Conditions: Hepatitis C Virus Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the antiviral efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) in hepatitis C virus (HCV)-infected adults who are undergoing liver transplantation.

Detailed description:

Arms:
arm 1: SOF/VEL FDC for 4 weeks starting on the day of or day after the participant's liver transplant

Interventions: intervention 1: SOF/VEL
Intervention descriptions: intervention 1: 400/100 mg FDC tablet administered orally once daily

Protocol document:
Prot_000.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label Study to Investigate the Safety and Efficacy 
of SofosbuvirN elpatasvir Fixed Dose Combination Administered for 
Four Weeks in Patients Infected with Chronic HCV in the 
Peri-Operative Liver Transplantation Setting 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-2083 
Name: 
PPD 
Telephone: 
PPD 
Email: 
1-'1-'U 
I 
Name: 
Benedetta Massetto, MD 
Telephone: 
PPD 
Email: 
PPD 
Original 
26 Febmruy 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particulru·ly 1mpublished data, is the prope1iy or 
under conti"ol 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 infmmation is only to be used by you in 
collllection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the info1mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


Sofosbuvir/Velpatasvir Fixed-Dose Combination
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Gilead Sciences, Inc. 
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Investigational Medicinal Product Name...............................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Pharmacology Studies..........................................................................................................15
1.2.3.
Clinical Trials of SOF/VEL .................................................................................................20
1.3.
Additional Clinical Studies ....................................................................................................................20
1.4.
Study GS-US-342-1138 (ASTRAL-1)...................................................................................................20
1.5.
Study GS-US-342-1139 (ASTRAL-2)...................................................................................................23
1.6.
Study GS-US-342-1140 (ASTRAL-3)...................................................................................................27
1.7.
Study GS-US-342-1137 (ASTRAL-4)...................................................................................................31
1.8.
Rationale for This Study ........................................................................................................................35
1.8.1.
Rationale for the Dose of SOF/VEL ....................................................................................36
1.9.
Risk/Benefit Assessment for the Study..................................................................................................36
1.10.
Compliance ............................................................................................................................................37
2.
OBJECTIVES.....................................................................................................................................................38
3.
STUDY DESIGN................................................................................................................................................39
3.1.
Endpoints ...............................................................................................................................................39
3.2.
Study Design..........................................................................................................................................39
3.3.
Study Treatments ...................................................................................................................................39
3.4.
Visit Schedule ........................................................................................................................................39
3.5.
Discontinuation Criteria.........................................................................................................................40
3.6.
Subject Stopping Rules ..........................................................................................................................40
3.7.
End of Study...........................................................................................................................................41
3.8.
Substudies ..............................................................................................................................................41
3.8.1.
Optional Archive Sample .....................................................................................................41
3.8.2.
Optional Consent for Testing of Explanted Liver ................................................................42
4.
SUBJECT POPULATION..................................................................................................................................43
4.1.
Number of Subjects and Subject Selection ............................................................................................43
4.2.
Inclusion Criteria....................................................................................................................................43
4.3.
Exclusion Criteria...................................................................................................................................44
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................45
5.1.
Description and Handling of SOF/VEL FDC ........................................................................................45
5.1.1.
Formulation..........................................................................................................................45
5.1.2.
Packaging and Labeling .......................................................................................................45
5.1.3.
Storage and Handling...........................................................................................................45
5.2.
Dosage and Administration of SOF/VEL FDC......................................................................................46
5.3.
Prior and Concomitant Medications.......................................................................................................46
5.4.
Accountability for SOF/VEL FDC.........................................................................................................47
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49
6.2.1.
Screening Visit/Pre-Surgery.................................................................................................49
6.2.2.
Day 1 Assessments...............................................................................................................49
6.3.
Treatment Assessments (± 2 days).........................................................................................................49
6.4.
Early Termination (ET) Visit .................................................................................................................50
6.5.
Unscheduled Visits.................................................................................................................................50
6.6.
Post-Treatment Assessments..................................................................................................................50
6.7.
Assessments for Premature Discontinuation from Study.......................................................................50
6.8.
End of Study...........................................................................................................................................51
6.9.
Procedures and Specifications................................................................................................................51
6.9.1.
Central Laboratory Analytes ................................................................................................51
6.9.2.
Medical History....................................................................................................................51
6.9.3.
Complete Physical Examination...........................................................................................52
6.9.4.
Vital Signs............................................................................................................................52
6.9.5.
MELD Score/Child-Pugh Score...........................................................................................52
6.9.6.
Creatinine Clearance (CrCL)................................................................................................53
6.9.7.
Ideal Body Weight (IBW)....................................................................................................53
6.9.8.
Body Mass Index (BMI).......................................................................................................53
6.9.9.
12-Lead ECGs......................................................................................................................54
6.9.10.
Pharmacokinetic (PK) Sample .............................................................................................54
6.9.11.
Viral RNA Sequencing / Phenotyping Sample.....................................................................54
6.9.12.
Pregnancy Testing................................................................................................................54
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................55
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................55
7.1.1.
Adverse Events.....................................................................................................................55
7.1.2.
Serious Adverse Events........................................................................................................55
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................56
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................56
7.2.2.
Assessment of Severity ........................................................................................................57
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.4.
Gilead Reporting Requirements.............................................................................................................58
7.5.
Reporting Requirements for Liver Transplant and Complications of Liver Transplant.........................59
7.6.
Special Situations Reports......................................................................................................................59
7.6.1.
Definitions of Special Situations..........................................................................................59
7.6.2.
Instructions for Reporting Special Situations.......................................................................60
8.
STATISTICAL CONSIDERATIONS................................................................................................................63
8.1.
Analysis Objectives and Endpoints........................................................................................................63
8.1.1.
Analysis Objectives..............................................................................................................63
8.1.2.
Primary Endpoint .................................................................................................................63
8.1.3.
Secondary Endpoint .............................................................................................................64
8.1.4.
Safety Endpoint....................................................................................................................64
8.1.5.
Other Endpoints of Interest ..................................................................................................64
8.2.
Analysis Conventions.............................................................................................................................64
8.2.1.
Analysis Sets ........................................................................................................................64
8.3.
Data Handling Conventions ...................................................................................................................65
8.4.
Demographic Data and Baseline Characteristics ...................................................................................66
8.5.
Efficacy Analysis ...................................................................................................................................66
8.5.1.
Primary Efficacy Endpoint...................................................................................................66


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8.5.2.
Secondary Efficacy Endpoint...............................................................................................67
8.6.
Safety Analysis.......................................................................................................................................67
8.6.1.
Extent of Exposure...............................................................................................................67
8.6.2.
Adverse Events.....................................................................................................................67
8.6.3.
Laboratory Evaluations ........................................................................................................68
8.7.
Pharmacokinetic Analysis......................................................................................................................68
8.8.
Sample Size............................................................................................................................................69
8.9.
Data Monitoring Committee ..................................................................................................................69
9.
RESPONSIBILITIES..........................................................................................................................................70
9.1.
Investigator Responsibilities ..................................................................................................................70
9.1.1.
Good Clinical Practice..........................................................................................................70
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................70
9.1.3.
Informed Consent.................................................................................................................70
9.1.4.
Confidentiality......................................................................................................................71
9.1.5.
Study Files and Retention of Records ..................................................................................71
9.1.6.
Case Report Forms...............................................................................................................72
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................73
9.1.8.
Inspections............................................................................................................................73
9.1.9.
Protocol Compliance............................................................................................................73
9.2.
Sponsor Responsibilities ........................................................................................................................73
9.2.1.
Protocol Modifications.........................................................................................................73
9.2.2.
Study Report and Publications .............................................................................................74
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................74
9.3.1.
Payment Reporting...............................................................................................................74
9.3.2.
Access to Information for Monitoring..................................................................................74
9.3.3.
Access to Information for Auditing or Inspections ..............................................................75
9.3.4.
Study Discontinuation..........................................................................................................75
10.
REFERENCES ...................................................................................................................................................76
11.
APPENDICES ....................................................................................................................................................78
Appendix 1.
Investigator Signature Page....................................................................................................79
Appendix 2.
Study Procedures Table..........................................................................................................80
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............83
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................105


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LIST OF IN-TEXT TABLES
Table 1-1.
NGMN, NG, EE, and VEL Plasma PK Parameters Following Administration of 
NGM/EE alone or with VEL..................................................................................................17
Table 1-2.
Summary of LH, FSH, and Progesterone Concentrations Following Administration 
of NGM/EE alone or with VEL..............................................................................................18
Table 1-3.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs ............................................................................................19
Table 1-4.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes ..................................................21
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................47
Table 6-1.
Child-Pugh-Turcotte Classification of the severity of cirrhosis .............................................52


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label Study to Investigate the Safety and Efficacy 
of Sofosbuvir/Velpatasvir Fixed Dose Combination Administered for 
Four Weeks in Patients Infected with Chronic HCV in the 
Peri-Operative Liver Transplantation Setting
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
Not Applicable
Not Available
Study Centers 
Planned:
Approximately one center in New Zealand
Objectives:
The primary objectives of this study are as follows:

To explore the antiviral efficacy of treatment with 
sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) 
therapy administered for four weeks following liver 
transplantation as measured by sustained virologic response 
(SVR) 12 weeks after cessation of treatment(SVR12)

To evaluate the safety and tolerability of SOF/VEL in 
HCV-infected subjects in the peri-operative and post-transplant 
period
The secondary objectives of this study are as follows: 

To determine the percentage of subjects who attain SVR at 
4 weeks after cessation of treatment (SVR4)

To evaluate the proportion of subjects with virologic failure

To assess rates of graft survival, graft function, acute rejection 
and immunosuppressive therapy during treatment with SOF/VEL

To evaluate the emergence of viral resistance to SOF and VEL 
during treatment and after cessation of treatment 

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment 

To characterize pharmacokinetics of SOF/VEL


SofosbuvirN elpatasvir Fixed-Dose Combination 
Protocol GS-GS-US-342-2083 
Gilead Sciences, Inc. 
Study Design: 
Sub-Study: 
Original 
The exploratory objectives of this study are as follows: 
PPD 
This is an open-label study that will evaluate the safety, tolerability 
and antiviral efficacy of SOF/VEL administered for 4 weeks in 
HCV -infected adult male and female subjects who are undergoing 
liver transplantation. 
For all subjects SOF/VEL tablet (400/100 mg) once daily will be 
started the day of the subject's liver transplant if the transplant is 
completed before noon and the following day if it is completed after 
noon and will continue for 4 weeks. Treatment initiation may be 
delayed for up to 1 day ifwarranted by the subject's medical 
condition post-surgery. 
HCV RNA will be assessed at each visit. 
Phannacogenomics (PG) Sub-study 
PPD 
Phannacokinetic (PK) Sub-study (Required) 
All subjects will participate in a PK sub-study in which intensive 
serial PK sample collection (samples obtained over 24 hours) will be 
performed on Day 1 to determine pharmacokinetics of SOF, its 
metabolites GS-566500 and GS-331 007, and VEL. 
Number of Subjects 
Approximately 10 
Planned: 
Target Population: 
HCV infected adults who are undergoing primary liver 
transplantation 
Duration of 
Subjects will be treated for 4 Weeks 
Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
HCV infected, male and non-pregnant/non-lactating female subjects, 
ages 18 years or older, who are undergoing liver transplantation, may 
be eligible for the study. 
Reference Section 4.2 and 4.3 of the protocol for detailed Inclusion 
and Exclusion criteria. 
Page 7 
26 February 2016 


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Study Procedures/
Frequency:
Screening assessments will be completed at the time a subject is 
identified as a potential study participant to give sufficient time for 
the subject to provide informed consent and perform screening 
assessments. Subject’s screening data will be confirmed in the 
pre-operative period (within 48 hours of the planned transplant) at the 
Pre-surgery visit if the screening visit occurs more than 48 hours 
before the liver transplant surgery is started.
All subjects will complete the following study visits: Screening; 
Pre-surgery (if needed); On-Treatment visits Days 1, 3, 5, 7, 14, 21, 
and 28; and Post-treatment Visits at Weeks 1, 2, 4, and 12 following 
the last dose of study drug.
After consent is obtained, initial screening assessments will include 
physical examination, medical history, height (initial screening only), 
weight, vital signs, resting 12-lead electrocardiogram (ECG), 
screening procedure-related adverse events (AEs), concomitant 
medications (CMs), CPT and MELD score, safety laboratory tests 
(including hematology, chemistry, and coagulation), estimated 
creatinine clearance (Clcr), HCV RNA, HCV genotype, serology 
(HIV, HCV, HBV), serum β-hCG (females of child bearing 
potential only), and urinalysis. 
If the screening visit occurs more than 48 hours before the liver 
transplant surgery is started, the subject will also be reassessed within 
48 hours of transplantation to determine their continued eligibility at 
the pre-surgery visit. The assessments will include physical 
examination, re-review of the medical history, weight, vital signs, 
resting ECG, AEs, CMs, CPT and MELD score, safety laboratory 
tests, estimated Clcr, HCV RNA, urine pregnancy tests (females of 
childbearing potential only) and pregnancy prevention counseling.
If a separate informed consent is signed, samples of the explanted 
liver will be taken during surgery.
If the transplant is completed before noon, the subject will take their 
first dose that day after the transplant which will be considered Day 1. 
If the transplant is completed after noon, the subject will take their 
first dose the following morning which will be considered Day 1. The 
planned first dose may be delayed for up to 1 day if, in the 
investigators opinion, delay is in the subject’s medical interest. The 
subject will receive 4 weeks of study drug.
On-treatment assessments starting at Day 1 will include vital signs, 
ECG (only at Day 28), AEs, CMs (including immunosuppressive 
therapy), safety laboratory tests, estimated Clcr, HCV RNA, study 
drug dosing adherence and urine pregnancy tests (females of 
childbearing potential only).


SofosbuvirN elpatasvir Fixed-Dose Combination 
Protocol GS-GS-US-342-2083 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Pharmacokinetics: 
CONFIDENTIAL 
Original 
Post-treatment assessments through Post-treatment week 4 only 
include AEs and CMs. Weight, vital signs, and urine pregnancy tests 
(females of child bearing potential only) will only be done at 
Post-treatment week 4. Pregnancy prevention counseling will be done 
at Post-treatment week 1 only. Safety laboratory tests, HCV RNA and 
viral sequencing samples will be collected through all Post-treatment 
visits. 
Samples for viral RNA sequencing/phenotyping will be collected 
starting at Day 1 and every visit thereafter. 
PPD 
SOF/VEL is manufactured as a FDC tablet, consisting of 400 mg 
SOF and 100 mg of VEL, for oral administration. Subjects will take 
1 tablet daily with or without food. 
None 
AEs and safety laboratory tests will be collected throughout the study 
(through the Post-treatment week 4 visit). 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
performed using Roche COBAS® AmpliPrep/COBAS® TaqMan® 
HCV Test, v. 2.0. 
A single PK blood sample will be collected at each on-treatment visit 
for all subjects except on Days 1, 3 and 5. 
All subjects will be required to participate in an intensive serial PK 
sub-study to be performed on Day 1. The PK of SOF (and its 
metabolites GS-566500 and GS-331 007), and VEL will be assessed. 
Serial PK samples will be collected at the following time points: 0 
(pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose. 
Page 9 
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Statistical Methods:
The primary efficacy endpoint is the percentage of subjects who 
achieve SVR12 (HCV RNA < lower limit of quantitation [LLOQ] 
12 weeks after stopping study drug) for subjects in the Full Analysis 
Set (FAS).
Secondary efficacy endpoints include the percentage of subjects who 
attain SVR at 4 weeks after cessation of treatment (SVR4); the 
percentage of subjects who have HCV RNA <LLOQ at each 
on-treatment visit; and the percentage of subjects with virologic 
failure (VF, defined as HCV RNA ≥LLOQ at end of treatment or 
relapse during the Post-treatment follow-up period).
The primary safety endpoint is the percentage of subjects who 
discontinue from study drug due to an adverse event. Deaths, graft 
loss, and rejection episodes will also be listed or summarized, as 
appropriate.
Other endpoints of interest include changes to immunosuppressive 
therapy and the emergence of viral resistance to SOF or VEL during 
and after cessation of treatment, and HCV RNA levels (IU/mL) at 
each on-treatment visit, if relevant.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
BMI
body mass index
BW
body weight
CI
confidence interval
CrCL
creatinine clearance
CM
concomitant medication
CP
Child-Pugh
CPK
creatinine phosphokinase
CPT
Child-Pugh-Turcotte
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
CSA
colony stimulating agents
DAA
Direct acting antiviral
dL
Deciliter
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
EOT
End of Treatment
ET
Early Termination
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
FEV1
forced expiratory volume in one second
G
Gram
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)


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Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
Interferon
IL28B
IL28B gene
IMP
Investigational Medical Product
INR
International Normalized Ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
Kg
Kilogram
L
Liter
LDL
low-density lipoprotein
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MCV 
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MGB
minor groove binder
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
non-structural protein
PCR
polymerase chain reaction
PEG
pegylated interferon
PG
Pharmacogenomics
PO
per os, by mouth or orally
PT
preferred term or prothrombin time


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QD
once daily (use only in tables)
RBC
red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
Scr 
serum creatinine
SAE
serious adverse event
SD
standard deviation
SOC
system organ class
SOF
Sofosbuvir
Sofosbuvir
Formerly GS-7977
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
SVR
sustained virologic response
ULN
upper limit of the normal range
US
United States
VEL
Velpatasvir
VF
Virologic failure
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) infection is a global health challenge with estimates ranging up to 
150 million individuals infected worldwide {World Health Organization (WHO) 2014}. In the 
United States (US), approximately 2.7 million people have chronic HCV infection {Denniston et 
al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, although under-
reporting of HCV infection on death certificates may contribute to as much as a 5-fold 
underestimation of the actual number of deaths {Mahajan et al 2014}. Successful treatment of 
chronic HCV infection reduces the need for liver transplant, the incidence of HCC and overall 
mortality {Backus et al 2011}. Thus, the public health benefit of safe and effective HCV 
treatment regimens is high.
The development of sofosbuvir (Sovaldi®, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated, and result in higher SVR rates than prior therapies. SOF is currently
approved in the US for the treatment of genotype (GT) 1, 2, 3 and 4 HCV infection {Gilead 
Sciences Inc 2015b} and in the European Union for GT1-6 with different regimens and durations 
dependent on the HCV genotype {Gilead Sciences Limited 2015}. SOF is also approved in both 
the US and Europe to be used in combination with ribavirin in patients awaiting liver 
transplantation in order to prevent HCV reoccurrence, and in Europe in patients who have 
already received liver transplants {Gilead Sciences Inc 2015b}, {Gilead Sciences Limited 
2015}.  
The next wave of therapies for the treatment of HCV includes combinations of direct acting 
antivirals (DAAs) including SOF that offer even higher response rates without the need for 
pegylated interferon (PEG-IFN), and often without the need for ribavirin, depending on patient 
characteristics and HCV genotype. The first of these treatments, a fixed dose combination (FDC) 
of SOF and the HCV nonstructural protein 5A (NS5A) inhibitor ledipasvir (LDV), has been 
approved in the US for genotypes 1, 4, 5, and 6 {Gilead Sciences Inc 2016}and Europe for 
genotypes 1, 3, and 4, 5, and 6 infections {Gilead Sciences Inc 2015a}. Currently, LDV/SOF in 
combination with ribavirin is approved in Europe for the treatment of genotypes 1, 4, 5, and 6 
HCV in patients after liver transplantation. There are no currently approved ribavirin-free 
regimens for treatment of HCV in patients with who have had a liver transplant. 
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most  
prevalent HCV genotype in developed countries {Gower et al 2014}. However, over half of all
HCV infections are non-GT1: estimates from 2 recent meta-analyses indicate GT3 HCV is the
next most common accounting for 22-30% of infections, while GT2 and GT4 each account for
approximately 8 to 13%, GT6 for approximately 2 to 5%, and GT5 for approximately 1% of
HCV infections worldwide.  
The availability of a well-tolerated, all oral, ribavirin-free, short duration therapy such as 
SOF/VEL that is effective across all HCV genotypes would be a major advance for the treatment 


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of HCV infection globally.  This is particularly true for patients with who also have liver 
transplants who often have reduced blood cell counts or GFRs at baseline, making them 
susceptible to ribavirin-associated toxicities.
1.2.
Investigational Medicinal Product Name
Sofosbuvir/velpatasvir fixed-dose combination (SOF/VEL FDC) combines two HCV specific 
direct acting antivirals (DAAs) into a single tablet for the treatment of chronic HCV infection.
Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor currently approved in the US 
and other regions for the treatment of HCV infection as a component of an antiviral treatment 
regimen. VEL (formerly known as GS-5816) is a HCV NS5A inhibitor that has demonstrated 
activity against HCV genotypes 1, 2, 3, and 4 HCV in a 3-day monotherapy study. Phase 2 
studies of SOF +VEL administered as single agents have demonstrated that the combination of 
SOF 400 mg and VEL100 mg administered for 12 weeks is well tolerated and results in high 
SVR rates across a broad range of HCV genotypes. The SOF/VEL FDC (400 mg/100 mg) is a 
co-formulation of SOF 400 mg and VEL 100 mg that has demonstrated similar exposure of each 
component compared to co-administration of the single agents.  
The development of SOF/VEL may have a major impact of the global prevalence and burden of 
HCV as it may represent a simple, well tolerated, highly efficacious pangenotypic treatment for 
all HCV infected patients.
1.2.1.
General Information
Please refer to the Investigator’s Brochure (IB) for additional information on SOF/VEL, and the 
individual components, including:

In-Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Pharmacology Studies
1.2.2.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction study in healthy 
female subjects of childbearing age evaluating the effect of VEL on the pharmacokinetics of a 
representative hormonal contraceptive medication, norgestimate/ethinyl estradiol (NGM/EE, 
OC). Following screening, eligible subjects were enrolled in a lead-in period (Part A) of 28 days 
during which they completed dosing with the hormonal contraceptive (OC) prior to baseline 
assessments and initiation of Cycle 1 (Part B). Subjects with a documented history of taking OC 
for at least 1 menstrual cycle could be enrolled directly into Cycle 1. The PK, safety, and 


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tolerability of OC and OC + VEL were assessed in Part B of the study, which consisted of 
2 cycles: subjects received OC alone during Cycle 1, and OC plus VEL 100 mg once daily 
during days 8-14 of Cycle 2. Fifteen subjects were enrolled, and 13 completed the study. 
Two subjects were discontinued from the study prior to initiation of Cycle 2 (OC+VEL) for 
laboratory abnormalities. 
Table 1-1 presents the steady-state PK parameters and statistical comparisons of NGM 
metabolites norelgestromin (NGMN) and norgestrel (NG) and EE following administration alone 
or in combination with VEL. Steady-state VEL PK parameters were also assessed. Norgestimate 
was not quantifiable for all subjects at most time points. Similar systemic exposure of NGMN 
and NG were achieved following NGM/EE administration with VEL relative to administration of 
NGM/EE alone. A modest increase in EE Cmax was observed when administered with VEL with 
no change in overall exposure (AUC) or Ctau. The magnitude of increase in EE Cmax when 
administered with VEL is similar to that observed with the concomitant administration of other 
drugs such as voriconazole and etravirine, which did not warrant dose adjustment {Andrews et al 
2008, Janssen Pharmaceuticals Inc. 2013}. VEL exposures were consistent with historical data 
(Studies GS-US-281-0115, GS-US-342-0104).


