ied 
by subject identification (ID) number in ascending order, visit date, and time (if applicable), 
unless othe1wise specified. Data collected on log fonns, such as AEs, will be presented in 
chronological order within subject. Age, sex at biith, race, and ethnicity will be included in the 
listings, as space pennits. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and then· definitions 
ai·e provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. 
For each analysis set, the number and percentage of subjects eligible for inclusion will be 
provided in the disposition table as detailed in Section 4. 
3.1.1. 
All Enrolled Analysis Set 
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening. 
3.1.2. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who took at least 1 dose of study diug. This is the 
primaiy analysis set for safety analyses. 
3.1.3. 
Pharmacokinetic Analysis Sets 
The Phaimacokinetic (PK) Analysis Sets will include all enrolled subjects who took at least 
1 dose of study diug and have at least 1 nonmissing concentration value repo1ied by the PK 
laborato1y for the coITesponding analytes. These ai·e the primaiy analysis sets for all PK 
analyses. -
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3.1.5. 
Pharmacodynamic Analysis Sets 
The Phannacodynamic (PD) Analysis Sets will include all enrolled subjects who received at 
least 1 dose of study drng and have at least 1 nonmissing PD value for each respective PD 
parameter. -
3.2. 
Strata and Covariates 
This study did not use a stratified randomization schedule when enrolling subjects. No covariates 
will be included in efficacy and safety analyses. 
3.3. 
Examination of Subject Subgroups 
There are no prespecified subject subgroupings for analyses. 
3.4. 
Multiple Comparisons 
Adjustments for multiplicity will not be made, because no fo1mal statistical testing will be 
perfo1med in this study. 
3.5. 
3.5.1. 
Missing Data and Outliers 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
For missing last dosing date of study drng, imputation mies are described in Section 4.2. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2. 
3.5.2. 
Outliers 
Outliers of non-PK data 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. 
3.6. 
Data Handling Conventions and Transformations 
The following conventions will be used for the imputation of date of bi1ih when it is paiiially 
missing or not collected: 
• 
If only month and year of bi1i h is collected, then "15" will be imputed as the day of bi1i h. 
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
If only year of birth is collected, then “01 July” will be imputed as the day and month of 
birth.

If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a subject, then age derived based on date of birth and the Day 1 
visit date will be used instead. If an enrolled subject was not dosed with any study drug, the 
enrollment date will be used instead of the Day 1 visit date. For screen failures, the date the first 
informed consent was signed will be used for the age derivation. Age required for longitudinal 
and temporal calculations and analyses (eg, estimates of creatinine clearance, age at date of AE) 
will be based on age derived from date of birth and the date of the measurement or event, unless 
otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or <0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.

A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as the bullet point above.

The lower or upper 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 lower or upper LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters in 
intensive PK samples, if applicable. Concentration values that are below the limit of quantitation 
(BLQ) will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be 
treated as 0 at predose time points, and one-half the value of the LOQ at postdose time points for 
summary purposes.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
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
If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.” 

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.” 

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.” 

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) and summary statistics will be 
displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting, if applicable. 
3.7.
Analysis Visit Windows
3.7.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date 
Therefore, study Day 1 is the day of first dose of study drug administration.
Additional calculations for subjects who require a PI-approved study drug interruption are as 
follows. Post-interruption study day will be calculated from the first dosing date of study drug 
subsequent to post-interruption and derived as follows:

For post-interruption dosing resumed from 30 mg: Assessment Date – First Post-interruption 
Dosing Date + 1

For post-interruption dosing resumed from 60 mg: Assessment Date – First Post-interruption 
Dosing Date + 29