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Table 1-1.
NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE + VEL
vs. NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + VEL
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.90 (0.82, 0.98)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.88, 1.07)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.83, 1.03)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.15)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.78, 1.19)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.73, 1.18)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.04 (0.87, 1.24)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.39 (1.17, 1.66)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.83 (0.65, 1.06)
Velpatasvir
AUCtau (ng•h/mL)
--
4680 (35.1)
--
Cmax (ng/mL)
--
626 (22.0)
--
Ctau (ng/mL)
--
68.3 (47.6)
--
Note: preliminary data presented to 3 significant figures.
a
N = 12
Luteinizing hormone (LH), follicle stimulating hormone (FSH), and progesterone concentrations 
were similar in both treatment cycles, as presented in Table 1-2. Luteinizing hormone and 
progesterone median values were lower than those expected for ovulatory or luteal phases, 
respectively {Quest Diagnostics 2013b}, {Quest Diagnostics 2013a}, {Barditch-Crovo et al 
1999}. Follicle stimulating hormone was lower or within the expected range for the ovulatory 
phase {Quest Diagnostics 2013a}. These results are consistent with a possible decrease in serum 
LH and FSH by hormonal contraceptives and absence of ovulation, as assessed by very low 
progesterone values on cycle Day 21.


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Table 1-2.
Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL 
PD Analyte
Median (Q1, Q3)
OC Alone (N = 15)
OC + VEL (N = 13)
LH (mIU/mL)
8.0 (2.9, 12.7)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 5.9)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.17, 0.39)
0.27 (0.18, 0.80)
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with VEL. 
Study GS-US-334-0146 previously demonstrated that the use of SOF with contraceptives 
(eg, norgestimate/ethinyl estradiol) is permitted. Accordingly, the use of hormonal 
contraceptives with VEL as a single agent or as part of SOF/VEL FDC is permitted. 
1.2.2.2.
Drug-Drug Interaction Studies with SOF/VEL and Gastric Acid Suppressants
GS-US-342-1346 and GS-US-342-1709 were open-label, Phase 1, single-dose drug-drug 
interaction studies in healthy volunteers evaluating the effect of gastric acid suppressants 
(H2RAs and PPIs) on the PK of SOF/VEL. These studies were conducted because VEL has 
demonstrated pH-dependent solubility in vitro.  A summary of results from these studies is 
presented in the table below.
Study GS-US-342-1346 demonstrated that simultaneous or staggered (12 hour) administration of 
SOF/VEL, administered under fasting conditions, with famotidine 40 mg resulted in no change 
to the AUC of SOF or VEL, suggesting that SOF/VEL can be administered simultaneously or 
staggered with H2RAs at doses comparable to famotidine 40 mg. Study GS-US-342-1346 also 
demonstrated that simultaneous or staggered (12 hour) administration of SOF/VEL, administered 
under fasting conditions, with omeprazole 20 mg resulted in a reduction in VEL AUC of 37% 
and 56%, respectively. The AUC of SOF also decreased 29% to 44%, respectively, though these 
effects are secondary to the impact of PPIs on VEL, as SOF does not demonstrated pH-
dependent solubility. Based on these data, the use of SOF/VEL under fasting conditions with 
PPIs is not recommended.
Study GS-US-342-1709 evaluated the effect of omeprazole 20 mg or 40 mg on the PK of 
SOF/VEL when SOF/VEL is administered with food. Administration of SOF/VEL with food and 
omeprazole did not alter the overall exposure (AUC) of SOF or its metabolites, regardless of 
timing or dose of omeprazole. Administration of SOF/VEL with food and omeprazole resulted in 
a decrease in VEL exposure. The smallest decrease in VEL exposure (AUC: 26%, Cmax: 33%) 
was observed following administration of SOF/VEL with food 4 hours before omeprazole 
20 mg. A slightly greater decrease in VEL exposure (AUC: 38%, Cmax: 48%) was observed when 
SOF/VEL was administered with food 2 hours after omeprazole 20 mg. The largest decline in 
VEL exposure (AUC: 53%, Cmax: 56%) was observed following SOF/VEL administration with 
food 4 hours before the higher dose of omeprazole 40 mg.


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Collectively, these studies indicate that PPIs can impact the PK of SOF/VEL. Administration of 
SOF/VEL with food reduces the effect of omeprazole on SOF/VEL PK. The overall exposure of 
SOF and its metabolites were not affected by omeprazole 20 mg when SOF/VEL was 
administered with food, and the reduction in VEL exposure was less when administered with 
food (26% to 38%) compared to fasted administration (37% to 56%). Staggering timing of 
omeprazole 20 mg and SOF/VEL administration also modestly impacted VEL exposure; VEL 
AUC was least impacted when administered 4 hours before omeprazole 20 mg (equivalent to 
20 hours after the previous omeprazole dose). 
Study GS-US-342-1709 also demonstrates that the nature of VEL exposure decrease was not 
uniform across the study population. The largest decreases were observed in subjects with the 
highest exposure at the reference condition of dosing, with SOF/VEL fasted without an acid 
reducing agent, and those with low exposure at the reference condition were generally unaffected 
by administration with a PPI. These data suggests that gastric pH is a contributor to the natural 
variability of VEL, and the range of exposure for HCV-infected subjects on PPIs is expected to 
be within that observed in Phase 3 ASTRAL studies. Accordingly, PPI doses comparable with 
omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL is administered with 
food.
Table 1-3.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs 
Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
GS-US-
342-1346 
(N=60)
SOF/VEL 
(fasted) with 
simultaneous 
FAM 40 mg
↔
↔
↔
↔
↔
↔
↔
↔
↔
SOF/VEL 
(fasted) with 
12 hours 
after FAM 
40 mg
↔
↔
↓23%
↔
↔
↔
↔
↔
↔
SOF/VEL 
(fasted) with 
simultaneous 
OME 20 mg
↓29%
↓29%
↓34%
↔
↔
↔
↓37%
↓36%
↓37%
SOF/VEL 
(fasted) 12 
hours after 
OME 20 mg 
↓44%
↓44%
↓45%
↔
↔
↔
↓56%
↓55%
↓57%
GS-US-
342-1709
(N=40)
SOF/VEL 
(fed) 2 hours 
After OME
20 mg
↔
↔
↓16%
↔
↔
↔
↓38%
↓38%
↓48%
SOF/VEL 
(fed)  4 hours 
Before OME
20 mg
↔
↔
↓21%
↔
↔
↔
↓26%
↓26%
↓33%


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Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
SOF/VEL 
(fed) 4 hours 
Before OME
40 mg
↔
↔
↓30%
↔
↔
↔
↓53%
↓53%
↓56%
FAM = famotidine; OME = omeprazole. The 90% CIs of the %GLSM ratios were within (↔), or extended below (↓) the 
predetermined PK alteration boundary of 70%.
1.2.3.
Clinical Trials of SOF/VEL
1.3.
Additional Clinical Studies
Four Phase 3 studies are ongoing evaluating the efficacy and safety of SOF/VEL in subjects with 
genotype 1-6 HCV infection. Three studies enrolled subjects without cirrhosis or with 
compensated cirrhosis, GS-US-342-1138 (ASTRAL-1), GS-US-342-1139 (ASTRAL-2) and 
GS-US-342-1140 (ASTRAL-3); and one study enrolled subjects with decompensated cirrhosis 
GS-US-342-1137 (ASTRAL-4). Summaries of interim results from the individual Phase 3 
studies are presented below.
1.4.
Study GS-US-342-1138 (ASTRAL-1)
Design
This ongoing Phase 3, randomized, double-blind, placebo-controlled, multicenter, international 
study is assessing the antiviral efficacy, safety, and tolerability of 12 weeks of SOF/VEL 
treatment compared with 12 weeks of SOF/VEL placebo treatment in subjects with chronic 
genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection.  This study was conducted in 
Belgium, Canada, France, Germany, Hong Kong, Italy, United Kingdom, and United States.
Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment 
with SOF/VEL for 12 weeks (SOF/VEL 12 Week group) or SOF/VEL placebo for 12 weeks 
(Placebo 12 Week group). Subjects with genotype 5 HCV infection were enrolled to the 
SOF/VEL 12 Week group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and 
indeterminate) and the presence or absence of cirrhosis at screening.
Disposition
A total of 740 subjects were enrolled and treated; 624 subjects in the SOF/VEL 12 Week group 
and 116 subjects in the Placebo 12 Week group.
The majority of subjects (99.3%) completed study treatment. Five subjects (0.7%) prematurely 
discontinued study treatment; 2 subjects in the SOF/VEL group and 3 subjects in the placebo 
group. The reasons for premature discontinuation of study drug for subjects in the SOF/VEL 
12 Week group were an AE (1 subject) and lost to follow-up (1 subject) and for subjects in the 
Placebo 12 Week group were AEs (2 subjects) and investigator discretion (1 subject).


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Demographics and Baseline Characteristics
Demographics and baseline disease characteristics were generally balanced between the 
SOF/VEL 12 Week and Placebo 12 Week groups.
In the SOF/VEL 12 Week group, the majority of subjects were male (59.9%), and 21.6% of 
subjects had a body mass index (BMI) 30 kg/m2, 19.4% had cirrhosis and most subjects 
(73.9%) had baseline HCV RNA ≥800,000 IU/mL. Of the 624 subjects who received SOF/VEL, 
328 subjects (52.6%) had genotype 1 HCV infection (210 subjects [33.7%] with HCV 
genotype 1a and 118 subjects [18.9%] with HCV genotype 1b), 104 subjects (16.7%) had 
genotype 2 HCV infection, 116 subjects (18.6%) had genotype 4 HCV infection, 35 subjects 
(5.6%) had genotype 5 HCV infection, and 41 subjects (6.6%) had genotype 6 HCV infection.
Efficacy Results 
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was statistically 
superior relative to the prespecified performance goal of 85% (p < 0.001). The SVR12 rate was 
as follows:

SOF/VEL 12 Week group: 99.0% (95% CI: 97.9% to 99.6%) of subjects (618 of 624) 
achieved SVR12.
Table 1-4 presents the SVR12 results for the SOV/VEL 12 Week group overall and by HCV 
genotype. A total of 6 of 624 subjects (1.0%) who received SOF/VEL did not achieved SVR12. 
Two subjects had relapse determined at Post-treatment week 4; one treatment-naive subject with 
genotype 1a HCV infection without cirrhosis and one treatment experienced subject with 
genotype 1b infection and cirrhosis. Four additional subjects (3 with genotype 1 and 1 with 
genotype 5) did not achieve SVR12 (1 subject withdrew consent, 2 subjects had not returned for 
the Post-treatment Week 12 visit, and 1 subject died prior to the Post-treatment Week 4 visit). 
Table 1-4.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes 
SOF/VEL
12 Weeks 
Total
(All 
Genotypes)
(N = 624)
GT-1a
(N = 210)
GT-1b
(N = 118)
GT-1
Total
(N = 328)
GT-2
(N = 104)
GT-4
(N = 116)
GT-5
(N = 35)
GT-6
(N = 41)
SVR12
618/624 
(99.0%)
206/210 
(98.1%)
117/118 
(99.2%)
323/328 
(98.5%)
104/104 
(100.0%)
116/116 
(100.0%)
34/35 
(97.1%)
41/41 
(100.0%)
GT = genotype
The SVR4 results for subjects with genotype 1, 2, 4, 5, or 6 HCV infection were the same as the 
SVR12 results with the exception of 1 subject with genotype 1a HCV infection who achieved 
SVR4 but had not returned for his Post-treatment Week 12 visit at the time of the interim 
analysis.


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HCV RNA declined rapidly with similar decreases in HCV RNA observed across all HCV 
genotypes in the SOF/VEL 12 Week group. Consistent with the rapid and sustained decline in 
HCV RNA, > 88.5% of subjects in the SOF/VEL 12 Week group had HCV RNA LLOQ at 
Week 4. Time to virologic suppression was not associated with treatment outcome overall or in 
any genotype.
Virologic Resistance
Deep sequence analyses indicated that subjects in the SOF/VEL 12 Week group had a diverse 
population of HCV with more than 30 subtypes across genotypes 1, 2, 4, 5, 6, and 7. 
Approximately 42% and 9% of subjects in the SOF/VEL 12 Week group had baseline NS5A 
resistance-associated variants (RAVs) and NS5B RAVs, respectively. Baseline NS5A or NS5B 
RAVs had no impact on SVR12, with high SVR12 across all subtypes/genotypes regardless of 
the presence of NS5A RAVs or NS5B RAVs. Two subjects had virologic failure and both had 
baseline NS5A RAVs. At virologic failure time points, both subjects developed additional NS5A 
RAVs (Y93N and Y93H) that conferred a high (> 700) fold shift in EC50 to VEL. No NS5B 
RAVs were detected at baseline or Post-treatment in either subject with virologic failure.
Safety Results
Treatment with SOF/VEL was well tolerated. Subjects in the SOF/VEL 12 Week treatment 
group had similar type, incidence, and severity of AEs as subjects in the Placebo 12 Week group.
Grade 3 (severe) and Grade 4 (life-threatening) AEs were rare, 19 of 624 (2.9%) in the SOF/VEL 
12 Week group and 1 of 116 (0.9%) in the Placebo 12 Week group. Two subjects (0.3%) in the 
SOF/VEL 12 Week group had Grade 4 AEs. One subject had a Grade 4 AE of malignant lung 
neoplasm and 1 subject had a Grade 4 AE of sudden death. Both events were assessed by the 
investigators as unrelated to study drugs.
SAEs were rare and occurred in 15 subjects (2.4%) in the SOF/VEL 12 Week group. All SAEs 
were assessed by the investigators as unrelated to study drugs. No placebo treated subjects had 
SAEs. No trends in SAE type or onset time were observed, and no SAE was reported in 
> 1 subject. No SAEs led to treatment discontinuation. One subject death was reported in the 
study. This subject completed 12 weeks of treatment with SOF/VEL and died in his sleep on
Post-treatment Day 8. The death was assessed as not related to study drug by the investigator. 
One subject (0.2%) in the SOF/VEL 12 Week group discontinued study treatment due to a 
Grade 3 AE of anxiety and 2 subjects (1.7%) in the Placebo 12 Week group discontinued study 
treatment due to meeting the prespecified stopping criteria of elevated ALT and/or AST levels 
≥5 nadir.
Most laboratory abnormalities were Grade 1 or 2 in severity. Subjects in the SOF/VEL 12 Week 
group had Grade 3 or 4 chemistry abnormalities of elevated AST (Grade 3; 1 subject [0.2%]), 
elevated creatine kinase (Grade 3; 2 subjects [0.3%], Grade 4; 2 subjects [0.3%]), hyperglycemia 
(Grade 3, 15 subjects [2.4%]), and elevated lipase (Grade 3; 14 subjects [2.2%], Grade 4, 
2 subjects [0.3%]). Among subjects in the SOF/VEL 12 Week, all Grade 3 or 4 creatinine kinase 


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elevations were transient, all Grade 3 or 4 lipase elevations were asymptomatic and generally 
transient, and Grade 3 or 4 hyperglycemia occurred in subjects with a medical history of 
diabetes. The most frequently observed Grade 3 or 4 laboratory abnormalities observed in 
placebo treated subjects were elevated ALT (Grade 3; 6 subjects [5.2%] and Grade 4; 2 subjects 
[1.7%]) consistent with ongoing HCV infection.
No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure, 
or pulse) were observed during the study. No trends in ECG findings suggestive of cardiotoxicity 
were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its primary efficacy endpoint demonstrating that the SVR12 rate of 99.0% 
(95% CI: 97.9% to 99.6%) in genotype 1, 2, 4, 5, and 6 HCV-infected subjects treated for 
12 weeks with SOF/VEL was statistically superior to the prespecified SVR12 performance 
goal of 85% (p<0.001).

High SVR12 rates were achieved across all HCV genotypes and subgroups
Among subjects with cirrhosis, the SVR rate was 99.2%
Among subjects with prior treatment failure, the SVR rate was 99.5%
Among subjects with baseline NS5A RAVs, the SVR12 rate was 99.2%

Treatment with SOF/VEL for 12 Weeks was generally well tolerated with a safety profile 
similar to that of placebo treatment. There was a low incidence of SAEs, discontinuations 
due to AEs and no clinically relevant laboratory abnormalities.
1.5.
Study GS-US-342-1139 (ASTRAL-2)
Study Design
This ongoing Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 12 weeks of 
SOF+RBV treatment in subjects with chronic genotype 2 HCV infection. The study was 
conducted in the United States (US).
Subjects with genotype 2 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 12 weeks (SOF+RBV 12 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs. treatment experienced).


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Disposition
A total of 266 subjects were randomized and treated; 132 in the SOF/VEL 12 Week group and 
134 in the SOF+RBV 12 Week group. The majority of subjects (99.2%) completed study 
treatment. Two subjects (0.8%), 1 in each treatment group, prematurely discontinued study 
treatment. One subject in the SOF/VEL 12 Week group discontinued study treatment on Day 1 
(after receiving 1 dose of study drug) due to AEs of disturbance in attention, headache, and 
anxiety. One subject in the SOF+RBV 12 Week group completed the Week 10 study visit, but 
did not return for any subsequent study visits and was assumed to be lost to follow-up; the last 
confirmed dosing date was Day 71.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across both treatment 
groups. The majority of subjects were male (59.4%), and 32.7% of subjects had a BMI 
30 kg/m2. A total of 38 subjects (14.3%) had cirrhosis at screening. Overall, the majority of 
subjects had HCV RNA 800,000 IU/mL (79.7%). Overall, 14.7% (39 subjects) were treatment 
experienced.
Efficacy Results
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was noninferior 
to the SVR12 rate in the SOF+RBV 12 Week group. The SVR12 rates were as follows:

SOF/VEL 12 Week group: 99.3% (95% CI: 95.9% to 100%) of subjects (133 of 134) 
achieved SVR12

SOF+RBV 12 Week group: 93.9% (95% CI: 88.4% to 97.3%) of subjects (124 of 132) 
achieved SVR12
The strata-adjusted difference (95% CI) in the proportions was 5.2% (0.2% to 10.3%). Since the 
lower bound of the 2-sided 95% CI for the difference between groups was greater than the 
prespecified noninferiority margin of −10%, the efficacy of SOF/VEL for 12 weeks was 
demonstrated to be statistically noninferior to SOF+RBV for 12 weeks. There was sufficient 
evidence to demonstrate the statistical superiority of treatment with SOF/VEL for 12 weeks over 
SOF+RBV for 12 weeks for SVR12 (p = 0.018; CMH test stratified by cirrhosis status and prior 
treatment experience).
In the SOF/VEL 12 Week group, 1 of 134 subjects (0.7%) did not achieve SVR12: the subject 
discontinued study treatment on Day 1 (after receiving 1 dose) due to AEs of difficulty 
concentrating, headache, and anxiety. The subject never achieved HCV RNA LLOQ. In the 
SOF+RBV 12 Week group, 8 of 132 subjects (6.1%) did not achieve SVR12. Of these, 
6 subjects relapsed and 2 were lost to follow-up. Four relapses occurred by the Post-treatment
Week 4 visit and 2 relapses occurred between the Post-treatment Week 4 and 12 visits. The low 
number of virologic failures in the study precluded meaningful subgroup analysis of SVR.


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The SVR4 results were similar to the SVR12 results with the exception of 3 subjects in 
SOF+RBV 12 Week group: 1 subject was lost to follow-up after Post-treatment Week 4 and 
2 subjects relapsed between the Post-treatment Week 4 and Week 12 visits.
HCV RNA levels (log10 IU/mL) declined rapidly with similar decreases in HCV RNA observed 
in both treatment groups. After 1 week of treatment, the mean change from baseline in HCV 
RNA levels was 4.51 log10 IU/mL in both treatment groups. The decreases in HCV RNA were 
maintained from Weeks 2 through 12. Consistent with the rapid and sustained decline in 
HCV RNA, 90.2% of subjects in both treatment groups had HCV RNA LLOQ at Week 4.
There was a lack of correlation of time to suppression with virologic outcome in the SOF/VEL 
12 week group as all subjects who completed treatment achieved SVR regardless of the time to 
suppression.
Virologic Resistance
Deep sequencing analyses indicated that genotype 2a and 2b were the predominant HCV 
subtypes in subjects who were randomized and treated in this study. Approximately 60% and 
10% of subjects in the SOF/VEL 12 Week group had pretreatment NS5A and NS5B RAVs, 
respectively. The most prevalent NS5A RAV observed was L31M in 51% of subjects. Despite 
the presence of pretreatment NS5A and NS5B RAVs, no subjects in the SOF/VEL 12 Week 
group experienced virologic failure in this study. Two of the 6 subjects who relapsed in the 
SOF+RBV 12 Week group had low levels of the NS5B NI RAV L159F detectable at failure.
Safety Results
Overall, treatment with SOF/VEL or SOF+RBV for 12 weeks was generally safe and well 
tolerated. A smaller percentage of subjects in the SOF/VEL 12 Week group experienced any AE 
(68.7%, 92 of 134) compared with the SOF+RBV 12 Week group (76.5%, 101 of 132), 
including treatment-related AEs (SOF/VEL, 33.6%; SOF+RBV, 56.8%) and AEs leading to 
modification or interruption of any study drug (SOF/VEL, 0; SOF+RBV, 9.8%).
The most common AEs (ie, AEs reported in > 10% of subjects in either group) were reported by 
a smaller percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
12 Week group, including fatigue (14.9% vs. 35.6%), headache (17.9% vs. 22.0%), nausea 
(10.4% vs. 14.4%), and insomnia (4.5% vs. 13.6%). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
rare (SOF/VEL, 2.2%; SOF+RBV, 2.3%). No Grade 4 (life-threatening) AEs were reported. 
Anxiety was the only Grade 3 AE reported in > 1 subject in the SOF/VEL 12 Week group (n = 2, 
1.5%).
Serious adverse events (SAEs) were also rare (1.5%, 4 of 266 subjects [2 in each treatment 
group]). No SAE was reported in 1 subject. All SAEs were considered by the investigators to 
be not related to study drug. Two non-treatment-emergent deaths were reported during the study 
(metastatic lung cancer and cardiac arrest after treatment completion). No pregnancies were 
reported during the study. Only 1 subject permanently discontinued any study drug (SOF/VEL) 


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due to AEs. After receiving 1 dose of SOF/VEL, the subject, who had a medical history of 
depression, insomnia and post-traumatic stress disorder, discontinued study treatment due to 
Grade 3 AEs of difficulty concentrating, headache, and anxiety that were assessed as related to 
study drugs by the investigator.
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(104 of 266 subjects, 39.1%) or Grade 2 (70 of 266 subjects, 26.3%) in severity. A smaller 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(7.5%, 10 subjects) compared with the SOF+RBV 12 Week group (13.6%, 18 subjects). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed with 
RBV therapy. No subjects in the SOF/VEL 12 Week group had a Grade 3 or 4 hematology 
laboratory abnormality. The only Grade 3 hematology laboratories abnormality in the SOF+RBV 
12 Week group were decreased hemoglobin (5.3%, 7 subjects) and increased lymphocytes 
(0.8%, 1 subject). The most common Grade 3 or 4 chemistry laboratory abnormalities in both 
treatment groups were increased serum glucose (hyperglycemia) and increased lipase. Grade 3 
increases in lipase were reported for 7 subjects (5.3%) in the SOF/VEL 12 Week group and 
2 subjects (1.5%) in the SOF+RBV 12 Week group. Grade 4 increases in lipase were reported for 
1 subject (0.8%) in each treatment group. All of the Grade 3 lipase elevations were transient and 
asymptomatic, with no cases of clinical pancreatitis. In the SOF/VEL 12 Week group, 1 subject 
each experienced a Grade 3 or 4 increase in creatine kinase following workout sessions. Grade 3 
hyperbilirubinemia was only observed in the SOF+RBV 12 Week group and was consistent with 
RBV-associated hemolysis. Grade 4 chemistry laboratory abnormalities were reported for lipase 
and creatine kinase.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) or 
ECGs were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint, demonstrating that the SVR12 rate 
of 99.3% with SOF/VEL for 12 weeks was noninferior to the SVR12 rates of 93.9% with 
SOF+RBV for 12 weeks.

Treatment with SOF/VEL for 12 weeks led to a statistically superior SVR12 rate compared 
with SOF+RBV for 12 weeks (p = 0.018). 

No subjects treated with SOF/VEL experienced virologic failure, including subjects with 
cirrhosis (14%), prior treatment failure (14%), and baseline NS5A RAVs (60%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
or clinically relevant laboratory abnormalities were observed.


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1.6.
Study GS-US-342-1140 (ASTRAL-3)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 24 weeks of 
SOF+RBV treatment in subjects with chronic genotype 3 HCV infection.
Subjects with genotype 3 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 24 weeks (SOF+RBV 24 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs. treatment-experienced).
Disposition
A total of 552 subjects were randomized and treated (277 subjects in the SOF/VEL 12 Week 
group and 275 subjects in the SOF+RBV 24 Week group). A total of 21 subjects (7.6%) in the 
SOF+RBV 24 Week group discontinued treatment compared with 2 subjects (0.7%) in the 
SOF/VEL 12 Week group. The most common reason for discontinuation of treatment for 
subjects in the SOF+RBV 24 Week group was AEs (9 subjects, 3.3%).
Demographics and Baseline Characteristics
The majority of subjects were male (62.3%), and 20.3% of subjects had a BMI ≥30 kg/m2. 
Overall, the majority of subjects had HCV RNA ≥800,000 IU/mL (69.7%). A total of 
163 subjects (29.5%) had cirrhosis at screening. Overall, 25.7% (142 subjects) were treatment 
experienced.
Efficacy Results
The study met the primary efficacy endpoint. The SVR12 rate for the SOF/VEL 12 Week group 
was statistically noninferior to the SVR12 rate for the SOF+RBV 24 Week group. The SVR12 
rates were as follows:

SOF/VEL 12 Week group: 95.3% (95% CI: 92.1% to 97.5%) of subjects (264 of 277) 
achieved SVR12.

SOF+RBV 24 Week group: 80.4% (95% CI: 75.2% to 84.9%) of subjects (221 of 275) 
achieved SVR12.
The strata-adjusted difference (95% CI) in the proportions was 14.8% (9.6% to 20.0%). The 
superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks for SVR12 
was also demonstrated (p < 0.001; CMH test stratified by cirrhosis status and prior treatment 
experience).
In the SOF/VEL 12 Week group, 13 of 277 subjects (4.7%) did not achieve SVR12. Of these, 
no subjects had on-treatment virologic failure, 11 subjects relapsed, and 2 subjects were lost to 
follow-up. In the SOF+RBV 24 Week group, 54 of 275 subjects (19.6%) did not achieve SVR12. 


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Of these, 1 subject had on-treatment virologic failure (nonresponse), 38 subjects relapsed, and 
15 subjects did not achieve SVR12 for reasons other than virologic failure. These 15 subjects 
included 6 subjects who were lost to follow-up or who did not attend a Post-treatment Week 12 
visit, 4 subjects who withdrew from the study due to AEs, 2 subjects who withdrew consent from 
the study, 2 subjects who died, and 1 subject who only received 2 days of study drug, did not 
achieve HCV RNA < LLOQ on treatment, and did not meet the protocol definition for virologic 
failure.
Most relapses occurred by the Post-treatment Week 4 visits. In the SOF/VEL 12 Week group, 
8 of 11 relapses occurred by Post-treatment Week 4, and 3 of 11 relapses occurred between Post-
treatment Weeks 4 and 12. 
Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. Within each treatment group, the SVR12 rates for 
most subgroups were generally consistent with those observed in the overall population. In the 
SOF/VEL 12 Week group, the SVR12 rates for subjects with and without cirrhosis were 91.3% 
(73 of 80) and 97.0% (191 of 197), respectively, and the SVR12 rates for treatment-naive and 
treatment-experienced subjects were 97.1% (200 of 206) and 90.1% (64 of 71), respectively. In 
the SOF+RBV 24 Week group, subjects with cirrhosis had considerably lower SVR12 rates 
(66.3%; 55 of 83) than subjects without cirrhosis (87.2%; 163 of 187), and subjects with prior 
treatment experience had considerably lower SVR12 rates (63.4%; 45 of 71) than 
treatment-naive subjects (86.3%; 176 of 204).
HCV RNA levels (log10 IU/mL) declined rapidly, with similar decreases in HCV RNA observed 
in both treatment groups. Consistent with the rapid and sustained decline in HCV RNA, 91.7% 
of subjects in the SOF/VEL 12 Week group and 88.2% of subjects in the SOF+RBV 24 Week 
group had HCV RNA < LLOQ at Week 4. Time to virologic suppression did not impact 
virologic outcomes in the SOV/VEL 12 Week group: SVR12 rates were 96.0% and 95.7% 
among those subjects with HCV RNA < LLOQ and those with HCV RNA ≥LLOQ at Week 4, 
respectively.
Virologic Resistance
Pretreatment NS5A and NS5B NI RAVs were present in 16% and 4% of subjects, respectively, 
in the SOF/VEL 12 Week group. There was a numerically lower SVR12 rate in 
SOF/VEL-treated subjects with baseline NS5A RAVs compared with subjects without NS5A 
RAVs (88% vs. 97%, respectively). All subjects with NS5B NI RAVs in the SOF/VEL 12 Week 
group achieved SVR12.
A total of 10 subjects in the SOF/VEL 12 Week group relapsed, and 1 subject was reinfected. All 
10 subjects had the NS5A RAV Y93H detected at relapse time points. No SOF/VEL-treated 
subjects had NS5B NI RAVs emerge at relapse. The NS5B NI RAVs (N142T, L159F, or 
V321A) emerged in 7 of 39 subjects in the SOF+RBV 24 Week group who had virologic failure.


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Safety Results
Overall, treatment with SOF/VEL for 12 weeks or SOF+RBV for 24 weeks was generally safe 
and well tolerated. A lower percentage of subjects in the SOF/VEL 12 Week group experienced 
any AE (88.4%; 245 of 277) compared with the SOF+RBV 24 Week group (94.5%; 260 of 275). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
reported for 4.3% (12 subjects) in the SOF/VEL 12 Week group and 7.3% (20 subjects) in the 
SOF+RBV 24 Week group. Grade 4 (life-threatening) AEs were reported for no subjects in the 
SOF/VEL 12 Week group and 1.1% (3 subjects) in the SOF+RBV 24 Week group (death due to 
natural causes in 1 subject, cerebrovascular accident in 1 subject, and multiple gunshot wounds 
in 1 subject).
Of the most common AEs (ie, AEs reported in ≥10% of subjects in either treatment group), a 
lower percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
24 Week group experienced fatigue (25.6% vs. 38.2%), insomnia (11.2% vs. 26.9%), nausea 
(16.6% vs. 21.1%), irritability (8.3% vs. 14.5%), cough (5.1% vs. 12.7%), pruritus (2.9% vs.
12.7%), and dyspepsia (3.2% vs. 10.9%).
Serious adverse events were reported for 2.2% (6 subjects) in the SOF/VEL 12 Week group and 
5.5% (15 subjects) in the SOF+RBV 24 Week group. No SAE was reported in > 1 subject, and 
no SOV/VEL-treated subject had a treatment-related SAE. Three subject deaths were reported 
during the study (1 treatment-emergent death due to natural causes, 1 treatment-emergent death 
due to multiple gunshot wounds, and 1 nontreatment-emergent death due to an unknown cause); 
all 3 subjects were in the SOF+RBV 24 Week group. A total of 9 subjects (in the SOF+RBV 
24 Week group) prematurely discontinued study drugs due to an AE. The most common AE 
resulting in discontinuation of study drug in the SOF+RBV 24 Week group was insomnia 
(1.1%, 3 subjects).
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(36.3%; 200 of 551 subjects) or Grade 2 (29.6%; 163 of 551 subjects) in severity. A lower 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(5.8%, 16 of 276) compared with the SOF+RBV 24 Week group (14.2%, 39 of 275). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed during 
treatment with RBV. Grade 4 laboratory abnormalities were similarly low in the SOF/VEL 
12 Week group (1.4%, 4 of 276) compared with the SOF+RBV 24 Week group (2.9%, 8 of 275).
The only Grade 3 or 4 hematology laboratory abnormality in the SOF/VEL 12 Week group 
occurring in more than 1 subject was decreased lymphocytes (1.1%, 3 of 276 subjects). 
One subject had normal lymphocytes throughout treatment and a Grade 3 decrease at the Post-
treatment Week 4 visit. The other 2 subjects had Grade 2 or 3 decreased lymphocytes at baseline 
that transiently decreased by 1 grade during treatment.
The most common Grade 3 or 4 chemistry laboratory abnormalities in both treatment groups 
were increased lipase, increased serum glucose (hyperglycemia), and increased creatine kinase. 
Grade 3 or 4 increases in lipase were reported for 9 subjects (3.3%) in the SOF/VEL 12 Week 


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group and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 increases 
in lipase were asymptomatic, with no cases of clinical pancreatitis. Grade 3 increases in serum 
glucose (hyperglycemia) were reported for 4 subjects (1.4%) in the SOF/VEL 12 Week group 
and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All subjects with Grade 3 increased 
serum glucose had either a medical history of diabetes or HbA1c ≥6.0% at screening. Grade 3 
or 4 increases in creatine kinase were reported for 2 subjects (0.7%) in the SOF/VEL 12 Week 
group and 4 subjects (1.5%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 creatine 
kinase elevations were transient and asymptomatic; the majority were associated with exercise. 
Grade 3 or 4 increases in total bilirubin (hyperbilirubinemia) were observed only in the 
SOF+RBV 24 Week group (Grade 3: 2 subjects, 0.7%; Grade 4: 1 subject, 0.4%). The timing 
and magnitude of the increases in total bilirubin were consistent with RBV-induced hemolysis.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint: subjects with genotype 3 HCV 
infection in the SOF/VEL 12 Week group achieved an SVR12 rate of 95.3% that was 
statistically noninferior to the SVR12 rate of 80.4% achieved by subjects with genotype 3 
HCV infection in the SOF+RBV 24 Week group.
The superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks 
for SVR12 was also demonstrated (p < 0.001).

Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. 
For subjects with cirrhosis, the SVR12 rates (SOF/VEL 12 Weeks vs. SOF+RBV 
24 Weeks) were 91.3% and 66.3%, respectively.
For treatment-experienced subjects, the SVR12 rates (SOF/VEL 12 Weeks vs.
SOF+RBV 24 Weeks) were 90.1% and 63.4%, respectively.

Among the 16% of SOF/VEL-treated subjects with baseline NS5A RAVs, the SVR12 rate 
was numerically lower (88%) compared with subjects without baseline NS5A RAVs 
(SVR12 rate of 97%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
discontinuations due to AEs, or clinically relevant laboratory abnormalities were observed in 
SOF/VEL-treated subjects.


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1.7.
Study GS-US-342-1137 (ASTRAL-4)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of SOF/VEL±RBV for 12 weeks and SOF/VEL for 24 weeks in 
subjects with chronic HCV infection and Child-Pugh-Turcotte (CPT) class B cirrhosis. The study 
was conducted in the US.
Subjects with genotype 1 to 6 HCV infection with CPT class B cirrhosis were randomized 
(1:1:1) to SOF/VEL for 12 weeks (SOF/VEL 12 Week group), SOF/VEL+RBV for 12 weeks 
(SOF/VEL+RBV 12 Week group), or SOF/VEL for 24 weeks (SOF/VEL 24 Week group). 
Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Disposition
A total of 267 subjects were included in the Safety and Full Analysis Sets (90 subjects in the 
SOF/VEL 12 Week group, 87 subjects in the SOF/VEL+RBV 12 Week group, and 90 subjects in 
the SOF/VEL 24 Week group).
Of the 90 subjects in the SOF/VEL 12 Week group, 89 subjects (98.9%) completed study drug 
and 1 subject (1.1%) discontinued due to an AE.
Of the 87 subjects in the SOF/VEL+RBV 12 Week group, 82 subjects (94.3%) completed study 
drug; 4 subjects (4.6%) discontinued due to AEs and 1 subject (1.1%) discontinued due to 
virologic failure (pharmacokinetic [PK] data for this subject indicated noncompliance with study 
drugs).
Of the 90 subjects in the SOF/VEL 24 Week group, 84 subjects (93.3%) completed study drug; 
4 subjects (4.4%) discontinued due to AEs, 1 subject (1.1%) discontinued due to virologic 
failure, and 1 subject (1.1%) discontinued due to noncompliance with study drug.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across the treatment 
groups. Of the 267 subjects randomized and treated, 207 subjects (77.5%) had genotype 1 HCV 
infection, 12 subjects (4.5%) had genotype 2 HCV infection, 39 subjects (14.6%) had genotype 3 
HCV infection, 8 subjects (3.0%) had genotype 4 HCV infection, and 1 subject (0.4%) in the 
SOF/VEL 24 Week group had genotype 6 HCV infection. The majority of subjects were male 
(69.7%), and 42.3% of subjects had a BMI 30 kg/m2. Most subjects (55.1%) had prior 
treatment experience and the majority of subjects had HCV RNA ≥800,000 IU/mL (55.8%).
Efficacy Results
The SVR12 rates were as follows:

SOF/VEL 12 Week group: 83.3% (95% CI: 74.0% to 90.4%) of subjects (75 of 90) achieved 
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
SOF/VEL+RBV 12 Week group: 94.3% (95% CI: 87.1% to 98.1%) of subjects (82 of 87) 
achieved SVR12

SOF/VEL 24 Week group: 85.6% (95% CI: 76.6% to 92.1%) of subjects (77 of 90) achieved 
SVR12
All 3 treatment groups met their primary efficacy endpoints with SVR12 rates that were
statistically superior compared with the assumed spontaneous rate of 1%. The p-value 
was < 0.001 for the comparison with the SVR12 for each treatment group. 
Among subjects with genotype 1 HCV infection, the SVR12 rate was higher for those in the 
SOF/VEL+RBV 12 Week group (95.6%, 65 of 68) compared with the SOF/VEL 12 Week group 
(88.2%, 60 of 68) or the SOF/VEL 24 Week group (91.5%, 65 of 71). Similarly, among subjects 
with genotype 3 HCV infection, the SVR12 rate was higher for those in the SOF/VEL+RBV 
12 Week group (84.6%, 11 of 13) compared with the SOF/VEL 12 Week group (50.0%, 7 of 14) 
or the SOF/VEL 24 Week group (50.0%, 6 of 12).
All subjects with genotype 2, 4, or 6 HCV infection achieved SVR12 across all treatment groups 
with the exception of 1 subject with genotype 2 HCV infection in the SOF/VEL 24 Week group 
who died 39 days after completing 28 days of treatment.
Most virologic failures were due to relapse. One subject with genotype 3 HCV infection in the 
SOF/VEL+RBV 12 Week group had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug and 1 subject with 
genotype 3 HCV infection in the SOF/VEL 24 Week group had on-treatment breakthrough.
There was 1 subject (1.5%) with genotype 1 HCV infection with virologic failure in the 
SOF/VEL+RBV 12 Week group compared with 5 subjects (7.4%) in the SOF/VEL 12 Week 
group and 3 subjects (4.2%) in the SOF/VEL 24 Week group. Among subjects with genotype 3 
HCV infection, the lowest rate of virologic failure was observed in the SOF/VEL+RBV 12 Week 
group with 2 failures (15.4%) compared with 6 (42.9%) in the SOF/VEL 12 Week group and 
5 (41.7%) in the SOF/VEL 24 Week group. 
There were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection in any of the 
treatment groups.
Treatment with SOF/VEL+RBV for 12 weeks resulted in high SVR12 rates irrespective of 
genotype, prior treatment history, baseline HCV RNA, and presence of pretreatment NS5A or 
NS5B RAVs. Furthermore, there was no impact of demographic factors such as age, sex, BMI, 
or IL28B genotype on treatment outcome in the SOF/VEL+RBV 12 Week group.
Overall, 108 subjects (47.2%) had an improvement in CPT score (range: 1−5 points) while 
99 subjects (43.2%) had no change. A minority of subjects (9.6%, 22 subjects) experienced an 
increase (worsening) in CPT score from baseline to Post-treatment Week 12. A higher 
percentage of subjects receiving SOF/VEL for 24 weeks (54.7%) compared with subjects 
receiving SOF/VEL±RBV for 12 weeks (40.7%−46.6%) had improvements in CPT score from 


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baseline to Post-treatment Week 12; this difference likely reflects the longer time of observation 
with HCV RNA suppression. The improvements in CPT score were largely due to improvements 
in bilirubin and albumin. 
Overall, the majority of subjects who achieved SVR12 also had a decrease (improvement) 
(55.5%, 127 of 229 subjects) in MELD score between baseline and Post-treatment Week 12 
(range: 1−11 points). Among subjects who had MELD score < 15 at baseline and achieved 
SVR12, 197 of 203 subjects (97.0%) remained < 15 at Post-treatment Week 12. A total of 
16 subjects (61.5%) with baseline MELD score ≥15 who achieved SVR12 improved to < 15. 
Improvements in MELD score were largely due to improvements in total bilirubin.
Virologic Resistance
Pretreatment NS5A RAVs were observed in 26% to 29% of subjects across the treatment groups. 
The presence of pretreatment NS5A RAVs did not impact treatment outcome in the 
SOF/VEL+RBV 12 Week group. Slightly lower SVR rates were observed in subjects with 
genotype 1 HCV infection with NS5A RAVs treated with SOF/VEL for 12 or 24 weeks 
compared to subjects without pretreatment NS5A RAVs. No virologic failures were observed in 
subjects with genotype 2, 4, or 6 HCV infection. The small numbers of subjects with genotype 3 
HCV infection with pretreatment NS5A RAVs precluded meaningful subgroup analysis. The 
presence of pretreatment NS5B RAVs did not impact treatment outcome in any treatment group.
The majority of subjects had NS5A RAVs present at virologic failure with Y93H being the most 
common variant. NS5B NI RAVs were less common and typically observed at low levels. Of the 
9 subjects with genotype 1 HCV infection with virologic failure, 6 had NS5A RAVs at failure 
(5 treatment emergent and 1 maintained from pretreatment). Two genotype 1 HCV-infected 
subjects had L159F and S282T NS5B NI RAVs present at failure; both of these subjects had 
multiple NS5A RAVs at pretreatment that reduce susceptibility to VEL. All 13 subjects with 
genotype 3 HCV infection with virologic failure had Y93H at failure (10 were treatment 
emergent). Three genotype 3 HCV-infected subjects had low levels of NS5B NI RAVs emerge at 
virologic failure.
Safety Results
Overall, treatment with SOF/VEL±RBV for 12 weeks or SOF/VEL for 24 weeks was generally 
safe and well tolerated. Adverse events were consistent with the expected clinical sequelae in the 
setting of decompensated cirrhosis and, in addition, with the known toxicities of RBV in the 
SOF/VEL+RBV 12 Week group.
A smaller percentage of subjects in the SOF/VEL 12 Week and SOF/VEL 24 Week groups 
experienced any AE (81.1% in each group) compared with the SOF/VEL+RBV 12 Week group 
(90.8%). The higher frequency of AEs observed in the SOF/VEL+RBV 12 Week group was 
primarily due to AEs consistent with RBV-associated toxicity. No treatment-related Grade 3 AEs 
were reported in > 1 subject in any group or overall. 