For post-interruption dosing resumed from 100 mg: Assessment Date – First Post-
interruption Dosing Date + 57
Therefore, the day of first post-interruption dose of study drug administration can be Post-
interruption study Day 1, 29, or 57, depending on the dose level when PI-approved study drug 
dose interruption occurs.
3.7.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
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On-treatment visit windows will be calculated from study Day 1 or the first post-interruption 
study drug dosing date for selected efficacy measures, elastography, and safety laboratory data. 
Selected safety and efficacy data, unless otherwise specified, collected up to and including the 
last dosing date + 30 days, will be mapped according to the following analysis windows unless 
the nominal visit name is early termination (ET) or Follow-Up. 
The analysis windows for selected measures are provided in Table 3-1 to Table 3-3. The 
algorithm for assigning baseline analysis window does not apply to the liver tests (ALP, total 
bilirubin, ALT, AST, and GGT). For these 5 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.
Table 3-1.
Analysis Visit Windows for Chemistry, eGFR, Hematology, Coagulation, 
Child-Pugh (CP)/ Model for End-stage Liver Disease (MELD) Scores, 
Pruritus VAS, 5D-Itch and Biomarkers, Including hsCRP, ELF™ Score and 
Components, FibroSURE/FibroTest® and Selected Components, Bile Acids, 
FGF19, C4.
Visit Window Study Day/Post-
interruption Study Day
Nominal Visit
Nominal Study 
Day/Post-interruption 
Study Day
Lower Limit
Upper Limit
Baseline/Post-interruption Day 1
1
(none)
1
Week 1/Post-interruption Week 1
8
2
18
Week 4/Post-interruption Week 4
29
19
42
Week 8/Post-interruption Week 8
57
43
70
Week 12/Post-interruption Week 12
85
71
≥85
Table 3-2.
Analysis Visit Windows for IBD Symptoms
Visit Window Study Day/Post-
interruption Study Day
Nominal Visit
Nominal Study 
Day/Post-interruption 
Study Day
Lower Limit
Upper Limit
Baseline/Post-interruption Day 1
1
(none)
1
Week 4/Post-interruption Week 4
29
2
42
Week 8/Post-interruption Week 8
57
43
70
Week 12/Post-interruption Week 12
85
71
≥85


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Table 3-3.
Analysis Visit Windows for QoL Questionnaires and FibroScan
Visit Window Study Day/Post-
interruption Study Day
Nominal Visit
Nominal Study 
Day/Post-interruption 
Study Day
Lower Limit
Upper Limit
Baseline/Post-interruption Day 1
1
(none)
1
Week 12/Post-interruption Week 12
85
2
≥85
Data relating to unscheduled visits may be assigned to a particular visit or time point based on 
the visit windows. The following conventions will be followed:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who prematurely discontinue from the study, early termination (ET) data will be 
summarized as a separate visit, labeled as “Early Termination Visit.”

Data collected on a follow-up visit will be summarized as a separate visit and labeled 
“Follow-up Visit.”

Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) will 
be excluded from the summaries but will be included in the listings.
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the first dosing date of study drug will 
be selected, unless specified differently. If there are multiple records with the same time or 
no time recorded on the same day, the baseline value will be the average of the 
measurements for continuous data, or the measurement with the lowest severity for 
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
For each liver test (ALP, total bilirubin, ALT, AST, and GGT), the baseline value will be 
determined by averaging all values obtained between Screening and Baseline/Day 1 
(inclusive). The corresponding baseline reference range will be defined as the one associated 
with the latest visit that was included for computing the baseline value, 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 or more records that are equidistant from the nominal day, the later record 
will be selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worst severity will be taken for categorical data, unless otherwise 
specified.
FGF19 and C4 obtained on the same day will not be averaged. The predose value would 
be selected to represent the study visit, when the data are summarized by study visit and 
not by timepoint within a visit. The summary by timepoint is described separately in 
Section 9.3. 
Liver stiffness by transient elastography data in each analysis visit window will be chosen based 
on the following rules:

For baseline, measurements by M probe will be selected for analysis if available, otherwise 
measurements by XL probe will be selected.