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Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Overall, the most commonly 
reported Grade 3 or 4 AEs were hepatic encephalopathy and sepsis (5 subjects each), which are 
consistent with the natural history of disease progression in a population with decompensated 
liver disease. 
Serious adverse events (SAEs) occurred in 17.6% of subjects in similar proportions across 
treatment groups, and only 1 subject (0.4%) experienced SAEs considered related to SOF/VEL. 
The most commonly reported SAEs were hepatic encephalopathy and sepsis (5 subjects each). 
Nine deaths occurred during the study, 2 of which were treatment emergent, and none of which 
was assessed as related to study drugs. One subject in the SOF/VEL 24 Week group underwent a 
liver transplantation on Post-treatment Day 8 after completing 35 days of treatment.
Nine subjects discontinued all study drugs due to an AE (SOF/VEL 12 Week group: 1.1%, 
1 subject; SOF/VEL+RBV 12 Week group: 4.6%, 4 subjects; SOF/VEL 24 Week group: 4.4%, 
4 subjects). No AE leading to discontinuation of study drugs was reported in > 1 subject. A total 
of 31.0% (27 of 87) of subjects had modified or interrupted RBV dosing due to AEs, and 10.3% 
(9 of 87) of subjects permanently discontinued RBV due to AEs while continuing SOF/VEL.
The majority of subjects had at least 1 Grade 3 or 4 laboratory abnormality (42.7% and 12.4%, 
respectively) with the highest rates observed in the SOF/VEL+RBV group (Grade 3: 43.7%; 
Grade 4 18.4%) due to a higher rate of hematologic abnormalities. The most commonly observed 
Grade 3 or 4 hematology laboratory abnormalities were decreased lymphocytes, hemoglobin, 
and platelet counts, all of which are a known effect of RBV therapy or expected in a subject 
population with decompensated liver disease. 
The most commonly observed Grade 3 or 4 chemistry laboratory abnormalities were increased 
glucose and increased total bilirubin. All of the Grade 3 or 4 increased glucose abnormalities 
occurred in subjects with a history of diabetes mellitus or had elevated glucose at baseline or 
continuing through the Post-treatment period. The majority of subjects with Grade 3 or 4 
increased total bilirubin (71.7%, 22 of 31 subjects) were in the SOF/VEL+RBV 12 Week group, 
primarily in a pattern that was consistent with RBV-induced hemolysis. 
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study. No trends in electrocardiogram findings suggestive of 
cardiotoxicity were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

Treatment with SOF/VEL±RBV for 12 or 24 weeks in subjects with decompensated cirrhosis 
resulted in high SVR12 rates:
In the SOF/VEL 12 Week group, the SVR12 rate was 83.3% (75 of 90 subjects).
In the SOF/VEL+RBV 12 Week group, the SVR12 rate was 94.3% (82 of 87 subjects).
In the SOF/VEL 24 Week group, the SVR12 rate was 87.8% (79 of 90 subjects).


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
The SVR12 rates were highest in subjects treated with SOF/VEL+RBV for 12 weeks with 
few virologic failures:
In subjects with genotype 1 HCV infection, the virologic failure rate was 1.5% (1 of 
68 subjects).
In subjects with genotype 3 HCV infection, the virologic failure rate was 15.4% (2 of 
13 subjects), of which 1 subject had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug.

Overall, there were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection.

The SVR12 rates between the SOF/VEL 12- and 24-week treatment durations were similar 
across all genotypes.

The presence of pretreatment NS5A and NS5B RAVs did not impact treatment outcome with 
SOF/VEL+RBV for 12 weeks.

Approximately half of subjects who achieved SVR12 experienced an early improvement in 
CPT and MELD scores, primarily related to improvements in synthetic function (albumin) 
and decreases in bilirubin.

SOF/VEL was generally well tolerated in these subjects with decompensated liver disease, as 
evidenced by low rates of study treatment discontinuation and the majority of Grade 3 and 4 
AEs, SAEs, and laboratory abnormalities being consistent with clinical sequelae of advanced 
liver disease and RBV toxicity.
1.8.
Rationale for This Study
This is a Phase 2 study designed to evaluate the efficacy and safety of the SOF/VEL tablet
administered for 4 weeks to subjects starting in the perioperative period of liver transplantation.
After transplantation, recurrence of HCV infection occurs in almost all patients {Feray et al 
1992}, {Wright et al 1992} who have HCV RNA detectable prior to transplantation. HCV 
recurrence is associated with cirrhosis, fibrosing cholestatic hepatitis, graft loss, liver re-
transplantation, and death {Prieto et al 1999}, {Wiesner et al 2003}, {Berenguer et al 2002},
{Gane et al 2008}, {Crespo et al 2012}, {Charlton et al 2014}, {Berenguer et al 2000}, {Forman 
et al 2002}, {Firpi et al 2009}. HCV RNA levels fall significantly in the anhepatic phase of liver 
transplantation and continue to fall during the first 12-24 hours post transplantation. Serum HCV 
RNA then begin to rise rapidly from the second post-operative week and peak by the fourth 
month {Charlton 2003}.
Deposition of fibrotic tissue in most HCV transplanted livers is highly accelerated with the
development of bridging fibrosis and cirrhosis in 20-54% at 5 years and 32-51% at 7 years
{Berenguer et al 2013}. Once cirrhosis is established, the probability of liver graft failure is 42% 
within 12 months {Berenguer et al 2002}.


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There is great advantage to administering a well-tolerated direct acting antiviral without the use
of PEG-IFN or RBV in the immediate postoperative period while the HCV RNA virus is at its
lowest level. We hypothesize that the time period prior to re-infection is unique and mimics that
of acute infection, as the nidus of HCV chronic infection (pretransplant liver) has been removed.
For this reason, we believe that a short course of therapy (eg, 4 weeks), is likely to be successful. 
If the progression of the HCV virus can be halted before the progressive liver fibrosis activity is 
initiated both the new graft and the patient stand a greater chance of survival.
Additionally, patients who start HCV treatment pre-transplant may not have time to complete the
full duration of treatment when a liver becomes available. The results of this study can inform on
the safety and efficacy of continuing SOF/VEL treatment through transplantation.
1.8.1.
Rationale for the Dose of SOF/VEL
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without Peg-IFN
has demonstrated broad genotypic efficacy and favorable safety profile in over
1700 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials. This 
dose is the approved marketed dose of sofosbuvir for the treatment of HCV-infection and, as 
such, was selected for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg was administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. VEL 100 mg was selected for co-formulation with 
SOF based on the Phase 2 safety, PK and antiviral activity (studies GS-US-342-0102, 
GS-US-342-0109, and GS-US-337-0122 [Cohort 4]). The Phase 1 study GS-US-281-0102 
established the anti-HCV activity of VEL and indicated that the exposures achieved following 
administration of doses > 25 mg provide at least 80% of maximal antiviral response in all HCV 
genotypes. SOF/VEL (400 mg /100 mg) as a FDC tablet was evaluated in the phase 3 ASTRAL 
program.
The favorable safety and efficacy profiles of SOF 400 mg and VEL 100 mg support further 
evaluation of this combination and doses in clinical development.
1.9.
Risk/Benefit Assessment for the Study
The regimen to be assessed in this study combines a potent HCV nucleotide inhibitor with a 
potent HCV NS5A inhibitor in patients who are in the immediate post-transplant operative 
period. This study will provide information of the safety and efficacy of SOF/VEL, a potent 
HCV nucleotide inhibitor and a potent HCV NS5A inhibitor. This combination has the potential 
to be the first once-daily, PEG-free, RBV-free, pangenotypic regimen for the treatment of 
chronic HCV infection in patients who have received a liver transplant. The potential benefits of 
early treatment in the peritransplant period with SOF/VEL:

The once-daily, single tablet, short duration, pangenotypic HCV regimen would offer a 
simple algorithm for patients infected with HCV undergoing liver transplants, regardless of 
genotype

A short duration of therapy which should lead to better outcomes through improved 
adherence.


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The safety profile of SOF in clinical studies includes over 1700 chronic HCV-infected subjects
that have been administered 12 weeks of SOF and RBV+/-Peg-IFN. No clinical safety issues
specifically related to SOF have been identified to date
The safety profile of SOF + VEL 25mg or VEL 100mg administered for 8 or 12 weeks has been 
established in over 800 patients in Phase 2 studies. The safety profile of the proposed therapeutic 
regimen of SOF 400 mg and VEL 100 mg administered for 12 weeks has been established in 
237 subjects enrolled in Phase 2 studies.  No clinical safety issues specifically related to VEL or 
SOF + VEL have been identified to date. No clinical safety issues specifically related to the 
NS5A inhibitor class including daclatasvir (DCV) and LDV have been identified to date {Afdhal 
et al 2014a}, {Afdhal et al 2014b}, {Kowdley et al 2014}.
The safety profile of SOF/VEL has been studied in 4 Phase 3 trials (ASTRAL 1-4) in 1302 
patients.  Twelve weeks of SOF/VEL was generally well tolerated, and lead to a similar 
incidence of AEs and SAEs compared to placebo in patients with GT 1, 2, 4, 5, or 6 HCV (See 
Section 1.2.2.1). When 12 weeks of SOF/VEL was compared to SOF + RBV for 12 weeks in 
patients with GT2 or 3 HCV, therapy with SOF/VEL was again well tolerated with few 
differences in AEs or SAEs, minus the avoidance of RBV associated toxicities (See 
Section 1.2.2.2).  Patients who received SOF/VEL for either 12 or 24 weeks with decompensated 
cirrhosis experienced AEs and SAEs typical for patients with decompensated cirrhosis in no 
pattern that could be attributed to study drug. Patients with decompensated cirrhosis who 
received SOF/VEL + RBV for 12 weeks also experienced AEs and SAEs consistent with 
underlying liver disease as well as toxicities expected with RBV treatment.
In summary, there is currently no approved treatment for patients with recurrent HCV
posttransplantation. Treatment during the time period prior to re-infection may be unique and 
mimics that of acute infection, as the nidus of HCV chronic infection (pretransplant liver) has 
been removed. Thus this may offer an opportunity for a short course of therapy (eg, 4 weeks), to 
be successful. If high rates of SVR can be obtained with a short, IFN-free, RBV-free, 
pangenotypic regimen in the peri-operative period, this would render the patient’s new liver graft 
free from HCV and the sequelae of events towards end stage liver disease post transplantation 
could be avoided.
During the conduct of this study, the sponsor together with the investigator will perform ongoing 
safety review.
1.10.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The primary objectives ofthis study are: 
Original 
• 
To explore the antiviral efficacy oftreatment with SOF/VEL FDC therapy administered for 
four weeks following liver transplantation as measured by sustained virologic response 
12 weeks after cessation oftreatment (SVR12) 
• 
To evaluate the safety and tolerability of SOF/VEL in HCV-infected subjects in the peri-
operative and post-transplant period 
The secondary objectives ofthis study are: 
• 
To determine the percentage of subjects who attain SVR at 4 weeks after cessation of 
treatment (SVR4) 
• 
To evaluate the proportion of subjects with virologic failure 
• 
To assess rates of graft survival, graft function, acute rejection and immunosuppressive 
therapy during treatment with SOF/VEL 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation oftreatment 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To characterize pharmacokinetics of SOF/VEL 
The exploratory objectives ofthis study are: 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The primary efficacy endpoint is SVR12 (HCV RNA < lower limit of quantification [LLOQ] 
12 weeks after the date of last dose of study drug) for subjects in the Full Analysis Set.
The secondary endpoint of this study is:

The proportion of subjects with HCV RNA < LLOQ at 4 weeks after cessation of treatment 
(SVR4)

The proportion of subjects with HCV RNA < LLOQ on treatment

The proportion of subjects with virologic failure (defined as HCV RNA ≥ LLOQ at end of 
treatment or relapse during Post-treatment follow-up)
3.2.
Study Design
This is an open-label study that will evaluate the safety, tolerability and antiviral efficacy of 
SOF/VEL administered for 4 weeks in HCV-infected adult male and female subjects who are 
undergoing liver transplantation.
HCV RNA will be assessed at each visit.
3.3.
Study Treatments
For all subjects SOF/VEL tablet (400 mg/100 mg) once daily will be started the day of the 
subject’s liver transplant if the transplant is completed before noon and the following day if it is 
completed after noon and will continue for 4 weeks. The planned first dose may be delayed for 
up to 1 day if, in the investigators opinion, delay is in the subject’s medical interest. The subject 
will receive 4 weeks of study drug.
3.4.
Visit Schedule 
All subjects will complete the following study visits: Screening; Pre-surgery (if needed); 
On-Treatment visits Days 1, 3, 5, 7, 14, 21, and 28; and Post-treatment Visits at Weeks 1, 2, 4, 
and 12 following the last dose of study drug.
Screening assessments will be completed at the time a subject is identified as a potential study 
participant to give sufficient time for the subject to provide informed consent and perform 
screening assessments. Subject’s screening data will be confirmed in the pre-operative period 
(within 48 hours of the planned transplant) at the Pre-surgery visit if the screening visit occurs 
more than 48 hours before the liver transplant surgery is started.


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If a separate informed consent is signed, samples of the explanted liver will be taken during 
surgery.
The assessments performed at each visit are described in Section 6 and Appendix 2.
3.5.
Discontinuation Criteria
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7.6 of the protocol, 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

If a subject experiences graft dysfunction (including primary graft non-function) requiring 
relisting for liver transplant, treatment will be stopped

If subject is relisted for transplantation for any reason treatment will be stopped

Subject receives a 2nd liver transplant while on study treatment

Pregnancy of female subject

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Discontinuation of the study at the request of Gilead, regulatory agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
If a subject meets discontinuation criteria during treatment, an Early Termination visit will be 
required (Section 6.4) Subjects who permanently discontinue all study drugs for any reason 
including safety and/or tolerability concerns prior to completion of the assigned dosing period 
will be followed according to the Post-treatment study assessments to determine whether the
subject achieves SVR.
3.6.
Subject Stopping Rules
The Gilead Medical Monitor must be consulted prior to discontinuation of study drug unless the
investigator believes that immediate action is warranted to ensure the continued safety of the
subject.
Administration of study medication may be discontinued due to a clinical or laboratory event.
There is no option for SOF/VEL dose reduction. If SOF/VEL is stopped due to toxicity, it must


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not be restarted and the subject must complete an ET visit. Any interruptions of study medication 
must be discussed with the Sponsor Medical Monitor prior to restarting. 
Subjects who meet any of the following laboratory or medical criteria must stop all study 
medication(s): 
• 
Any medical condition (in the opinion of the Medical Monitor) for which the risks of 
treatment outweigh the benefits 
• 
Commencement of dialysis 
• 
Any Grade 3 or greater rash associated with constitutional symptoms 
• 
Any Grade 4 adverse event assessed as related to SOF/VEL 
3.7. 
End of Study 
Subjects are considered to have completed the study after the Post-treatment Week 12 follow-up 
visit, regardless of treatment duration, unless the subject early terminates because HCV RNA is 
2: LLOQ. If the subject terminates early due to HCV RNA 2: LLOQ, the subject will complete 
the post treatment Week 4 visit as their final visit. 
3.8. 
Sub studies 
3.8.1. 
Optional Archive Sample 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 10 subjects with chronic HCV awaiting liver transplantation will be enrolled.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening
assessments performed.
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 provide written informed consent or for those subjects where hepatic 
encephalopathy affects their ability to provide initial or ongoing consent, has an appropriate 
and legally-authorized representative (LAR) willing and able to provide consent on behalf of 
the subject.
2) Male or female, age 18 years 
3) HCV RNA infection with quantifiable virus at Screening or documented in the patient’s 
medical record.
4) Chronic HCV infection (≥ 6 months) as documented by either prior medical history or liver 
biopsy
5) Currently on the liver transplantation wait list (both transplant from deceased or living donor
will be considered acceptable)
6) Screening ECG without clinically significant abnormalities.
7) A negative serum pregnancy test is required for female subjects (unless surgically sterile or 
greater than two years post-menopausal; see Appendix 4 for definitions).
8) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 4.  
9) Male subjects must agree and refrain from sperm donation from the date of screening until at 
least 30 days after the last dose of study drug.
10) Lactating females must agree to discontinue nursing before the study drug is administered.


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11) Subject must be able to comply with the dosing instructions for study drug administration 
and be able to complete the study schedule of assessments, including all required Post-
treatment visits.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Receipt of an HCV infected liver
2) Any serious or active medical or psychiatric illness which, in the opinion of the investigator, 
would interfere with subject treatment, assessment, or compliance
3) HIV infection or a positive hepatitis B virus surface antigen result 
4) Current malignancy (with exception of HCC within local listing criteria, certain resolved skin 
cancers or other early cancer for which surgical resection is considered to be completely 
curative)
5) Treatment with any approved or experimental medication with known anti-HCV activity 
within 1 month prior to screening date
6) Prior exposure to a HCV NS5B nucleotide/side inhibitor including SOF or to an HCV NS5A 
inhibitor
7) Patients on hemodialysis prior to or at the time of transplantation will be excluded
8) Participation in a clinical study with an investigational drug or biologic within 28 days prior 
to screening visit, unless information on the investigational drug is available to indicate that 
there is no potential drug interaction (safety or efficacy)
9) Use of any prohibited concomitant medications as described in Section 5.3.Known 
hypersensitivity to the SOF, VEL, the metabolites, or formulation excipient.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of SOF/VEL FDC
5.1.1.
Formulation
The SOF/VEL (400 mg/100 mg) FDC tablets are pink, diamond-shaped, film-coated tablets, 
debossed with “GSI” on one side and “7916” on the other side. In addition to the active 
ingredients, the SOF/VEL tablets contain copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
iron oxide red.
5.1.2.
Packaging and Labeling
SOF/VEL (400 mg/100 mg) FDC tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
SOF/VEL bottles to be distributed to centers in participating countries shall be labeled to meet 
all applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products),
and/or other local regulations.
5.1.3.
Storage and Handling
SOF/VEL FDC tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77 F); excursions are permitted 
between 15C and 30C (59F to 86F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL tablets.
Sufficient quantities of SOF/VEL FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from the Gilead Clinical Supply Management Team (or its 
designee).


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5.2.
Dosage and Administration of SOF/VEL FDC
SOF/VEL tablet is to be administered once daily with or without food. Each subject must be 
given instructions to maintain approximately the same daily dosing interval between study drug 
doses. If the subject is unable to swallow the SOF/VEL tablet, the tablet may be crushed and 
delivered by nasograstric tube.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose of 
study medication as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances.
5.3.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, up to and including 30 days 
after the last dose of study need to be recorded in the source documents and eCRFs.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (such as substrates, 
inhibitors or inducers of drug transporters or metabolizing enzymes, eg, P-gp or CYP3A) with 
the study drug may result in pharmacokinetic interactions resulting in increases or decreases in 
exposure of the study drug or these medications.
Table 5-1 below contains medications that are prohibited from 21 days prior to Day 1 through 
the end of treatment and those medications that may be used with caution. The use of 
amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment.


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Table 5-1.
List of Disallowed /Use with Caution Medications
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medicationsc
Amiodaroned
Diltiazem, Verapamil, Dronedarone, 
Quinidine, Ranolazine, Bosentan, 
Olmesartan, Valsartan, Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea. Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day)
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
Proton pump inhibitor (PPI) doses comparable with omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL 
is administered with food. H2-receptor antagonists must not exceed a dose of 40 mg famotidine or equivalent and can be 
taken simultaneously with SOF/VEL and/or staggered by 12 hours. Antacids that directly neutralize stomach acid (ie Tums, 
Maalox) may not be taken within 4 hours (before or after) of SOF/VEL administration.
b
May result in a decrease in the concentration of study drugs.
c
May result in an increase in the concentration of study drugs and/or concomitant medications
d
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment
e
Monitor for signs and symptoms of digoxin toxicity. 
f
Use with SOF/VEL may result in an increase in the concentration of HMG-CoA Reductase Inhibitors, rosuvastatin. Monitor 
for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (eg, HIV infection) are not listed 
under this Concomitant Medication section and are disallowed in the study.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must 
notify Gilead as soon as he/she is aware of the use of the excluded medication.
5.4.
Accountability for SOF/VEL FDC
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug (SOF/VEL FDC). This includes acknowledgement 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.


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SOF/VEL accountability records will be provided to each study site to:

Record the date received and quantity of study drug shipments

Record the date, subject number, subject initials, the study drug bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
Subjects must be instructed to bring back all study drugs in the original container at every post-
Day 1 study visit through the end of treatment.
5.4.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and Return.


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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 study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit/Pre-Surgery
Subjects will be initially screened to determine their eligibility for participation in the study 
(they are required to be on the waitlist for liver transplantation). If the screening visit occurs 
more than 48 hours before the liver transplant surgery is started, the subject will also be 
reassessed within 48 hours of transplantation to determine their continued eligibility at the pre-
surgery visit.
Screening period is the time from initial screen (ie, identification of the subject as being on the 
liver transplant waitlist and potentially meeting inclusion/exclusion criteria for the study) until 
administration of the first dose of study treatment.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (eCRF).  All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  See 
Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments
Day 1 will be the morning following the transplant (if the subject is out of transplant before 
12:00 pm the Day 1 dose will occur that day. If the subject is out of transplant after 12:00 pm the 
Day 1 dose will occur the following morning).
6.3.
Treatment Assessments (± 2 days)
Subjects meeting all of the inclusion and none of the exclusion criteria will begin study treatment 
on Day 1. In addition to those assessments listed in the Schedule of Events, study personnel will 
observe the subject taking their first dose of study drug and record the date and time the first 
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For all subjects receiving 4 weeks of therapy, treatment procedures/assessments are to be 
completed on Days 3, 5, 7, 14, 21, and 28 post start of Day 1 treatment. Please refer to 
Appendix 2 for a schedule for assessments.
6.4.
Early Termination (ET) Visit
For subjects who have completed an ET visit, the Post-treatment Weeks 1, 2, and 4, and 12
follow-up visits will be scheduled from the date of the last dose of study drug.
The sponsor (eg, Medical Monitor and Clinical Program Manager)/CRO must be informed as 
soon as possible if a subject discontinues treatment.
6.5.
Unscheduled Visits
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion as clinically indicated, but the investigator should 
at a minimum collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure a Viral RNA Sequencing/ Phenotyping 
Sample must be collected.
The Sponsor (eg, Medical Monitor and Clinical Program Manager)/CRO must be informed, as 
soon as possible, when a subject discontinues treatment.
6.6.
Post-Treatment Assessments
Post-treatment Weeks 1, 2, 4, and 12 visits must be scheduled from the date of the last dose of 
study drug.
Subjects who have HCV RNA ≤LLOQ at end of treatment and do not relapse will complete all 
post-treatment visits at Weeks 1, 2, 4, and 12. Subjects that experience relapse will have 
confirmatory testing as soon as possible and will not be required to complete additional visits.
If a subject must undergo a second transplantation while on study treatment or is relisted for 
transplantation, all study treatment must be stopped.
If a subject is in the Post-treatment follow-up and undergoes a second liver transplant, the subject 
will continue with the follow-up visits from the first transplantation (for the assessment of 
Post-transplant recurrence). If the subject is more than 4 weeks after the last dose of study drug
at the time of the second transplant and had completed the safety follow-up period, it is not 
necessary to resume adverse event collection.
6.7.
Assessments for Premature Discontinuation from Study
Discontinuation from study drug dosing and discontinuation from the overall study including 
follow-up will be collected as two separate events. If a subject discontinues study treatment 
dosing every attempt should be made to keep the subject in the study and continue to perform the 
required study-related follow-up and procedures (see Section 6.6).


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6.8.
End of Study
Subjects are considered to have completed the study after the post-treatment Week 12 visit,
regardless of treatment duration or early termination of study drug.  If the subject terminates 
early due to HCV RNA ≥ LLOQ, the subject may discontinue follow up after the post treatment 
Week 4 visit.
6.9.
Procedures and Specifications
6.9.1.
Central Laboratory Analytes
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, Reticulocyte count and MCV.
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT),
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex Direct Bilirubin if Total is 
abnormal), Glucose, Lipase, Potassium, Sodium, and Gamma-glutamyl transferase (GGT).
Creatinine clearance will be calculated based on the lesser of actual weight and ideal body 
weight.
Urinalysis: Blood, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. Reflex to 
microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV, and HIV. HCV RNA will be measured using the
COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0. HCV genotype
and subtype will be determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0
Assay. Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype should
the above assays become unavailable or is not definitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β -hCG (if positive, requires immediate confirmation
with Serum β –hCG)
6.9.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening up to the day of dosing. This will include information regarding the subject’s HCV 
treatment history.


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6.9.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological.
6.9.4.
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 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.9.5.
MELD Score/Child-Pugh Score
MELD Score and Child-Pugh-Turcotte score should be assessed at Screening and on Day 1.
Table 6-1.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
Points
1
2
3
Encephalopathy
None
Grade 1-2
(medication-controlled)
Grade 3-4
(medication-refractory)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
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
Note: if the either ascites or encephalopathy is “none” because the patient is taking medication which has controlled the 
symptoms, the scoring should be 2 points (not 1 point).
CPT score is obtained by adding the points for each parameter
CPT class is scored as: 
A = 5-6 points
B = 7-9 points
C = 10-15 points


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MELD Score Calculation
The MELD score is calculated as:
10 × {[0.957 × Ln(Scr)] + [0.378 × Ln(Tbil]) + [1.12 × Ln(INR)] + 0.643)}
Where Scr = serum creatinine (in mg/dL), Tbil = Total Bilirubin (in mg/dL), INR = international 
normalized ratio, and Ln = natural log. If any lab value is less than 1.0, then set to 1.0 in the 
calculation. If the subject received dialysis at least twice in the past week, then Scr is set to 4.0 
mg/dL in the above formula. The result will be rounded to the nearest whole number.
For the components of the MELD score and the components of the CPT score which are based
on laboratory values, the data will be obtained from the central laboratory, and the scores will be
calculated within the clinical database.
6.9.6.
Creatinine Clearance (CrCL)
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976}. 
Creatinine clearance will be calculated based on the lesser of actual weight and ideal body 
weight.
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.9.7.
Ideal Body Weight (IBW)
Estimated ideal body weight in (kg)
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet
6.9.8.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI =
weight (pounds) 703
(height in inches)2
or
weight (kilograms)
(height in meters)2


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6.9.9.
12-Lead ECGs
Subjects will be required to rest in a supine position for ≥5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject’s 
Day 1 as part of routine safety monitoring.
6.9.10.
Pharmacokinetic (PK) Sample
Single PK blood samples will be collected at each on-treatment visit for all subjects except on 
Days 1, 3 and 5. PK analysis of SOF (and its metabolites GS-566500 and GS-331007), and VEL
may be conducted.
The exact date and time of the most recent dose of SOF/VEL taken prior to collection of the PK 
sample and the exact date and time the PK sample is drawn will be recorded on the appropriate 
eCRF.
All subjects will also be required to participate in an intensive PK sub-study (samples obtained 
over 24 hours) on Day 1 post-transplant. Serial PK samples will be collected at the following 
time points: 0 (pre-dose), 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. The PK of SOF, its 
metabolites GS-566500 and GS-331007, and VEL will be assessed.
Detailed regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.9.11.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and at each visit for viral sequence analysis. At any 
unscheduled visit initiated for the purpose of confirming virologic breakthrough or relapse, a 
plasma sample for viral sequence analysis must be collected. Untested samples may be archived.
Details regarding the collection, processing, and shipping of samples will be included in the lab
manual.
6.9.12.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing at the Screening/pre-
surgery visit, and Day 28 during the dosing period and for 30 days following the last dose of 
study drug. In the event of a positive urine pregnancy result, subjects will be instructed to stop 
study drugs immediately (if applicable) and return to the clinic as soon as possible for a serum 
pregnancy test.


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


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


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the 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
Severity should be recorded and graded according to the GSI Grading Scale for Severity of AEs
and Laboratory Abnormalities (Appendix 3). For AEs associated with laboratory abnormalities,
the event should be graded on the basis of the clinical severity in the context of the underlying
conditions; this may or may not be in agreement with the grading of the laboratory abnormality.
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, only those SAEs and adverse 
events related to protocol-mandated procedures should be reported on the case report form 
(eCRF).
Adverse Events
All AEs, expect those described in Section 7.5, regardless of cause or relationship, that occur 
from initiation of study medication until 30-days after last administration of study drug must be 
reported to the eCRF database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, except those described in Section 7.5, regardless of cause or relationship, that occur 
from initiation of study medication until 30 days after last administration of study drug, must be 
reported to the eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-associated procedures performed after 
informed consent is signed.
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 


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concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and repmt the event to Gilead DSPH. 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infmmation to Gilead DSPH within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infmmation electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event repmting 
fmm and submit within 24 hours to: 
GileadDSPH 
Gilead Medical Monitor 
Email: 
Fax: 
Name: 
Phone: 
Fax: 
Email: 
Safety_ FC@gilead.com 
+ 1 650-522-5477 
• 
As soon as it is possible to do so, any SAE repmted via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmted via a paper fmm because the eCRF database has been locked, no 
ftuther action is necessruy. 
• 
For fatal or life-threatening events, copies of hospital case repmts, autopsy repmts, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repmts. 
• 
Any medications necessmy for tJ.·eatJ.nent of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, 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 
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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Reporting Requirements for Liver Transplant and Complications of Liver
Transplant
Due to the nature of the subject population and the inclusion criteria, events that are clearly 
related to liver transplant should not be collected or reported as AEs and SAEs. In addition, these 
events will be exempt from global expedited reporting requirements for the duration of the study. 
These include:
1) The liver transplant procedure itself (and related hospitalization)
2) Events that are direct sequelae of the liver transplant or peri-operative care (central line 
insertions, etc)
3) Planned hospitalizations for testing or procedures that are part of the liver transplant
assessment and preparation process
These events should be reported as AEs/SAEs only if it is assessed that the events (including 
transplant itself) were not an anticipated or predictable part of the underlying disease transplant 
process or procedure. Events that are considered possibly or probably related to study medication 
must be reported using the usual reporting procedures, as described in Section 7.3. In addition, 
concomitant medications related to the transplant procedure do not need to be recorded 
(anesthetics, peri-operative pain medication, etc). If there are any questions about how an event 
should be reported, please contact the study Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.3 and 7.4. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 


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Original 
Pregnancies of female partners of male study subjects exposed to Gilead or other study dmgs 
must also be repotted and relevant information should be submitted to Gilead DSPH 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 rep01ted directly to Gilead DSPH, fax munber 
+1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 4 for Pregnancy Precautions, Defmition for Female of Childbearing Potential, 
and Contraceptive Requirements. 
7.6.2.2. 
Rep01ting Other Special Situations 
All special situations rep01ts (SSRs) will be recorded in the CRF/eCRF database within the 
timelines outlined in the CRF/eCRF completion guideline. 
Electronic Special Situations Rep01i ( eSSR) Rep01ting Process 
• 
Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
inf01mation to Gilead DSPH within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SSR inf01mation electronically, i.e., the eCRF 
database is not fimctioning, record the SSR on the paper serious adverse event rep01iing f01m 
and subtnit within 24 hours to: 
GileadDSPH 
Email: 
Fax: 
Gilead Medical Monitor 
Name: 
Phone: 
Fax: 
Email: 
Safety _FC@gilead.com 
+ 1 650-522-5477 
Benedetta Massetto 
PP9PPD 
Pa ppo 
1-'PLJ 
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF 
Database according to instmctions in the eCRF completion guidelines. 
If an SSR has been rep01ted via a paper f01m because the eCRF database has been locked, no 
fmiher action is necessruy. 
These rep01ts must consist of situations that involve study IMP ru1dlor Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
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Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a non-
Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives ofthis study are: 
Original 
• 
To explore the antiviral efficacy of treatment with SOF/VEL FDC therapy administered for 
four weeks following liver transplantation as measured by sustained virologic response 
12 weeks after cessation oftreatment (SVR12) 
• 
To evaluate the safety and tolerability of SOF/VEL in HCV-infected subjects in the peri-
operative and post-transplant period 
The secondary objectives ofthis study are: 
• 
To determine the percentage of subjects who attain SVR at 4 weeks after cessation of 
treatment (SVR4) 
• 
To evaluate the proportion of subjects with virologic failure 
• 
To assess rates of graft survival, graft function, acute rejection and immunosuppressive 
therapy during treatment with SOF/VEL 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation oftreatment 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To characterize pharmacokinetics of SOF/VEL 
The exploratory objectives ofthis study are: 
PPD 
8.1.2. 
Primary Endpoint 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of 
treatment) for subjects in the Full Analysis Set (F AS). 
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8.1.3.
Secondary Endpoint
Secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 weeks after cessation of treatment 
(SVR4)

The proportion of subjects with HCV RNA < LLOQ on treatment

The proportion of subjects with virologic failure (defined as HCV RNA ≥ LLOQ at end of 
treatment or relapse during Post-treatment follow-up)
8.1.4.
Safety Endpoint
The primary safety endpoint is any AE leading to premature discontinuation of study drug. Other 
important safety endpoints include deaths, graft losses, and rejection episodes.
8.1.5.
Other Endpoints of Interest
Other endpoints of interest include changes to immunosuppression and the emergence of viral 
resistance to SOF or VEL during and after treatment discontinuation, and HCV RNA levels 
(IU/mL) at each on-treatment visit, if relevant. 
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
The study drug in this study is SOF/VEL. Last dose of study drug will be used in the definition 
of treatment emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various posttreatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the FAS which includes subjects who were 
enrolled into the study, received a liver transplant while on study, and took at least one dose of 
study drug.
8.2.1.2.
Safety
The analysis set for safety analyses will include all subjects who took at least one dose of study 
drug.


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All safety data collected from the first dose of any study drug (including the perioperative dose 
of SOF/VEL) through the date of last dose of study drug plus 30 days will be included in safety 
summaries, unless otherwise specified.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include subjects who were enrolled and received at least one dose of
study drug, and have at least one nonmissing postdose concentration value for the corresponding 
analyte (VEL, SOF and its metabolite[s], as appropriate) in serum or plasma. The PK analysis set 
will be used for general analyses of PK.
The PK Substudy analysis set will include all subjects who were enrolled in the PK Substudy, 
have been administered at least one dose of study drug, and have at least one nonmissing 
postdose concentration value for the corresponding analyte (VEL, SOF and its metabolite[s], as 
appropriate) in serum or plasma. The PK Substudy analysis set will be used for intensive PK
profiles of these analytes.
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the
endpoints discussed below, values for missing data will not be imputed.
For the analysis of post-Day 1 categorical efficacy endpoints, if a data point is missing and is
preceded and followed in time by values that are deemed successes, then the missing data point
will be termed a success; otherwise the data point will be termed a failure.
If no HCV RNA values are obtained after the last dose of study medication, the subject will be
considered a treatment failure for the SVR endpoints. Subjects who have HCV RNA ≥ LLOQ at
end of treatment or relapse in off-treatment follow-up will be counted as failures at subsequent 
follow-up visits (ie, where no data is available).
Where appropriate, safety data for subjects that did not complete the study will be included in
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject
will be excluded from the calculation of summary statistics for that time point. If the subject
is missing a pre-dose value, then the subject will be excluded from the calculation of
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result
will be replaced with the most recent non-missing screening result, if available.


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Values for missing vital signs data will not be imputed; however, a missing Day 1 result will be
replaced with the most recent non-missing screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for
calculation of summary statistics for the actual HCV RNA value. The reported values will be
provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to
the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero at 
predose time points, and one-half the value of the lower limit of quantitation (LLOQ) at 
postbaseline time points, where LLOQ is corrected for the dilution factor (ie, reported 
LLOQ/dilution factor) for determination of summary and order statistics. For purposes of data 
presentation, individual values that are BLQ will be presented as “BLQ” in the concentration 
data listing. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as “BLQ”. 
If more than 25% of subjects have a concentration data value of BLQ for a given time point, then 
the minimum and the first quartile [Q1] will be displayed as “BLQ”. If more than 50% of the 
subjects have a concentration data value BLQ for the time point, then the minimum, first quartile 
[Q1], and median values will be displayed as “BLQ”. If more than 75% of the subjects have a
concentration value of BLQ for a given time point, then the minimum, 1st quartile [Q1], median,
and 3rd quartile [Q3] values will be displayed as “BLQ”. If all subjects have concentration data
values BLQ for the time point, then all order statistics (minimum, first quartile [Q1], median,
third quartile [Q3], maximum) will all be displayed as “BLQ”.
Pharmacokinetic parameters that are BLQ will be imputed as one-half LLOQ before log 
transformation or statistical model fitting.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods 
Demographic summaries will include sex, self-identified race, ethnicity, and age.
Baseline characteristic data will include body mass index, Day 1 HCV RNA level (log10 IU/mL), 
HCV genotype, IL28B genotype, MELD and CPT scores, and additional endpoints as necessary.
8.5.
Efficacy Analysis
8.5.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of 
treatment) for subjects in the FAS. The number and percentage of subjects who attain SVR12 


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will be presented. A 2-sided 95% confidence interval using the Clopper-Pearson method will 
also be constructed.
8.5.2.
Secondary Efficacy Endpoint
The number and percentage of subjects who attain SVR4 will be presented. Two-sided 95% 
confidence intervals using the Clopper-Pearson method will also be constructed.
The number and percentage of subjects who are <LLOQ will be presented by visit while on 
treatment. On-treatment HCV RNA visit windows will be calculated from the date of first dose 
of SOF/VEL after liver-transplantation (ie, from Study Day 1 as described in this protocol). 
Two-sided 95% confidence intervals using the Clopper-Pearson method will be provided.
A virologic outcome table will present the number and percentage of subjects with end of 
treatment virologic failure and relapse (ie, virologic failure).
8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, and 
vital signs measurements at various time points during the study, and by the documentation of 
AEs.
All safety data collected while “on treatment” (ie, on or after Study Day 1 up to 30 days after the 
last dose of study drug) will be summarized for subjects who receive SOF/VEL.
Safety endpoints will be summarized as the number (percentage) of subjects with events or
abnormalities for categorical data or as an 8-number summary (n, mean, standard deviation,
median, Q1, Q3, minimum, maximum) for continuous data.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration page of the eCRF. Exposure data will be summarized for subjects who receive 
SOF/VEL.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event with an onset date on or after the study drug 
start date and no later than 30 days after permanent discontinuation of study drug or any adverse 
event leading to premature discontinuation of study drug. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and preferred term) will be for subjects receiving SOF/VEL provided for:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory tests (ie, bilirubin, ALT, AST, platelets and creatinine) will be summarized 
by study visit to assess the effect of SOF/VEL treatment in combination with liver 
transplantation on liver and renal function over time. Visit windows will be assigned based on 
the Day 1, and last dose date of any study drug.
Values for missing safety laboratory data will not be imputed.
All laboratory values, whether they were low or high relative to the reference range, and the 
assigned laboratory toxicity grade will be included in the listings of laboratory data.
8.7.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time  may be summarized using descriptive 
statistics, provided sufficient data is available. PK parameters (eg Cmax AUC0-24) may be listed 
and summarized (as appropriate) for study drug (VEL, SOF and its metabolite[s], as appropriate) 
using descriptive statistics. Details of the pharmacokinetic analysis plan will be provided in the 
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8.8.
Sample Size
With a sample size of 10 subjects, a two-sided 95% exact confidence interval will extend at most 
63% in length.
8.9.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform interim 
reviews of safety data. The initial meeting will occur after the first 5 subjects have completed the 
study treatment period. The following one will be held after the remaining planned subjects have 
completed the treatment period. The DMC will provide recommendations, and whether the 
nature, frequency, and severity of adverse effects associated with study treatment warrant the 
early termination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications. The investigator, medical 
monitor, and study biostatistician will be members of the DMC.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the
DMC’s membership, conduct and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-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 IRB or IEC


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local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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
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 IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 


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the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB or IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
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 or IEC
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.