For postbaseline visits, measurements by the same probe type (XL or M) selected for the 
subject at baseline will be selected in each analysis visit window. If no measurement by the 
same probe type as baseline is available, the analysis value for the corresponding 
postbaseline visit will be considered missing. If there are multiple postbaseline records by the 
same probe type as baseline, the rules to choose postbaseline continuous measurements as 
described above will apply.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
Key study dates (ie, first subject screened, first subject enrolled, last subject enrolled, last subject 
last visit for the primary endpoint, and last subject last visit for the clinical study report) will be 
provided.
A summary of subject disposition will be provided. This summary will present the number of 
subjects screened, the number of subjects enrolled, and the number and percentage of subjects in 
each of the categories listed below. For the Safety Analysis Set category, the denominator for the 
percentage calculation will be the total number of subjects enrolled for each column. For all 
other categories, the denominator for the percentage calculation will be the total number of 
subjects in the Safety Analysis Set for each column.

Safety Analysis Set 

PK Analysis Set for each analyte 

PD Analysis Set for each parameter

Had PI approved study drug interruption and study drug dose level when the interruption 
occured

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study

Did not complete the study with reasons for premature discontinuation of study
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listing will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study drug or study discontinuation
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.
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4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1 (minus study drug interruption duration if there is a PI-approved study drug 
interruption, where the study drug interruption duration is defined as first post-interruption 
dosing date minus last dosing date prior to drug interruption minus 1), regardless of any 
temporary interruptions in study drug administration, and will be expressed in weeks using up to 
1 decimal place (eg, 4.5 weeks). If the last study drug dosing date is missing, the latest date 
among the study drug end date, clinical visit date, laboratory sample collection date, and vital 
signs assessment date that occurred during the on-treatment period will be used for subjects 
included in the final analyses.
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, 1 week, 4 weeks, and every 4 weeks thereafter. Summaries will be 
provided for the Safety Analysis Set.
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 eCRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















4.2.2.1.
Prescribed Adherence
The level of prescribed adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug specified by the 
protocol for a subject who completes treatment in the study, ie, 112 tabelets. For subjects who 
require a study drug interruption, the adherence calculation will account for the initial drug 
amount and the subsequent drug amount (after the interruption) at the respective dose level. For 
example, if a subject takes ten 100 mg tablets and requires an interruption, and subsequently 
takes twelve 100 mg tablets post interruption before discontinuing, the denominator would be 
122 (28 + 28 * 2 + 10 + 28, the last term 28 is because the protocol specifies that subjects should 
complete 28 consecutive days at each dose level).
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




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Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75%, ≥ 75 to < 90%, ≥ 90%) will be provided 
by total for the Safety Analysis Set. 
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 
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. A by-subject listing will be provided for those subjects with important protocol 
deviation. 
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct. Some subjects were unable to attend onsite visits due to shelter in 
place guidelines, site closures, or other reasons. This section describes how special situations due 
to COVID-19 will be handled in the analysis.
4.4.1.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviations related to 
COVID-19, if applicable. A separate listing will be provided for subjects with non-important 
protocol deviations related to COVID-19, if applicable.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized 
using descriptive statistics for continuous variables and using number and percentage of subjects 
for categorical variables. The summary of demographic data will be provided for the Safety 
Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

UDCA use (yes or no, based on concomitant medication page)

ALP, GGT, ALT, AST

Total bilirubin, direct bilirubin, albumin, INR

Fasting bile acids

MELD score, Child-Pugh (CP) score

ELF™ score and components

FibroSURE/FibroTest® and selected components 

Liver Stiffness Assessed by FibroScan

Platelets

Inflammatory bowel disease (IBD) history (yes or no, based on medical history data)

Ulcerative colitus (UC) history (yes or no, based on medical history data)

Crohn’s disease history (yes or no, based on medical history data)
These baseline characteristics will be summarized using descriptive statistics for continuous 
variables and using number and percentage of subjects for categorical variables. The summary of 
these baseline characteristics will be provided for the Safety Analysis Set. No formal statistical 
testing is planned.