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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 Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, et al. Pharmacokinetics and 
tolerability of voriconazole and a combination oral contraceptive co-administered 
in healthy female subjects. Br J Clin Pharmacol 2008;65 (4):531-9.
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE, et al. The effects of 
rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a 
combination oral contraceptive. Clin Pharmacol Ther 1999;65 (4):428-38.
Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis 
progression following liver transplantation: increase in recent years. J Hepatol 
2000;32 (4):673-84.
Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, et al. Contribution of 
donor age to the recent decrease in patient survival among HCV-infected liver 
transplant recipients. Hepatology 2002;36 (1):202-10.
Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: 
mechanisms, assessment and treatment. J Hepatol 2013;58 (5):1028-41.
Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C 
virus recurrence. Liver Transpl 2003;9 (11):S58-62.
Charlton M, Gane E, Manns MP, Brown RS, Jr., Curry MP, Kwo PY, et al. Sofosbuvir and 
Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection 
After Liver Transplantation. Gastroenterology 2014.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Crespo G, Marino Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. 
Gastroenterology 2012;142 (6):1373-83 e1.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
Feray C, Samuel D, Thiers V, Gigou M, Pichon F, Bismuth A, et al. Reinfection of liver graft by 
hepatitis C virus after liver transplantation. J Clin Invest 1992;89 (4):1361-5.
Firpi RJ, Clark V, Soldevila-Pico C, Morelli G, Cabrera R, Levy C, et al. The natural history of 
hepatitis C cirrhosis after liver transplantation. Liver Transpl 2009;15 (9):1063-
71.
Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C 
infection and survival after orthotopic liver transplantation. Gastroenterology 
2002;122 (4):889-96.


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
Gane E, Benhamou Y, Gladysz A, Zeuzem S, Germanidis G, Heathcote J, et al. Lack Of 
Influence Of Baseline Genotype On Antiviral Response In Subjects With Chronic 
Hepatitis B Infection Receiving Tenofovir DF 300 MG QD For 1 Year [poster 
#2780]. 43rd Annual Meeting of the European Association for the Study of the 
Liver (EASL) 2008; Milan, Italy. 
Gilead Sciences Inc. Harvoni 90 mg/400 mg film-coated tablets. Summary of Product 
Characteristics. Cambridge, United Kingdom. December.  2015a:
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. Revised August 2015b:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information. Foster City, CA. Revised February.  2016:
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of Product 
Characteristics. Cambridge, United Kingdom. June 2015.
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype 
distribution of the hepatitis C virus infection. J Hepatol 2014.
Janssen Pharmaceuticals Inc. INTELENCE® (etravirine) tablets for oral use. US Prescribing 
Information. 2008 Titusville NJ. Revised February 2013.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.
Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguello L, Carrasco D, et al. High incidence of 
allograft cirrhosis in hepatitis C virus genotype 1b infection following 
transplantation: relationship with rejection episodes. Hepatology 1999;29 (1):250-
6.
Quest Diagnostics. FSH and LH Reference Ranges.  2013a:
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013b:
Wiesner RH, Sorrell M, Villamil F. Report of the first International Liver Transplantation 
Society expert panel consensus conference on liver transplantation and hepatitis 
C. Liver Transpl 2003;9 (11):S1-9.
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March.  
2014.
Wright TL, Donegan E, Hsu HH, Ferrell L, Lake JR, Kim M, et al. Recurrent and acquired 
hepatitis C viral infection in liver transplant recipients. Gastroenterology 
1992;103 (1):317-22.


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 78
26 February 2016
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SofosbuvirN elpatasvir Fixed-Dose Combination 
Protocol GS-GS-US-342-2083 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
Gll.EAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Original 
A Phase 2, Open-Label Study to Investigate the Safety and Efficacy of 
SofosbuvirNelpatasvir Fixed Dose Combination Administered for Four Weeks in Patients 
Infected with Chronic HCV in the Peri-Operative Liver Transplantation Setting 
Original Protocol 
26 February 20 J 6 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed) 
e E:'t-t E-1">~ 
PPD 
Author 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including aJl appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 79 
26 February 2016 


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 80
26 February 2016
Appendix 2.
Study Procedures Table
Appendix Table 1.
Screening, On-Treatment Visits 
Clinical
Assessments
Screening
Pre-Surgery
(if more than 48 
hours from 
screening to 
transplant)
Day 1a
Days on Treatment (2 days)
3
5
7
14
21
28
ET/
Unschedulede
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
X
Physical Examination
X
X
X
Height and Weightb
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
CPT and MELD Scores
X
X
Adverse Events and Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
Coagulation
(PT, PTT and INR)
X
X
X
X
X
X
X
X
X
X
CrCL calculation
X
X
X
X
X
X
X
X
X
X
HCV RNA (Plasma) e
X
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing /Phenotyping 
Sample (Plasma)
X
X
X
X
X
X
X
X
Single Pharmacokinetic Sample
X
X
X
X
X
Pregnancy Testingf
X
X
X
X
X
Urinalysis
X
X


SofosbuvirNelpatasvir Fixed-Dose Combination 
Protocol GS-US-342-2083 
Gilead Sciences, Inc. 
Original 
Pre-Surgery 
Days on Treatment (±2 days) 
(if more than 48 
hours from 
Clinical 
screening to 
ET/ 
Assessments 
Screening 
transplant) 
Day 1a 
3 
5 
7 
14 
21 
28 
Unscheduled• 
IL28B Genotype 
X 
H CV Genotype 
X 
HCV, HIV, HBV Serology 
X 
X 
Archive Sampleg 
X 
X 
X 
]PPD 
PK Sub-study Collectioni 
X 
Study Drug Dosing 
X 
X 
X 
X 
X 
X 
X 
Review of Study Drug Adherence and 
X 
X 
X 
X 
X 
X 
X 
Drug Accountability! 
a 
If the transplant is completed before noon, the subject will take their first dose that day after the transplant which will be considered Day 1. If the transplant is completed after 
noon, the subject will take their first dose the following morning which will be considered Day 1. The planned first dose may be delayed for up to 1 day if, in the investigators 
opinion, delay is in the subject's medical interest. ET = Early Termination; at all unscheduled visits initiated for the purpose of confirmatory testing, a viral sequence analysis 
plasma sample must be obtained. 
b 
Weight should be done with inner clothing and without shoes and Height should be done at screening only. Height will be performed only at initial screening visit. Weight 
will be assessed at screening and Day 1 for CrCL calculations. CrCL calculation for all post-transplant visits will use the Day 1 weight. 
c 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
d 
Subjects will be required to rest in a supine position for :>: 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for gross abnormalities. 
e 
HCV RNA samples will be collected at all visits. An additional HCV RNA sample will be collected just before but as close to the transplant as possible. 
f 
For females of childbeari~otential only: serum P-hCG at Screenin , urine test thereafter. If urine is ositive, confirm immediately with serum P-hCG .. 
PPD 
PPD 
All subjects will have intensive serial PK samples drawn before the SOFIVEL dose on Day 1, then dose is given, then remaining samples are collected for 24hrs. The 24 hr 
sample should be collected before the dose of study drug on Day 2. Detailed instructions will be provided to each study site and will also be included in the lab manual. 
Study drug will be reconciled at every post-Day 1 visit by the investigator in order to monitor the subject's adherence with the dosing regimen. Subjects must be instructed to 
bring back all bottles of study drug in the original container at every post Day 1 study visits through the end of treatment. 
CONFIDENTIAL 
Page 81 
26 February 2016 
I 


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 82
26 February 2016
Appendix Table 2.
Post-Treatment Study Visits
Clinical Assessmentsa
Visit identified by Post-Treatment study week
Post-Treatment
Week 1
(3 days)
Post-Treatment
Week 2
(3 days)
Post-Treatment
Week 4
(5 days)
Post-Treatment
Week 12
(5 days)
Weight and Vital Signsb
X
Adverse Events and Concomitant Medications
X
X
X
Pregnancy Prevention Counseling
X
Hematology & Chemistry
X
X
X
X
Coagulation (PT, PTT and INR)
X
X
X
X
HCV RNA and Viral Sequencing Sample 
(Plasma)
X
X
X
X
Pregnancy Testingc
X
X
X
a
If a subject is in Post-treatment follow-up and undergoes liver transplant, they will continue the follow-up schedule.
b
Weight should be done with inner clothing and without shoes. Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
For females of childbearing potential only: serum β-hCG at Screening, urine test thereafter. If urine is positive, confirm immediately with serum β-hCG.


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 83
26 February 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 84
26 February 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.  


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 85
26 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 86
26 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 87
26 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 90
26 February 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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26 February 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 94
26 February 2016
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated [eg, 
tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences (eg, sepsis or 
perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (eg, 
obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences (eg, 
hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference 
with oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences (eg, 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
OR Medical intervention 
indicated 
Symptoms causing inability 
to perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences (eg, 
perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences (eg, 
hypotensive shock)


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
Gilead Sciences, Inc. 
Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting


Sofosbuvir/Velpatasvir Fixed-Dose Combination
Protocol GS-US-342-2083
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Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


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Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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Gilead Sciences, Inc. 
Original
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social &
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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Gilead Sciences, Inc. 
Original
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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


Sofosbuvir/Velpatasvir Fixed-Dose Combination
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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of SOF 
have demonstrated no adverse effect on fertility or embryo-fetal development
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of GS-
5816 have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information.
3) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  A pregnancy 
test will be performed at the Post Treatment Week 4 visit.   They must also agree to one of the 
following from Screening until 30 days of the last dose of SOF/VEL.

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.


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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Tubal sterilization
Essure micro-insert system 
Vasectomy in the male partner 
Barrier methods (one female barrier and one male barrier must be used in combination)
o
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
o
Male barriers: Male condom (with or without spermicide)
Hormonal methods
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel or etonorgestrel
o
Transdermal contraceptive patch
o
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of SOF/VEL.
4) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use  
condoms until 30 days after the last dose of SOF/VEL treatment when engaging in intercourse of 
reproductive potential. If their female partner is of childbearing potential (as defined above), 
their female partner must use 1 of the methods of birth control listed above from the date of 
Screening until 30 days after the last dose of SOF/VEL.
Male subjects must agree to refrain from sperm donation until 30 days after the last dose of 
SOF/VEL.


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5) Unacceptable Methods of Contraception
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
6) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of the last dose of SOF/VEL. Subjects who 
become pregnant or who suspect that they are pregnant must report the information to the 
investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.1.

SAP_001.pdf: 
Study Title: 
Name of Test Drug: 
Study N um her: 
Protocol Version/Date: 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
[!') GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Open-Label Study to Investigate the Safety and 
Efficacy ofSofosbuvirNelpatasvir Fixed Dose Combination 
Administered for Fom Weeks in Patients Infected with Chronic 
HCV in the Peri-Operative Liver Transplantation Setting 
SofosbuvirN elpatasvir Fixed Dose Combination 
GS-US-342-2083 
Original/26 February 2016 
SVR12 (Primary Endpoint and Final CSR) 
Version 1 
20 February 2018 
PPD 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


SOF/VEL Fixed-Dose Combination
GS-US-342-2083 Statistical Analysis Plan
Version 1
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size..............................................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Data Monitoring Committee Meetings.....................................................................................................9
2.2.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set.....................................................................................................10
3.1.2.
Full Analysis Set ..................................................................................................................10
3.1.3.
Safety Analysis Set...............................................................................................................10
3.1.4.
Pharmacokinetic Substudy Analysis Set ..............................................................................10
3.2.
Subject Grouping ...................................................................................................................................11
3.3.
Strata and Covariates..............................................................................................................................11
3.4.
Examination of Subject Subsets.............................................................................................................11
3.5.
Multiple Comparisons............................................................................................................................11
3.6.
Missing Data and Outliers......................................................................................................................11
3.6.1.
Missing Data ........................................................................................................................11
3.6.2.
Outliers.................................................................................................................................12
3.7.
Data Handling Conventions and Transformations .................................................................................12
3.8.
Visit Windows........................................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Windows................................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in a Window .......................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................17
4.1.
Subject Enrollment, Screen Fails, and Disposition ................................................................................17
4.1.1.
Subject Enrollment...............................................................................................................17
4.1.2.
Reasons for Screen Failure...................................................................................................17
4.1.3.
Subject Disposition ..............................................................................................................17
4.2.
Extent of Exposure.................................................................................................................................18
4.2.1.
Duration of Exposure to Study Drug....................................................................................18
4.2.2.
Adherence to Study Drug.....................................................................................................19
4.3.
Protocol Deviations................................................................................................................................19
5.
BASELINE DATA .............................................................................................................................................20
5.1.
Demographics and Baseline Characteristics ..........................................................................................20
5.2.
Medical History......................................................................................................................................22
6.
EFFICACY ANALYSES ...................................................................................................................................23
6.1.
Primary Efficacy Endpoint.....................................................................................................................23
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................23
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................23
6.1.3.
Analysis of the Primary Efficacy Endpoint..........................................................................23


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6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................23
6.2.
Secondary Efficacy Endpoints ...............................................................................................................23
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................23
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................24
6.3.
Exploratory Efficacy Analysis ...............................................................................................................24
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................24
7.
SAFETY ANALYSES........................................................................................................................................25
7.1.
Adverse Events and Deaths....................................................................................................................25
7.1.1.
Adverse Event Dictionary ....................................................................................................25
7.1.2.
Adverse Event Severity........................................................................................................25
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................25
7.1.4.
Serious Adverse Events........................................................................................................25
7.1.5.
Treatment-Emergent Adverse Events...................................................................................25
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................26
7.1.7.
Additional Analysis of Adverse Events ...............................................................................27
7.2.
Laboratory Evaluations ..........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................28
7.2.2.
Graded Laboratory Values ...................................................................................................28
7.3.
Body Weight, Height, BMI, and Vital Signs..........................................................................................28
7.4.
Prior and Concomitant Medications.......................................................................................................29
7.5.
Concomitant Immunosuppressant Medications .....................................................................................29
7.6.
Investigator Electrocardiogram Assessment ..........................................................................................30
7.7.
Other Safety Measures ...........................................................................................................................30
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................30
8.
PHARMACOKINETIC ANALYSIS .................................................................................................................31
8.1.
PK Sample Collection............................................................................................................................31
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................31
8.2.1.
Estimation of Pharmacokinetic Parameters..........................................................................31
8.2.2.
Pharmacokinetic Parameters ................................................................................................31
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
LIST OF IN-TEXT TABLES
Table 1.
Analysis Windows for On-Treatment HCV RNA, Safety Laboratory Data, and Vital 
Signs.......................................................................................................................................15
Table 2.
Analysis Windows for Posttreatment HCV RNA, Safety Laboratory Data and Vital 
Signs.......................................................................................................................................15
Table 3.
Pharmacokinetic Parameters for Each Analyte ......................................................................32


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemistry
BLQ
below limit of quantitation
BMI
body mass index
CI
confidence interval
CPT
Child-Pugh-Turcotte
CrCl
creatinine clearance
CSR
clinical study report
DAA
direct-acting antiviral
eCRF
electronic case report form
DMC
Data Monitoring Committee
ECG
electrocardiogram
FAS
full analysis set
FDC
fixed-dose combination
FU
posttreatment follow-up
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HLT
high level term
HLGT
high level group term
INR
international normalized ratio of prothrombin time
LLOQ
lower limit of quantitation
LLT
lower level term
LOQ
limit of quantitation (PK samples)
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End Stage Liver Disease
NAT
nucleic acid amplification test
NG
nasogastric
PCR
polymerase chain reaction
PEG
pegylated interferon
PG
pharmacogenetics
PK
pharmacokinetics
PO
oral
PT
preferred term
Q1
first quartile
Q3
third quartile
RBV
Ribavirin
RNA
ribonucleic acid


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SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
study days or standard deviation
SOC
system organ class
SOF
Sofosbuvir
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping all study drugs
TE
treatment-emergent
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of the normal range
VEL
Velpatasvir
VF
virologic failure
WBC
white blood cell
WHO
World Health Organization


SOF/VEL Fixed-Dose Combination 
GS-US-342-2083 Statistical Analysis Plan 
1. 
INTRODUCTION 
Version 1 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for the clinical study report (CSR) 
for Study GS-US-342-2083. This SAP is based on the original protocol dated 26 February 2016 
and the electronic case report form ( eCRF). The SAP will be finalized before data finalization. 
Any changes made after the finalization of the SAP will be documented in the CSR. 
1.1. 
Study Objectives 
The primary objectives ofthis study are as follows: 
• 
To explore the antiviral efficacy oftreatment with sofosbuvir/velpatasvir (SOF/VEL) fixed-
dose combination (FDC) therapy administered for 4 weeks following liver transplantation as 
measured by sustained virologic response (SVR) 12 weeks after cessation oftreatment 
(SVR12) 
• 
To evaluate the safety and tolerability of SOF/VEL in hepatitis C virus (HCV)-infected 
subjects in the perioperative and posttransplant period 
The secondary objectives ofthis study are as follows: 
• 
To determine the proportion of subjects who attain SVR at 4 weeks after cessation of therapy 
(SVR4) 
• 
To evaluate the proportion of subjects with virologic failure (VF) 
• 
To assess rates of graft survival, graft function, acute rejection and immunosuppressive 
therapy during treatment with SOF/VEL 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To characterize pharmacokinetics of SOF/VEL 
The exploratory objectives ofthis study are as follows: 
PPD 
CONFIDENTIAL 
Page 6 
20 February 2018 


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1.2.
Study Design
This is an open-label study that will evaluate the safety, tolerability and antiviral efficacy of
SOF/VEL administered for 4 weeks in HCV–infected adult male and non-pregnant/non-lactating 
female subjects 18 years of age or older who are undergoing liver transplantation. A detailed list 
of inclusion and exclusion criteria can be found in Sections 4.2 and 4.3 of the study protocol.
Screening assessments will be completed at the time the subject is identified as a potential 
participant for the study in order to allow the subject time to provide informed consent and to 
perform screening procedures. Subject’s screening data will be confirmed in the pre-operative 
period (within 48 hours of the planned transplant) if the screening visit was conducted more than 
48 hours prior to the start of the transplant. If a separate consent is signed for the liver explant
substudy, samples of the explanted liver will be taken during surgery.
For all subjects, SOF/VEL tablet (400/100 mg) once daily given orally or via nasogastric tube 
will be started the day of the subject’s liver transplant if the procedure is completed by noon and 
the following day if the transplant is completed after noon. Study personnel will observe the 
subject taking their first dose of study drug and record the date and time the first dose was taken.
The subject will receive treatment for 4 weeks. Treatment initiation may be delayed for up to 
1 day if warranted by the subject’s medical condition post-surgery.
All subjects will complete the following study visits: screening, pre-surgery (if screening was 
conducted more than 48 hours prior to start of liver transplant), on-treatment Days 1, 3, 5, 7, 14, 
21, and 28, and posttreatment Weeks 1, 2, 4, and 12 following last dose of study drug.
Pharmacokinetic (PK) Sub-study (Required)
All subjects will participate in a PK substudy in which intensive serial PK sample collection 
(samples obtained over 24 hours) will be performed on Day 1 to determine pharmacokinetics of 
SOF, its metabolites GS-566500 and GS-331007, and VEL.
The schedule of assessments can be found in Appendix 2 of the study protocol.
Subjects will be initially screened to determine their eligibility for participation in the study. 
Subjects will have an additional pre-surgery visit if the screening visit was conducted more than 
48 hours prior to the start of liver transplant (ie, duration of screening period is variable 
depending on availability of a donor organ).
Subjects will be treated for 4 weeks and followed off-treatment for 12 weeks. All subjects will be 
eligible to participate in the PG substudy if consent is obtained. A blood sample should be drawn 
at the Day 1 visit. If not obtained at the Day 1 visit, the sample may be drawn at any time during 
the study.
Subjects with VF (either at end of treatment or during follow-up) will have a confirmation 
sample collected. If VF is confirmed, the subject will be discontinued from study.