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A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of 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 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. Serious adverse events captured 
and stored in the clinical database will be reconciled with the SAE database from the Gilead 
Global Patient Safety Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided. All deaths observed in the study will 
also be included in this summary.

TEAE

TEAEs with Grade 2 or higher

TEAEs with Grade 3 or higher

TE treatment-related AEs

TE treatment-related AEs with Grade 2 or higher 

TE treatment-related AEs with Grade 3 or higher

TE SAEs

TE treatment-related SAEs

TEAEs leading to premature discontinuation of study drug

TEAEs leading to temporary interruption of study drug

Death


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The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC and PT for the AE categories described below:

TEAE

TEAEs with Grade 2 or higher

TE treatment-related AEs

TE SAEs

TEAEs leading to premature discontinuation of study drug

TEAEs leading to temporary interruption of study drug
Summaries of all TEAEs by PT only, and by SOC, PT, and maximum severity will also be 
provided.
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 (if applicable), and then by PT in 
descending order of total frequency within each SOC. For summaries by severity grade, the most 
severe grade will be used for those AEs that occurred more than once in an individual subject 
during the study. 
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All TEAEs with severity of Grade 2 or higher

All SAEs

All deaths

All AEs leading to premature discontinuation of study drug 

All AEs leading to temporary interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days. 
The analysis will be based on values reported in conventional units. When values are BLQ, 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 3.6. Hemolized test results will not be included in the 
analysis, but they will be listed in by-subject laboratory listings.


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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, eGFR, serum chemistry, coagulation, and urinalysis 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the Common Toxicity Criteria for Adverse Events (CTCAE) severity grade as 
described in Appendix 2 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 for laboratory tests will not be provided.
7.2.2.
Graded Laboratory Values
The CTCAE Version 5.0 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 
For the baseline ALP, total bilirubin, GGT, ALT and AST toxicity grades, the CTCAE version 
5.0 will be used to assign grades to the derived average values. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days. 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.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades or abnormal flags displayed.


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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.
For subjects with normal baseline ALT/AST (≤ ULN):

Subjects meeting criteria for close observation
ALT/AST > 3 × ULN

Subjects meeting any one of the following criteria for withholding study drug
ALT/AST > 8 × ULN
ALT/AST > 5 × ULN for 2 weeks
ALT/AST > 3 × ULN and total bilirubin > 2 × ULN (or direct bilirubin > 2 × baseline in 
subjects with Gilbert’s syndrome)
ALT/AST > 3 × ULN and INR > 1.5 (if not on anticoagulation)
For subjects with elevated baseline ALT/AST (> ULN)

Subjects meeting criteria for close observation
ALT/AST > 2 × Baseline or > 300 U/L

Subjects meeting any one of the following criteria for withholding study drug
ALT/AST > 8 × Baseline or > 500 U/L
ALT/AST > 3 × Baseline or > 300 U/L, and total bilirubin > 2 × ULN (or direct bilirubin 
> 2 x Baseline in subjects with Gilbert’s syndrome)
ALT/AST > 3 × Baseline or > 300 U/L, and INR > 1.5 (if not on anticoagulation)
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of subjects 
who met at least 1 of the above criteria will be provided.


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7.3.
Body Weight and Vital Signs
Body weight and vital signs will not be summarized or listed.
7.4.
Prior and Concomitant Medications
Prior and concomitant medications will not be summarized or listed.
7.5.
Electrocardiogram Results
Electrocardiogram data will not be summarized or listed.
7.6.
Other Safety Measures
A by-subject listing sorted by subject ID number will be provided for subjects who become 
pregnant during the study.
IBD Symptom Severity Assessment is a survey for the assessment of IBD that considers stool 
frequency, rectal bleeding, and physician assessment of IBD for disease severity assessment. A 
by-subject listing of IBD Symptom Severity Assessment will be provided by subject ID number 
and visit in chronological order for subjects with history of IBD.


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10.
REFERENCES
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J 
Dermatol 2010;162 (3):587-93.


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11.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
Phoenix WinNonlin® 8.2. Pharsight Corporation, Princeton, NJ, USA.


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12.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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13.
APPENDIX 
Appendix 1.
Study Procedures Table...........................................................................................................38
Appendix 2.
CTCAE Grade for Laboratory Parameters ..............................................................................41
Appendix 3.
Programming Specifications....................................................................................................44
 


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Appendix 1.
Study Procedures Table
Study Procedures Table – Screening to Follow-Up Visit
Treatment Visits (± 3 days)b c d
Assessments
Screeninga
Baseline/ 
Day 1
Week 1
Week 4
Week 8
Week 
12
ETe
Follow-Up 
(± 5 days)
Subject Fasting
X
X
X
X
X
X
X
Written Informed Consent
X
Medical History
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Physical Examinationf
X
X
X
X
X
X
X
X
Assess ascites and HE
X
X
X
X
X
X
X
X
CP and MELD Scores
X
X
X
X
X
X
X
X
Vital Signsg and Body 
Weight
X
X
X
X
X
X
X
X
Height
X
IBD Symptom Severity 
Assessmenth
X
X
X
X
X
X
X
Review for Active IBDj
X
X
X
X
X
X
X
12-lead ECG
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
CCI
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Treatment Visits (± 3 days)h < d 
Baseline/ 
Week 
Follow-Up 
Assessments 
Screening• 
Day 1 
Weeki 
Week4 
Week8 
12 
ET• 
(± 5 days) 
Review Study Drng 
X 
X 
X 
X 
X 
Compliance 
Laboratory Assessments 
Chemistry, eGFR, 
Hematology, Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
Panel 
Lipid Profile 
X 
X 
X 
X 
X 
X 
C-Peptide, Insulin and 
X 
X 
X 
X 
HbA1c 
HIV-1, HBV and HCV 
X 
Serology 
Urine Drng Screen 
X 
Pregnancy Testing1 
X 
X 
X 
X 
X 
X 
X 
SenunFSHm 
X 
Stool Collection 
X 
X 
(if available) 
Blood for Biomarkers 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; CLDQ = Chronic Liver Disease Questionnaire; CP = Child-Pugh; ECG = electrocardiogram; EDC = electronic data capture; eGFR = estimated glomemlar 
filtration rate; EQ-SD = Em·oQol five dimensions; ET = early termination; FSH = follicle-stimulating hormone; HBV = hepatitis B vims; HbA1c = hemoglobin A1c; 
HCV = hepatitis C vims; HE = hepatic encephalopathy; HIV-1 = human immunodeficiency vims type 1; IBD = inflammatory bowel disease; IWRS = interactive web response 
system; MELD = model for end-stage liver disease; PD = pharmacodynamic(s); PE = physical examination; PI = principal investigator; PK = pha1macokinetic{s); 
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PRO = patient-repo1t ed outcome; PSC = primary sclernsing cholangitis; QoL = quality of life; SIBDQ = sho1t inflammatory bowel disease questionnaire; VAS = visual analog 
scale 
a 
Subjects w-ill be screened up to 4 weeks prior to treatment. TI1e screening period may be extended under special circumstances with the explicit apprnval of the medical 
monitor. 
b 
C 
d 
e 
f 
g 
h r 
Ill I 
I 
I 
At the discretion of the PI, study drug dosing may be temporarily intem1pted if subject experiences an AE thought to be related to study dmg, including pmritus. In the event 
this occurs, the PI should notify the medical monitor and the subject should hold study dmg until the AE has resolved or pnu-itus has returned to baseline levels. When 
resuming study drug, the subject should resume dosing at the prior dose and resta1t a 4-week challenge on this dose. If subject tolerates study dmg for the subsequent 4 weeks, 
the subject may dose escalate at the discretion of the PI (refer to Section 7.5.5 of the protocol). The same in-clinic visits and associated study assessments dm-ing regular visits 
would be pe1fo1med when re-challenging a dose (referenced as postintem1ption visit in IWRS and EDC). If reinitiating dose stage of 30 mg study diug, subjects are not 
required to redo Baseline/Day! QoLs. 
Telephone follow-up visit will occtu· only for subjects on PI approved study dmg dose intem1ption. Dm-ing the period of study dmg dose intem1ption, subjects will be 
contacted on a weekly basis for up to 4 consecutive weeks (refer to Section 6.4.2 of the protocol). 
Treatment visits windows are ±3 days unless otherwise stated (see Section 6.4 of the protocol). 
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days oflast study visit. 
Symptom-directed PE. The focus of a symptom-driven physical exaniination will be dete1mined by the investigator based on subject complaint. A complete PE will be 
completed at screening. 
Vital signs include heart rate, systolic and diastolic blood pressm·e, respirato1y rate, and body temperature. 
For sub'ects with histo 
ofIBD. Assessment ofB!eedino Histo1 and Dail Bowel Movement Com1t as detailed in A 
· e pregnancy tests at Day I, Weeks 4, 8, 12 while on 
treatment. U1-ine pregnancy test to be taken at home eveiy 2 weeks dm-ing PI approved study dmg dose intem1ption. 
Appendix 4 of the protocol). 
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Appendix 2.
CTCAE Grade for Laboratory Parameters
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Anemia
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 
4.9 mmol/L; 
<100 - 80g/L
Hgb <8.0 g/dL; 
<4.9 mmol/L; <80 g/L; 
transfusion indicated
Life-threatening 
consequences; urgent 
intervention indicated
Death
Activated partial 
thromboplastin time 
prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; bleeding
 -
 -
Alanine 
aminotransferase 
increased
>ULN - 3.0 x ULN if baseline 
was normal; 
1.5 - 3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if baseline 
was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
 -
Alkaline phosphatase 
increased
>ULN - 2.5 x ULN if baseline 
was normal; 
2.0 - 2.5 x baseline if baseline 
was abnormal
>2.5 - 5.0 x ULN if baseline 
was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
 -
Aspartate 
aminotransferase 
increased
>ULN - 3.0 x ULN if baseline 
was normal; 
1.5 - 3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if baseline 
was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
 -
Blood bicarbonate 
decreased
<LLN and no intervention 
initiated
 -
 -
 -
 -
Blood bilirubin increased
>ULN - 1.5 x ULN if baseline 
was normal; 
> 1.0 - 1.5 x baseline if baseline 
was abnormal
>1.5 - 3.0 x ULN if baseline 
was normal; 
>1.5 - 3.0 x baseline if 
baseline was abnormal
>3.0 - 10.0 x ULN if baseline 
was normal; 
>3.0 - 10.0 x baseline if 
baseline was abnormal
>10.0 x ULN if baseline was 
normal; 
>10.0 x baseline if baseline 
was abnormal
 -
Cholesterol high
>ULN - 300 mg/dL; 
>ULN - 7.75 mmol/L
>300 - 400 mg/dL; 
>7.75 - 10.34 mmol/L
>400 - 500 mg/dL; 
>10.34 - 12.92 mmol/L
>500 mg/dL; 
>12.92 mmol/L
 -
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Creatinine increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN
>3.0 x baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
 -