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Subjects who prematurely discontinue from study drug but complete all posttreatment visits will 
be considered to have completed study.
1.3.
Sample Size
A total of 10 subjects are expected to be enrolled, receive a transplant, and be dosed with 
SOF/VEL. With a sample size of 10 subjects, a 2-sided 95% exact confidence interval (CI) will 
extend at most 63% in length.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Meetings
A data monitoring committee (DMC) will review the progress of the study and perform interim 
reviews of safety data. The initial meeting will occur after the first 5 subjects have completed the 
treatment period; a second meeting will occur after all subjects complete the treatment period.
The DMC will provide recommendations, and determine whether the nature, frequency, and 
severity of adverse effects associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should continue as planned, or 
the study should continue with modifications. The investigator, medical monitor/study director,
study biostatistician, and a sponsor representative who is not involved with the conduct of the 
study will be members of the DMC.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
2.2.
Final Analysis
After all subjects have completed the study (posttreatment Week 12 or prematurely discontinued 
from study), all outstanding data queries for the study have been resolved, and the database has 
been cleaned and finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects [n], mean, standard deviation [SD], median, first quartile [Q1], third 
quartile [Q3], minimum, and maximum will be presented.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number is ascending order, unless otherwise specified.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from each analysis set will be summarized or provided in 
a by-subject listing with reasons for exclusion by treatment group.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes subjects who were enrolled into the study (ie, subjects 
assigned a 5-digit subject ID). Subjects will be grouped by assigned treatment at enrollment
(SOF/VEL 4 Weeks).
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled subjects who received a liver transplant, and 
took at least 1 dose of study drug. Since all subjects enrolled in this study received a liver 
transplant and took at least 1 dose of study drug, the FAS will be the same as the Safety Analysis 
Set. 
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. Subjects are 
grouped within the Safety Analysis Set according to the treatment they actually received.
This is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Substudy Analysis Set
The Pharmacokinetic (PK) Substudy Analysis Set includes all subjects who took a dose of 
SOF/VEL on Study Day 1, and for whom PK parameters of the analytes of interest (SOF, its 
metabolites GS-566500 and GS-331007, and VEL) could be calculated based on intensive PK 
samples collected on Study Day 1 after the first posttransplant dose of SOF/VEL.
The PK Substudy Analysis Set will be used for analyses of the intensive PK data collected on 
study Day 1. 


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3.2.
Subject Grouping
The treatment group for all efficacy and safety analyses will be “SOF/VEL 4 Weeks.”
PK substudy analyses will be presented by SOF/VEL route of administration (“oral” or 
“nasogastric”) on Study Day 1; and overall (ie, “all subjects”).
3.3.
Strata and Covariates
There are no strata or covariates for this study.
3.4.
Examination of Subject Subsets
SVR12 will be presented for the SOF/VEL 4 Weeks group by: 

age (< 60 and ≥ 60 years)

sex at birth (male, female)

race (White, Asian, Native Hawaiian or Pacific Islander)

BMI (< 30 or ≥ 30 kg/m2)

HCV genotype

IL28B genotype (CC, CT, or TT)

prior HCV treatment (yes, no)

completed study drug (yes, no)
3.5.
Multiple Comparisons
No multiplicity adjustment will be made since SVR12 is the primary efficacy parameter.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.8.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 


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date of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of study drug is greater than or equal to the lower bound of a visit window, and the value at 
the visit is missing, then the value will be imputed. If the study day associated with the last 
dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing.
If an HCV RNA data point is missing and is preceded and followed in time by values that are 
“<LLOQ target not detected (TND),” then the missing data point will be set to “< LLOQ TND.” 
If a data point is missing and preceded and followed by values that are “< LLOQ detected,” or 
preceded by “< LLOQ detected” and followed by “< LLOQ TND,” or preceded by “< LLOQ 
TND” and followed by “< LLOQ detected,” then the missing value will be set to “< LLOQ 
detected.” In these situations the data point will be termed a bracketed success; otherwise, the 
data point will be termed a bracketed failure (ie, ≥ LLOQ detected). If a data point is missing and 
is not bracketed, the missing data point will also be termed a failure (ie, ≥ LLOQ detected).
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
By subject listings will be presented for all subjects in the Safety Analysis Set sorted by subject 
ID number, visit date, and time (if applicable) unless otherwise specified. Data collected on log 
forms, such as AEs, will be presented in chronological order within subject.
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug, then the date the informed consent was signed will be 
used in place of the first dose date of study drug for calculation of age.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “< x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported as < 1. For the values reported as < 1 or < 0.1, a value of 
0.9 or 0.09, respectively will be used for calculation of summary statistics. 

A value that is one unit above the limit of quantitation will be used for calculation of
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).


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LabPlus laboratories used COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, 
version 2.0 to determine HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL.
When the calculated HCV RNA IU/mL is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL.” This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical results.
When HCV RNA is not detected, the result is reported as “Not Detected” or “target not 
detected.” This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND.”
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL.” This result will be referred to in this document as “< LLOQ detected.”
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “target not detected” will also be set to 
LLOQ – 1 IU/mL. For selected analyses, HCV RNA data (IU/mL) will be transformed to the 
logarithmic (base 10) scale (log10 IU/mL).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma 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 postbaseline time points, where 
LOQ is corrected for the dilution factor (ie, reported LOQ/dilution factor) for determination of 
summary and order statistics.
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 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and 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) will be displayed as “BLQ.”
Pharmacokinetic parameters that are BLQ will be imputed as one-half LOQ before log 
transformation.


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3.8.
Visit Windows
3.8.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be
defined as the day of the first dose of study drug administration. 
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date
The last dose date of study drug will be the end date for SOF/VEL on the study drug 
administration eCRF for the record where the “subject permanently discontinued” flag is ‘Yes’.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, and on-treatment visit dates and 
laboratory collection dates (posttreatment visits and unscheduled visits are not included). 
3.8.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for purposes of analysis, 
visit windows will be utilized when a single value at a visit is required for analysis. 
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug.
HCV RNA, vital signs, and safety laboratory data collected up to last study drug dose 
date + 3 days will be considered to be on-treatment data; and HCV RNA, vital signs, and safety 
laboratory data collected after the last dose date + 3 days are considered posttreatment data.  The 
analysis windows for on-treatment HCV RNA, vital signs and safety laboratory data are 
provided in Table 1.


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Table 1.
Analysis Windows for On-Treatment HCV RNA, Safety Laboratory 
Data, and Vital Signs
Visit ID
SOF/VEL 4 Weeks
On-Treatment Visit Windows for HCV
RNA, Safety Laboratory Values and Vital Signs
Baseline/Day 1a
Date/time of lab sample (date for other) ≤  date/time (date for non-lab) of first 
dose SOF/VEL
Day 3
2 ≤Study Day ≤ 4
Day 5
5 ≤ Study Day ≤ 6
Day 7 (Week 1)
7 ≤Study Day ≤11
Day 14 (Week 2)a
12 ≤Study Day ≤17
Day 21 (Week 3)
18 ≤Study Day ≤ 24
Day 28 (Week 4)a
25 ≤Study Day ≤ 41
a
Pregnancy testing required at Day 1, Day 14, and Day 28 for SOF/VEL 4 Weeks.
Safety Labs include hematology, chemistry, urinalysis, and coagulation. 
Only the date of assessment is collected for vital signs data.
Pre-transplant CPT and MELD scores and ECGs are to be collected at screening, and pre-surgery 
(if more than 48 hours between screening visit and start of transplant), and will be listed with 
their nominal visit with study days assigned.
HCV RNA, vital signs, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to posttreatment visits. Visit windows will be calculated from the last dose date (ie, 
FU Day = Collection Date – Last Dose Date) as shown in Table 2.
Table 2.
Analysis Windows for Posttreatment HCV RNA, Safety Laboratory Data
and Vital Signs
Post-Trt 
FU Visit 
ID
Posttreatment Visit Windows
for HCV RNA a (Days from Date of 
Last SOF/VEL)
Safety Labsb
(Days from Date 
of Last SOF/VEL)
Vital Signsc
(Days from Date 
of Last SOF/VEL)
FU-1
4 FU Day 10
4 ≤ FU Day ≤10
N/A
FU-2
11 ≤ FU Day ≤20
11 ≤ FU Day ≤ 20
N/A
FU-4
21 FU Day 69
21 ≤ FU Day ≤ 30
4 ≤ FU Day ≤ 30
FU-12
70 FU Day 146
N/A
N/A
a
SVR follow-up visit window (lower bound) must occur within 7 (SVR4) and 14 (SVR12) days of target, respectively.
b
Safety labs will only be summarized up to posttreatment Week 4 (up to 30 days post last dose).
c
Vital Signs are only collected at posttreatment Week 4 (summarized up to 30 days post last dose).


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3.8.3.
Selection of Data in the Event of Multiple Records in a 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 one value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time is recorded for 
the same day, the average (arithmetic mean) will be used for the baseline value.

For postbaseline visits:
1) Select the record closest to the nominal day (ie, visit weeks × 7 days) for that visit; except for 
posttreatment HCV RNA follow-up visits, for which the latest record in the analysis window 
will be selected)
2) If there are 2 visits equidistant from the nominal day, the later record will be selected
3) If there is more than 1 record on the selected day, the average will be taken, unless otherwise 
specified
If multiple valid nonmissing categorical observations exist in a window, records will be selected 
as follows:

For baseline, the last available record on or prior to the date of first dose of study drug will be 
selected.  If there are multiple records with the same time or no time recorded on the same 
day, the values with the lowest severity will be selected (eg, normal will be selected over 
abnormal)

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal)  


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment, Screen Fails, and Disposition
4.1.1.
Subject Enrollment
A summary of subjects enrolled and treated will be provided for each country and investigator 
within country for the “SOF/VEL 4 Weeks” group for subjects in the safety analysis set.
4.1.2.
Reasons for Screen Failure
Reasons for screen failure will be summarized for each screen that was performed for the study. 
The total number of screens and number of screen failures will be provided. Screen failures will 
be split into the following 2 groups:

screen failures that did not meet eligibility criteria (with inclusion/exclusion criteria not met 
summarized) 

screen failures that met eligibility criteria (with reasons for non-enrollment summarized)
Percentages will be calculated for the screen failure rate (denominator is number of screens), 
each inclusion/exclusion criteria not met (denominator is screen fails that did not meet criteria), 
and reasons for non-enrollment (denominator is screen fails that met eligibility criteria). A listing 
of inclusion/exclusion criteria that were not met for screen failure subjects will be provided, 
sorted by screening ID for subjects who were screened but not treated.
4.1.3.
Subject Disposition
A summary of subject disposition will be provided for “SOF/VEL 4 Weeks.” The summary will 
present the number of subjects enrolled, and evaluated for each analysis set (ie, safety analysis 
set and/or FAS analysis set). 
In addition, the number and percentage of subjects in the safety analysis set who met the 
following criteria will be summarized: 

Completed the study treatment period 

Did not complete the study treatment period (with reasons for not completing the study 
treatment period)

Completed the study

Did not complete the study (with reasons for not completing the study)


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Among subjects who completed study treatment and those who prematurely discontinued study
treatment, the number and percentage of subjects will be summarized for subjects with: 

No HCV RNA at the posttreatment Week 4 assessment (ie, No FU-4 HCV RNA Assessment)

HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 assessment 
(ie, With FU-4 but No FU-12 HCV RNA Assessment)
If a subject has no HCV RNA assessments beyond 21 days after the last dose of any study drug 
(ie, lower bound of FU-4 visit for HCV), the subject is categorized as having “No FU-4 HCV 
RNA Assessment.” If a subject has an HCV RNA value for the FU-4 assessment but does not 
have any observed HCV RNA assessment beyond 70 days after the last dose of any study drug 
(ie, lower bound of FU-12 visit for HCV), the subject is categorized as having “With FU-4 but 
No FU-12 HCV RNA Assessment.”
A summary of the number of subjects in the PK Substudy analysis set will be provided by route 
of administration of SOF/VEL on Study Day 1 (PO or NG) and overall as part of the PK 
substudy analysis.
A data listing of date of informed consent, date/time transplant ended, first posttransplant dose 
date/time, last dose date (study day), completed study treatment (yes/no), completed study 
(yes/no) and reasons for premature study treatment/study discontinuation will be provided. The 
last observed non-missing HCV RNA value on/prior to the date the subject stopped SOF/VEL 
plus 3 days will be included in this listing.  
A listing of subjects who were excluded from the safety and/or FAS analysis set will be 
provided.
4.2.
Extent of Exposure
Extent of exposure to study drug will be examined by assessing the total duration of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Duration of exposure to SOF/VEL will be defined as (last dose date of SOF/VEL – first dose 
date of SOF/VEL + 1) regardless of temporary interruptions in study drug administration. All 
duration of exposure will be expressed in days. 
Duration of exposure to SOF/VEL will be summarized using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum and maximum) and using the number (ie, cumulative counts) and 
percentage of subjects exposed through the timepoints: Baseline (≥ 1 Day); Week 1 (≥7 Days); 
Week 2 (≥14 Days); Week 3 (≥21 Days) and Week 4 (≥28 Days). A ± 3 day window for the 
last assessment will be applied to match with the protocol-specified visit window. Summaries 
will be provided by treatment group for subjects in the safety analysis set.
A by-subject listing of study drug administration will be provided for subjects in the safety 
analysis set.


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4.2.2.
Adherence to Study Drug
Adherence will be calculated for SOF/VEL as:
[(Number of tablets taken) ÷ (Number of study drug tablets prescribed)] x 100
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
A descriptive summary (n, mean, SD, median, Q1, Q3, minimum and maximum) and the number 
and percentage of subjects with < 80% , ≥ 80 to < 90%, and ≥ 90% adherence will be presented 
for the safety analysis set for subjects assigned to receive SOF/VEL for 4 Weeks. 
A by-subject listing of adherence will be provided for subjects in the safety analysis set.
4.2.2.1.
Calculation of Number of Tablets Prescribed for Study Drug
Subjects assigned to receive 4 weeks of SOF/VEL will require 1 tablet/day for 28 days.
4.2.2.2.
Calculation of Number of Tablets Taken
The number of tablets taken for SOF/VEL during the treatment period will be calculated as the 
sum of (number of tablets dispensed – number of tablets returned) at each distinct dispensing 
period across all bottles dispensed. If a bottle is dispensed, and the bottle is returned empty, then 
the number of tablets returned will be entered as zero. If a bottle is dispensed but not returned 
(missing), the number of tablets taken from that bottle will be counted as zero. 
4.3.
Protocol Deviations
A listing of important protocol violations will be provided by the Clinical Operations group for 
subjects in the Safety Analysis set. The listing will include the criteria not met and related
comments.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
Subject demographic and baseline characteristics will be summarized for the SOF/VEL 4 Week
group for subjects in the Safety Analysis Set using descriptive statistics (n, mean, SD, median,
Q1, Q3, minimum and maximum) for continuous data and by the number and percentage of 
subjects for categorical data. Variables to be summarized include the following:

Age (on date of first dose of study medication) as a continuous variable and for categories 
(< 60 and ≥60 years)

Sex at birth (male, female)

Race (White, Black or African American, Asian, American Indian/Alaska Native, Native 
Hawaiian/Pacific Islander, Other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Baseline body mass index (BMI) as a continuous variable and for categories (< 30 kg/m2, 
≥30 kg/m2)

Pretransplant HCV genotype 

Pretransplant IL28B (CC, CT, TT) 

Pretransplant HCV RNA as a continuous variable and for categories (< 800,000 IU/mL and 
≥800,000 IU/mL)

Pretransplant Child-Pugh-Turcotte (CPT) class 

Pretransplant CPT score (eg. 5, 6, 8) as a categorical variable

Pretransplant native model for end stage liver disease (MELD) score as a continuous variable
and as a categorical variable for individual MELD scores

Pretransplant hepatocellular carcinoma (HCC) (yes, no)

Pretransplant Exception MELD (from liver transplant eCRF) as a continuous variable

Donor Type (living, cadaveric brain death, cadaveric cardiac death)

Cadaveric Donor Type (split, whole)

Prior HCV treatment (yes, no)


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
Response to last HCV treatment regimen (non–responder, relapse/breakthrough, early 
discontinuation)

Last HCV treatment regimen (pegylated interferon [PEG], PEG+RBV)

Baseline HCV RNA as a continuous variable and for categories (< 800,000 IU/mL 
and ≥800,000 IU/mL)

Baseline alanine aminotransferase (ALT) as a continuous variable (absolute value) and for 
categories (≤1.5 × upper limit of normal [ULN] and > 1.5 × ULN)

Baseline creatinine clearance (CrCL) using the Cockcroft-Gault formula (using for weight 
the lesser of ideal body weight and actual body weight)
Age of the patient will be calculated as the integer of age in years on the date of first dose of 
study medication. 
Pretransplant CPT and native MELD scores will be listed by nominal visit (eg, screening and 
pre-surgery) and will be calculated using the following formulas:
CPT score is calculated as: the sum of the scores related to the 5 items in the table below (if any 
of the components are missing, the score is not calculated):
MEASURE
1 point
2 points
3 points
Total Bilirubin (mg/dL)
< 2
2-3
> 3
Serum Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
International normalized 
ratio for prothrombin time 
(INR)
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Slight/Moderate 
(medically controlled)
Severe (medically 
uncontrolled)
Hepatic Encephalopathy
None
Slight/Moderate 
(medically controlled)
Severe (medically 
uncontrolled)
Native MELD score is calculated as: 
10 × {[0.957 × Ln(Scr)] + [0.378 × Ln(Tbil]) + [1.12 × Ln(INR)] + 0.643)}
Where Scr = serum creatinine (in mg/dL), Tbil = Total Bilirubin (in mg/dL), INR = international 
normalized ratio, and Ln = natural log. If any lab value is less than 1.0, then set to 1.0 in the 
calculation. If the subject received dialysis at least twice in the past week, or if the serum 
creatinine value is > 4.0, then Scr is set to 4.0 mg/dL in the above formula. The result will be 
rounded to the nearest whole number.


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MELD Exception score
At this site in New Zealand, subjects with HCC eligible for liver transplantation may be awarded 
additional MELD score points if they meet exception point criteria. Subjects will have an 
exception score of 22 assigned if they have a single HCC lesion greater than 2 centimeters or 
more than 1 lesion of any size. Two additional points are awarded every 3 months that the 
subject is on the liver transplant waitlist.
The laboratory collection date for each laboratory test used to calculate the pretransplant MELD 
and CPT scores are collected on the MELD/CPT eCRF form and are to be merged, individually 
for each laboratory test with the laboratory collection date on the COVLAB dataset to obtain the 
numeric result for the test.
By-subject listings of demographic and baseline characteristics will be provided for subjects in 
the safety analysis set. 
A separate by-subject listing for prior HCV treatment and response will be provided. 
A by-subject listing of transplant information and donor organ characteristics will be provided 
for subjects in the FAS and will include: transplant start and end date/time, hours and minutes 
(HH:MM) of cold/ischemia time, pretransplant HCC (yes/no), pretransplant MELD native score, 
pretransplant MELD exception score (when applicable), donor type, cadaveric donor type, cause 
of donor death, donor age/sex/race/ethnicity [when available], donor hepatitis C nucleic acid 
amplification test (NAT) status, and location of organ (local, regional, national).
5.2.
Medical History
Clinically relevant medical history (ie, conditions not specific to the disease being studied that 
are clinically relevant) will be listed only. General medical history will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12, defined as HCV RNA < LLOQ (ie, 15 IU/mL) 12 
weeks after cessation of treatment in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan® 
HCV Quantitative Test, version 2.0 will be used to measure and report HCV RNA results. 
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
No hypothesis testing will be performed.
6.1.3.
Analysis of the Primary Efficacy Endpoint
The estimate of SVR12 and a 2-sided 95% CI calculated using the Clopper-Pearson method
{Clopper et al 1934} will be provided for the “SOF/VEL 4 Week” treatment group.
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint
Point estimates and the 2-sided exact 95% CI calculated using the Clopper-Pearson method will 
be presented for each subgroup presented in Section 3.4.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints to be summarized for the “SOF/VEL 4 Week” treatment group for 
subjects in the FAS include:

The proportion of subjects with SVR at 4 weeks after cessation of treatment (SVR4)

The proportion of subjects with HCV RNA < LLOQ by visit while on treatment

The proportion of subjects with VF. End of treatment VF and relapse will be defined by:
End of Treatment Virologic Failure: HCV RNA ≥ 15 IU/mL at last observed HCV RNA 
measurement on or prior to last dose date of SOF/VEL + 3 days after completion of 28 ± 3 days 
of SOF/VEL treatment.
Relapse: HCV RNA ≥ 15 IU/mL during the posttreatment follow-up period having achieved 
HCV RNA < 15 IU/mL at the end of treatment, confirmed with 2 consecutive values or last 
available posttreatment measurement.