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
GGT increased
>ULN - 2.5 x ULN if baseline 
was normal; 
2.0 - 2.5 x baseline if baseline 
was abnormal
>2.5 - 5.0 x ULN if baseline 
was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
 -
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Hemoglobin increased
Increase in >0 - 2 g/dL
Increase in >2 - 4 g/dL
Increase in >4 g/dL
 -
 -
INR increased
>1.2 - 1.5; >1 - 1.5 x baseline if 
on anticoagulation; monitoring 
only indicated
>1.5 - 2.5; >1.5 - 2.5 x 
baseline if on 
anticoagulation; dose 
adjustment indicated
>2.5; >2.5 x baseline if on 
anticoagulation; bleeding
 -
 -
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN and 
asymptomatic
>2.0 - 5.0 x ULN with signs 
or symptoms; >5.0 x ULN 
and asymptomatic
>5.0 x ULN and with signs or 
symptoms
 -
Lymphocyte count 
decreased
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Lymphocyte count 
increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Neutrophil count 
decreased
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Platelet count decreased
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 
- 25.0 x 10e9 /L
<25,000/mm3; 
<25.0 x 10e9 /L
 -
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN and 
asymptomatic
>2.0 - 5.0 x ULN with signs 
or symptoms; >5.0 x ULN 
and asymptomatic
>5.0 x ULN and with signs or 
symptoms
 -
White blood cell 
decreased
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 /L
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Hypercalcemia
Corrected serum calcium of 
>ULN - 11.5 mg/dL; 
>ULN - 2.9 mmol/L; Ionized 
calcium >ULN - 1.5 mmol/L
Corrected serum calcium of 
>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L; Ionized 
calcium 
>1.5 - 1.6 mmol/L; 
symptomatic
Corrected serum calcium of 
>12.5 - 13.5 mg/dL; >3.1 - 
3.4 mmol/L; Ionized calcium 
>1.6 - 1.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; life-threatening 
consequences
Death


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L; 
intervention initiated
>6.0 - 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; life-threatening 
consequences
Death
Hypermagnesemia
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L
 -
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 mmol/L
>8.0 mg/dL; >3.30 mmol/L; 
life-threatening consequences
Death
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L; 
intervention initiated
>155 - 160 mmol/L; 
hospitalization indicated
>160 mmol/L; life-threatening 
consequences
Death
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 
1.71 mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL; 
>3.42 mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL; 
>5.7 mmol/L - 11.4 mmol/L
>1000 mg/dL; 
>11.4 mmol/L; 
life-threatening consequences
Death
Hyperuricemia
>ULN without physiologic 
consequences
 -
>ULN with physiologic 
consequences
Life-threatening consequences
Death
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening 
consequences; urgent 
intervention indicated
Death
Hypocalcemia
Corrected serum calcium of 
<LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; Ionized 
calcium <LLN - 1.0 mmol/L
Corrected serum calcium of 
<8.0 - 7.0 mg/dL; 
<2.0 - 1.75 mmol/L; Ionized 
calcium <1.0 - 0.9 mmol/L; 
symptomatic
Corrected serum calcium of 
<7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L; Ionized 
calcium <0.9 - 0.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L; 
Ionized calcium <0.8 mmol/L; 
life-threatening consequences
Death
Hypoglycemia
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L
<30 mg/dL; <1.7 mmol/L; 
life-threatening 
consequences; seizures
Death
Hypokalemia
<LLN - 3.0 mmol/L
Symptomatic with 
<LLN - 3.0 mmol/L; 
intervention indicated
<3.0 - 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; life-threatening 
consequences
Death
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5 
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4 
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3 
mmol/L
<0.7 mg/dL; <0.3 mmol/L; 
life-threatening consequences
Death
Hyponatremia
<LLN - 130 mmol/L
125-129 mmol/L and 
asymptomatic
125-129 mmol/L 
symptomatic; 
120-124 mmol/L regardless 
of symptoms
<120 mmol/L; 
life-threatening consequences
Death
*
Since anticoagulation medication is NOT captured in lab data, the condition for anticoagulation medication is ignored in the grade derivation. 
Note: Refer to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, which can be found at https://evs nci.nih.gov/ftp1/CTCAE/CTCAE_5.0


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SAP GS-US-428-5443 v.1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 15-Dec-2021
00:02:32
General Other
15-Dec-2021
03:01:18
Clinical Pharmacology
eSigned
18-Dec-2021
20:12:34
Biostatistics eSigned
20-Dec-2021
08:21:58
PPD
PPD
PPD
PPD
-