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
All secondary efficacy endpoints will be evaluated for the “SOF/VEL 4 Week” treatment group
for subjects included in the FAS. For analyses of HCV RNA < LLOQ by visit while on treatment 
and during the posttreatment (SVR) follow-up period, subjects will be assigned a value at each 
visit based on the analysis visit windows specified in Section 3.8.2. Missing values will be 
imputed based on the categorical imputation rules described in Section 3.6.1. Estimates of the
proportion of subjects < LLOQ by visit and the 95% exact CI using the Clopper-Pearson method 
will be calculated. The overall category for “HCV RNA < LLOQ” will be split into the 
subcategories “< LLOQ TND” for subjects with target not detected and “< LLOQ detected” for 
subjects with < LLOQ in tabular displays.
A summary table of the number and proportion of subjects with SVR12, VF, and Other will be 
presented for the “SOF/VEL 4 Week” treatment group. All subjects who achieve SVR12 will be 
categorized as SVR12. VF will be summarized for “end of treatment failure” and “relapse” 
(relapse will be broken down by study drug completed yes/no). Subjects who do not achieve 
SVR12 or VF will be categorized as Other.
The denominator for relapse will be the number of subjects who had HCV RNA < LLOQ on 
their last observed on-treatment HCV RNA measurement; the denominator for end of treatment 
response will be the number of subjects who completed 28 ± 3 days of treatment; otherwise, the 
denominator will be the number of subjects in the FAS.
For analyses of HCV RNA < LLOQ by visit while on treatment, subjects will be assigned a 
value at each visit based on the categorical imputation rules described in Section 3.7 of this SAP. 
Subjects with HCV RNA < LLOQ will be displayed into 2 subcategories: < LLOQ TND and 
< LLOQ detected. Point estimates and 2-sided exact 95% CIs using the Clopper-Pearson method 
will be displayed for the proportion of subjects < LLOQ at each visit.
A listing of HCV RNA (log10 IU/mL) will be provided for FAS subjects, FAS subjects with VF, 
and FAS subjects with Other Virologic Outcome.
Drug resistant substitutions will be discussed as part of the clinical study report.
6.3.
Exploratory Efficacy Analysis
None
6.4.
Changes From Protocol-Specified Efficacy Analyses
None


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7.
SAFETY ANALYSES
Safety data will be summarized for the SOF/VEL 4 Week group for the Safety Analysis Set.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high level group term (HLGT), high level term (HLT), 
preferred term (PT), and lower level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings, and the most 
severe will be considered (for sorting purpose only) in data 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.” Events for which the investigator did not record 
relationship to study drug will be considered to be related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
eCRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definition of SAE specified in the study protocol. Serious adverse events captured and stored in 
the clinical database will be reconciled with the SAE database from the Pharmacovigilance and 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
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
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 


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not prior to the first dose date of study drug. The event is considered treatment emergent if both 
of the following 2 criteria are met:

The AE onset and end date 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 dose date of study drug will be considered to be treatment-emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided for the SOF/VEL 4 Week group. The
number and percentage of subjects who had the following: any AE; any treatment-related AE; 
any AE of Grade 3 or above; any treatment-related AE of Grade 3 or above; any AE of Grade 2 
or above; any treatment-related AE of Grade 2 or above; any SAE; any treatment-related SAE; 
any AE leading to premature discontinuation of SOF/VEL; and any AE leading to interruption of 
SOF/VEL. All deaths (including those that are treatment-emergent and those that are not 
treatment-emergent) observed during the study will also be summarized and included in this 
table.
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT for the SOF/VEL 4 Week group based on the the Safety Analysis Set as follows:

All AEs

All treatment-related AEs

AEs of Grade 3 or above

Treatment-related AEs of Grade 3 or above

AEs of Grade 2 or above

Treatment-related AEs of Grade 2 or above

All SAEs

Treatment-Emergent Non-Serious Adverse Events Occurring in At Least 5% of Subjects
Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending 
incidence within an SOC. In summaries by severity grade, the most severe grade will be used for 
those AEs that occurred more than once in an individual subject during the study.
In addition to the above summary tables, TEAEs will also be summarized for the SOF/VEL 4 
Week treatment group by PT only, in order of descending incidence for: 


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
AEs that occurred in > 1 subject

AEs leading to interruption of SOF/VEL

AEs leading to premature discontinuation of SOF/VEL 

All SAEs

All treatment-related SAEs
In addition to the by-treatment summaries described above, by-subject data listings, with a 
variable indicating whether the event is treatment-emergent, will be provided for the following:

All AEs

AEs leading to premature discontinuation of SOF/VEL

All AEs of Grade 3 or above

SAEs

All Deaths

Graft Loss
7.1.7.
Additional Analysis of Adverse Events
None
7.2.
Laboratory Evaluations
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 for subjects who have permanently 
discontinued the study drug. The analysis will be based on values reported in conventional units. 
When values are below the lower limit of quantitation, they will be listed as such, and the closest 
imputed value will be used for the purpose of calculating summary statistics as described in 
Section 3.7 of this SAP.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for screening lab tests, hematology, serum chemistry, and urinalysis
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the Gilead Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be flagged in the data listings, as appropriate. 
A listing of the LabPlus laboratory normal ranges will be provided. Ranges are based on the sex 
and age of the patient on the date of collection of the laboratory sample.


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No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum) will be provided 
for the SOF/VEL 4 Week group by analysis visit for: ALT, aspartate aminotransferase (AST), 
alkaline phosphatase, total bilirubin, direct bilirubin, white blood cell (WBC), neutrophils 
(absolute), lymphocytes (absolute), reticulocyte count, hemoglobin, platelets, albumin,
international normalized ratio of prothrombin time (INR), serum creatinine, and creatinine 
clearance (CrCl).
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. The mean, median, Q1, Q3, minimum and maximum will 
be displayed to reported number of digits, and SD to reported number of digits +1 for each on-
treatment visit. The posttreatment Week 1, 2, and 4 visits will be presented as additional separate 
visits. In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3 of this SAP.
The number and percentage of subjects with at least 1 postbaseline (up to 30 days post last dose) 
hemoglobin value < 10 g/dL and < 8.5 g/dL will be summarized. The denominator will be the 
number of subjects with at least 1 postbaseline hemoglobin value. 
A listing of subjects meeting the criteria for postbaseline hemoglobin < 10 g/dL and < 8.5 g/dL
will be provided.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades (0 to 4) to laboratory results. Grade 0 includes all values that 
do not meet the criteria for an abnormality of at least Grade 1. Some laboratory tests have criteria
for both increased and decreased levels.
Toxicity grading will be presented in listings of laboratory data. No summary tables for toxicity 
grading will be produced due to the effects of liver transplantation on laboratory values in the 
immediate post-operative period. 
7.3.
Body Weight, Height, BMI, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg] and pulse [bpm]) at each visit will be 
summarized for the Safety Analysis Set using descriptive statistics (n, mean, SD, median, Q1, 
Q3, minimum, and maximum) for the SOF/VEL 4 Week group. The baseline value will be 
defined as the last available value collected on or prior to the date of first dose of study drug. In 
the case of multiple values in an analysis window, data will be selected for analysis as described 
in Section 3.8.3 of this SAP. No inferential statistics will be generated.


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A by-subject listing of height (cm), body weight (kg), BMI (kg/m2) and vital signs (systolic and 
diastolic blood pressure [mmHg], pulse [bpm], respiration [breaths/min], and body temperature 
[°C]) will be provided. Data will be sorted for each subject and visit in chronologic order.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.  The medications will be categorized 
as prior or concomitant using the following definitions: 

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug
Concomitant medications (other than study drug and drugs administered to prevent rejection of 
the transplanted organ) will be summarized by preferred drug name using the number and 
percentage of subjects for the SOF/VEL 4 Week group. A subject reporting the same medication 
for a preferred drug name more than once will be counted once only per subject. The summary of 
concomitant medications will be ordered by descending frequency of preferred drug name. For
preferred drug names with the same frequency, sorting will be done alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated.
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or start date that is after the last study drug dosing date will be excluded from a 
concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug start date will be excluded from the concomitant medication summary. If a partial
start date is entered, then any medication with the month and year (if day is missing) or year (if 
day and month are missing) after the study drug stop date will be excluded from the concomitant 
medication summary.
All prior and concomitant medications (other than per-protocol study drugs and drugs 
administered to prevent rejection of the transplanted organ) will be provided in a by-subject 
listing sorted by subject ID number and administration date in chronologic order.
7.5.
Concomitant Immunosuppressant Medications
Immunosuppressant medications administered to prevent rejection of the transplanted organ
collected at screening and during the study will be coded using the current version of the World 
Health Organization (WHO) Drug dictionary. Concomitant (as described in Section 7.4) 
immunosuppressant medications will be summarized by preferred drug name for the SOF/VEL 4 
Week group for subjects in the Safety Analysis Set.


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All prior and concomitant immunosuppressant medications administered to prevent rejection of 
the transplanted organ will be presented in a by-subject listing sorted by subject ID number and 
start date of administration for subjects in the safety analysis set.
7.6.
Investigator Electrocardiogram Assessment
A by-subject listing for ECG assessment results collected at screening and at the pre-surgery visit 
including comments regarding clinically significant abnormalities will be provided for subjects 
in the safety analysis set. ECGs will be listed by the nominal visit and will be presented in 
chronological order.
7.7.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.8.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSIS
The plasma concentrations of SOF (and its metabolites GS-566500 and GS-331007) and VEL 
will be determined using validated bioanalytical assays.
8.1.
PK Sample Collection
A single PK blood sample will be collected at Study Days 7, 14, 21, and 28 (or end of treatment).
A PK Substudy will be performed on Study Day 1 for all subjects. PK samples will be collected 
predose, and at 0.5, 1, 2, 4, 8, 12, and 24 hours postdose to determine the PK of SOF, SOF 
metabolites GS-566500 and GS-331007, and VEL.
8.2.
PK Analyses Related to Intensive PK Sampling
PK over a 24-hour dosing interval will be determined in subjects in the PK Substudy analysis set. 
Concentrations of SOF, GS-566500, GS-331007, and VEL in plasma collected on Study Day 1 
will be determined using validated bioanalytical assays.
8.2.1.
Estimation of Pharmacokinetic Parameters
Pharmacokinetic (PK) parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear up/log down trapezoidal rule will be used in 
conjunction with the appropriate noncompartmental model, with input values for dose level, 
dosing time, plasma concentration, and corresponding real time values, based on drug dosing 
times whenever possible.
All predose sample times before time-zero will be converted to 0.
For area under the curve (AUC), samples BLQ of the bioanalytical assay occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile by profile basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.2.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be generated for all subjects in the PK substudy analysis set 
based on intensive PK samples collected on Study Day 1. 


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The pharmacokinetic parameters for VEL, SOF, GS-566500 and GS-331007 will be computed 
for all subjects with evaluable PK profiles. For each subject, the following PK parameters will be 
calculated, as appropriate:
Table 3.
Pharmacokinetic Parameters for Each Analyte
Parameter
Description
AUC0-24
area under the concentration versus time curve over the dosing interval
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of drug in plasma
C24
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
λz
terminal elimination rate estimated by linear regression of the terminal elimination phase of 
the plasma concentration of drug versus time curve
Individual subject concentration data at each timepoint, and individual subject PK parameters for 
VEL, SOF, and SOF metabolites GS-566500 and GS-331007 in plasma will be listed and 
summarized using descriptive statistics (n, mean, SD, coefficient of variation [%CV], median, 
min, max, Q1, and Q3) by route of SOF/VEL administration (PO or NG) on Study Day 1. In 
addition, for individual subject PK parameter data, the geometric mean, 95% CI, and the mean 
and SD of the natural log-transformed values will be presented. 
Individual concentration data listings and summaries (intensive PK) will include all subjects with 
concentration data. The sample size for each time point will be based on the number of subjects 
with nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower limit of quantitation (LLOQ) for the analyte being 
summarized at postdose time points, where LLOQ is corrected for the dilution factor (ie, 
reported dilution/dilution factor). 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by route of SOF/VEL administration (PO 
or NG) and overall on study Day 1:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics


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The following figures may be provided for each analyte by SOF/VEL route of administration 
(PO or NG) on Study Day 1:

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Mean and median postdose concentration values that are ≤ LLOQ will not be displayed in the 
figures and remaining points connected.
The following listing will be provided:

PK sampling details (and PK concentrations) by subject that includes both intensive and 
sparse PK samples


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


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10.
SOFTWARE
SAS® Software Version 9.1. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland.


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Table 
Number
Title
Analysis Set
1
Subjects Enrolled and Treated by Investigator
Safety Analysis Set
2.1
Reasons for Screen Failure
Screened Subjects
2.2
Subjects Enrolled and Treated Who Did Not Meet 
Eligibility Criteria
Safety Analysis Set
3*
Subject Disposition
Enrolled Subjects
4*
Demographics and Baseline Characteristics 
Safety Analysis Set 
5*
Duration of Exposure to Study Drug
Safety Analysis Set 
6
Adherence to Study Drug
Safety Analysis Set 
7
Concomitant Medications
Safety Analysis Set 
8
Concomitant Immunosuppressant Medications
Safety Analysis Set 
9
SVR12
Full Analysis Set
10
Virologic Outcome
Full Analysis Set
11
SVR by Visit During Posttreatment Follow Up
Full Analysis Set
12
Virologic Outcome at Posttreatment Weeks 4 and 12
Full Analysis Set
13
SVR12 by Subgroup
Full Analysis Set
14*
Proportion of Subjects with HCV RNA Less Than LLOQ 
(15 IU/mL) While on Treatment by Visit
Full Analysis Set
15*
Adverse Events: Brief Summary
Safety Analysis Set 
16*
All Treatment-Emergent Adverse Events
Safety Analysis Set 
17
Treatment-Emergent Treatment-Related Adverse Events 
Safety Analysis Set 
18*
Treatment-Emergent Adverse Events of Grade 3 or Above
Safety Analysis Set 
19*
Treatment-Emergent Treatment-Related Adverse Events of 
Grade 3 or Above
Safety Analysis Set 
20
Treatment-Emergent Adverse Events of Grade 2 or Above
Safety Analysis Set 
21
Treatment-Emergent Treatment-Related Adverse Events of 
Grade 2 or Above
Safety Analysis Set 
22
Treatment-Emergent Serious Adverse Events
Safety Analysis Set 
23
Treatment-Emergent Non-Serious Adverse Events 
Occurring in At Least 5% of Subjects
Safety Analysis Set  
24*
Adverse Events That Led to Premature Discontinuation of
SOF/VEL by Preferred Term
Safety Analysis Set
25
Treatment-Emergent Adverse Events Occurring in > 1 
Subject by Preferred Term
Safety Analysis Set


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Table 
Number
Title
Analysis Set
26
Adverse Events Leading to Interruption of SOF/VEL by 
Preferred Term
Safety Analysis Set 
27*
Treatment-Emergent Serious Adverse Events by Preferred 
Term
Safety Analysis Set
28*
Treatment-Emergent Treatment-Related Serious Adverse 
Events by Preferred Term
Safety Analysis Set
29.1*
ALT (U/L) by Visit
Safety Analysis Set
29.2*
AST (U/L) by Visit
Safety Analysis Set
29.3*
Alkaline Phosphatase (U/L) by Visit
Safety Analysis Set
29.4*
Total Bilirubin (mg/dL) by Visit
Safety Analysis Set
29.5*
Direct Bilirubin (mg/dL) by Visit
Safety Analysis Set
29.6*
WBC (x 103/µL) by Visit
Safety Analysis Set
29.7*
Neutrophils (x 103/µL) by Visit
Safety Analysis Set
29.8*
Lymphocytes (x 103/µL) by Visit
Safety Analysis Set
29.9*
Reticulocyte Count (x 103/µL) by Visit
Safety Analysis Set
29.10*
Hemoglobin (g/dL) by Visit
Safety Analysis Set
29.11*
Platelets (x 103/µL) by Visit
Safety Analysis Set
29.12*
Albumin (g/dL) by Visit
Safety Analysis Set
29.13*
INR by Visit
Safety Analysis Set
29.14*
Serum Creatinine (mg/dL) by Visit
Safety Analysis Set
29.15*
Creatinine Clearance (mL/min)
Safety Analysis Set
30
Postbaseline Hemoglobin < 10 g/dL and < 8.5 g/dL 
Safety Analysis Set
31.1
Pulse (bpm) by Visit
Safety Analysis Set
31.2
Diastolic Blood Pressure (mmHg) by Visit
Safety Analysis Set
31.3
Systolic Blood Pressure (mmHg) by Visit
Safety Analysis Set
*
Included in DMC analysis.


SOF/VEL Fixed-Dose Combination
GS-US-342-2083 Statistical Analysis Plan
Version 1
CONFIDENTIAL
Page 39
20 February 2018
PK Table or 
Figure Number
Title
Analysis Set
PK Table 1
Subjects Evaluable by Study Day 1 SOF/VEL Route of 
Administration
PK Substudy Analysis Set
PK Table 2
Plasma SOF Concentrations (ng/mL) by Subject with Summary 
Statistics for Each Substudy Timepoint
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 3
Plasma GS-331007 Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Substudy Timepoint
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 4
Plasma GS-566500 Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Substudy Timepoint
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 5
Plasma VEL Concentrations (ng/mL) by Subject with Summary 
Statistics for Each Substudy Timepoint
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 6
Plasma SOF Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 7
Plasma GS-331007 Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 8
Plasma GS-566500 Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Table 9
Plasma VEL Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
(by Route of SOF/VEL Administration on Day 1)
PK Substudy Analysis Set
PK Figure 1
Mean (SD) Plasma Concentration – Time Profile (Analyte=SOF)
PK Substudy Analysis Set
PK Figure 2
Mean (SD) Plasma Concentration –Time Profile 
(Analyte=GS-331007)
PK Substudy Analysis Set
PK Figure 3
Mean (SD) Plasma Concentration –Time Profile 
(Analyte=GS-566500)
PK Substudy Analysis Set
PK Figure 4
Mean (SD) Plasma Concentration –Time Profile (Analyte=VEL)
PK Substudy Analysis Set
PK Figure 5
Median (Q1, Q3) Plasma Concentration –Time Profile 
(Analyte=SOF)
PK Substudy Analysis Set
PK Figure 6
Median (Q1, Q3) Plasma Concentration –Time Profile 
(Analyte=GS-331007)
PK Substudy Analysis Set
PK Figure 7
Median (Q1, Q3) Plasma Concentration –Time Profile 
(Analyte=GS-566500)
PK Substudy Analysis Set
PK Figure 8
Median (Q1, Q3) Plasma Concentration–Time Profile 
(Analyte=VEL)
PK Substudy Analysis Set


SOF/VEL Fixed-Dose Combination
GS-US-342-2083 Statistical Analysis Plan
Version 1
CONFIDENTIAL
Page 40
20 February 2018
Listing
Number
Title
Analysis Set
1#
Subject Disposition
Safety Analysis Set
2.1
Subjects Who Were Excluded from Safety and Full 
Analysis Sets
Enrolled Subjects
2.2
Inclusion and Exclusion Criteria Not Met
Subjects Not Treated 
3.1
Subject Demographics and Baseline Characteristics
Safety Analysis Set
3.2*
Transplant Information and Donor Characteristics
Safety Analysis Set
4
Medical History
Safety Analysis Set
5.1
Study Drug Administration
Safety Analysis Set
5.2
Study Drug Accountability and Adherence
Safety Analysis Set
6.1
Prior and Concomitant Medications
Safety Analysis Set
6.2
Prior HCV Medications
Safety Analysis Set
7
Immunosuppressant Medications
Safety Analysis Set
8*
All Adverse Events
Safety Analysis Set
9*
Adverse Events of Grade 3 or Above
Safety Analysis Set
10*
Adverse Events Leading to Premature Discontinuation of
SOF/VEL
Safety Analysis Set
11*
Serious Adverse Events
Safety Analysis Set
12*
Pregnancy
Safety Analysis Set
13.1*
Deaths
Safety Analysis Set
13.2*
Graft Loss
Safety Analysis Set
14*
LabPlus Laboratory Normal Ranges
15
Screen Labs: HBsAg, HIV-1,2 Ab, and Hepatitis C Ab
Safety Analysis Set
16.1*
Hematology: Hematocrit, Hemoglobin, Reticulocyte 
Count, MCV, RBC, WBC, and Platelets
Safety Analysis Set
16.2*
Hematology: WBC, Neutrophils, and Lymphocytes
Safety Analysis Set
16.3*
Hematology: Eosinophils, Basophils, and Monocytes
Safety Analysis Set
17.1*
Chemistry: Sodium, Potassium, Serum Creatinine, 
Creatinine Clearance (Cockcroft-Gault), and Glucose
Safety Analysis Set
17.2*
Chemistry: AST, ALT, Total Bilirubin, Direct Bilirubin, 
Alkaline Phosphatase, GGT, Albumin, and Lipase
Safety Analysis Set
18*
Coagulation Tests: INR and APTT
Safety Analysis Set
19.1
Urinalysis: Urine Blood, Glucose, pH, Protein, 
Urobilinogen, and Leukocyte Esterase
Safety Analysis Set
19.2
Urinalysis: RBC/HPF, WBC/HPF, Epithelial Cells, and 
Bacteria
Safety Analysis Set


SOF/VEL Fixed-Dose Combination
GS-US-342-2083 Statistical Analysis Plan
Version 1
CONFIDENTIAL
Page 41
20 February 2018
Listing
Number
Title
Analysis Set
20
Subjects with Postbaseline Hemoglobin < 10 g/dL and 
<8.5 g/dL
Safety Analysis Set
21
HCV RNA (log10 IU/mL) by Visit
Full Analysis Set
22.1
Subjects with Virologic Failure
Full Analysis Set
22.2
Subjects with Other Virologic Outcome
Full Analysis Set
23
Height, Weight, BMI, and Vital Signs
Safety Analysis Set
24
12–Lead Electrocardiogram (ECG) Results
Safety Analysis Set
25
Pretransplant Native Model for End Stage Liver Disease 
(MELD) Scores
Safety Analysis Set
26
Pretransplant Child-Pugh-Turcotte (CPT) Scores
Safety Analysis Set
PK Listing 
1
Plasma PK Sampling Details and PK Concentrations
PK Analysis Set
* Included in DMC analysis.
#=Premature discontinuations from study drug will be produced for DMC Meeting.