A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose Combination and Ribavirin for 12 Weeks in Subjects With Chronic HCV Infection and Child-Pugh-Turcotte Class C Cirrhosis
Phase: PHASE2
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy 
and Safety of Sofosbuvir/Velpatasvir Fixed-Dose Combination and 
Ribavirin for 12 Weeks in Subjects with Chronic HCV Infection and 
Child-Pugh-Turcotte Class C Cirrhosis
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
118605
2016-003066-10
Not Available
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-342-4022
Gilead Study Director:
Name:
Telephone:
Fax:
Email:
Protocol Version/Date:
Original: 
26 August 2016
Amendment 1:
22 November 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
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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.
Sofosbuvir/Velpatasvir Fixed-Dose Combination .................................................................................15
1.2.1.
General Information .............................................................................................................15
1.3.
Ribavirin (RBV).....................................................................................................................................15
1.4.
Rationale for This Study ........................................................................................................................15
1.5.
Rationale for Dose Selection of SOF/VEL ............................................................................................16
1.6.
Rationale for Dose Selection of Ribavirin..............................................................................................16
1.7.
Risk/Benefit Assessment for the Study..................................................................................................17
1.8.
Compliance ............................................................................................................................................17
2.
OBJECTIVES.....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Study Design..........................................................................................................................................19
3.2.
Visit Schedule ........................................................................................................................................19
3.3.
Duration of Treatment............................................................................................................................19
3.4.
Treatment Discontinuation.....................................................................................................................19
3.4.1.
Treatment Discontinuation Criteria......................................................................................19
3.4.2.
Toxicity-Based Stopping Criteria.........................................................................................20
3.5.
Virologic Response-Based Stopping Criteria.........................................................................................20
3.6.
Substudies and Registry Studies.............................................................................................................21
3.6.1.
 
...............................................................................................................................21
3.6.2.
Sequence Registry Study (GS-US-248-0123)......................................................................21
3.6.3.
Cirrhosis SVR Registry Study (GS-US-337-1431)..............................................................21
4.
SUBJECT POPULATION..................................................................................................................................22
4.1.
Number of Subjects and Subject Selection ............................................................................................22
4.2.
Inclusion Criteria....................................................................................................................................22
4.3.
Exclusion Criteria...................................................................................................................................23
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................26
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................26
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................26
5.2.1.
Formulation..........................................................................................................................26
5.2.2.
Packaging and Labeling .......................................................................................................26
5.2.3.
Storage and Handling...........................................................................................................26
5.3.
Description and Handling of Ribavirin (RBV) ......................................................................................27
5.3.1.
Formulation..........................................................................................................................27
5.3.2.
Packaging and Labeling .......................................................................................................27
5.3.3.
Storage and Handling...........................................................................................................27
5.4.
Dosage and Administration of SOF/VEL and RBV...............................................................................27
5.5.
Prior and Concomitant Medications.......................................................................................................28
5.6.
Accountability for SOF/VEL+RBV.......................................................................................................31
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5.6.1.
Study Drug Return or Disposal ............................................................................................31
6.
STUDY PROCEDURES ....................................................................................................................................32
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................32
6.1.1.
Screening Visit (Day -28 to Day 0)......................................................................................32
6.2.
Treatment Phase: Treatment Assessments .............................................................................................34
6.2.1.
Day 1 Assessments...............................................................................................................34
6.2.2.
Study Drug Administration ..................................................................................................35
6.2.3.
Week 2 (3 days) ................................................................................................................35
6.2.4.
Weeks 4 and 8 (3 days) .....................................................................................................36
6.2.5.
Week 12 (3 days) or Early Termination............................................................................37
6.3.
Posttreatment Assessments ....................................................................................................................38
6.3.1.
4-Week Posttreatment Visit (5 days).................................................................................38
6.3.2.
12 & 24 Week Posttreatment Visit (5 days)......................................................................38
6.4.
Assessments for Premature Discontinuation from Study.......................................................................39
6.5.
Procedures and Specifications................................................................................................................39
6.5.1.
Clinical Laboratory Analytes ...............................................................................................39
6.5.2.
Medical History....................................................................................................................40
6.5.3.
Complete Physical Examination...........................................................................................40
6.5.4.
Height & Weight Measurement............................................................................................40
6.5.5.
Vital Signs............................................................................................................................40
6.5.6.
Body Mass Index (BMI).......................................................................................................41
6.5.7.
MELD and CPT Score Calculations.....................................................................................41
6.5.8.
Creatinine Clearance ............................................................................................................42
6.5.9.
12-Lead ECG........................................................................................................................42
6.5.10.
Viral Sequencing (Archive)..................................................................................................42
6.5.11.
Single Pharmacokinetic (PK) Sample ..................................................................................42
6.5.12.
HBV DNA Sample...............................................................................................................42
6.5.13.
IL28B Testing ......................................................................................................................43
6.5.14.
Archive Plasma Sample........................................................................................................43
6.5.15.
..................................................................................................43
6.5.16.
Pregnancy Testing................................................................................................................43
6.5.17.
Health Related Quality of Life Survey.................................................................................43
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................44
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................44
7.1.1.
Adverse Events.....................................................................................................................44
7.1.2.
Serious Adverse Events........................................................................................................44
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................45
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................45
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................45
7.2.2.
Assessment of Severity ........................................................................................................46
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................46
7.3.1.
Adverse Events.....................................................................................................................46
7.3.2.
Serious Adverse Events........................................................................................................46
7.4.
Gilead Reporting Requirements.............................................................................................................48
7.5.
Toxicity Management ............................................................................................................................48
7.5.1.
Dose Adjustments ................................................................................................................48
7.5.2.
Management of Rejection ....................................................................................................48
7.6.
Special Situations Reports......................................................................................................................49
7.6.1.
Definitions of Special Situations..........................................................................................49
7.6.2.
Instructions for Reporting Special Situations.......................................................................50
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8.
STATISTICAL CONSIDERATIONS................................................................................................................52
8.1.
Analysis Objectives and Endpoints........................................................................................................52
8.1.1.
Analysis Objectives..............................................................................................................52
8.1.2.
Primary Endpoint .................................................................................................................52
8.1.3.
Secondary Endpoint .............................................................................................................53
8.1.4.
Other Endpoints of Interest ..................................................................................................53
8.2.
Analysis Conventions.............................................................................................................................53
8.2.1.
Analysis Sets ........................................................................................................................53
8.2.2.
Data Handling Conventions .................................................................................................54
8.3.
Demographic Data and Baseline Characteristics ...................................................................................55
8.4.
Efficacy Analysis ...................................................................................................................................55
8.4.1.
Primary Analysis..................................................................................................................55
8.4.2.
Secondary Analyses .............................................................................................................55
8.5.
Safety Analysis.......................................................................................................................................55
8.5.1.
Extent of Exposure...............................................................................................................56
8.5.2.
Adverse Events.....................................................................................................................56
8.5.3.
Laboratory Evaluations ........................................................................................................56
8.5.4.
Other Safety Evaluations......................................................................................................57
8.6.
Pharmacokinetic Analysis......................................................................................................................57
8.7.
Sample Size............................................................................................................................................57
9.
RESPONSIBILITIES..........................................................................................................................................58
9.1.
Investigator Responsibilities ..................................................................................................................58
9.1.1.
Good Clinical Practice..........................................................................................................58
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................58
9.1.3.
Informed Consent.................................................................................................................58
9.1.4.
Confidentiality......................................................................................................................59
9.1.5.
Study Files and Retention of Records ..................................................................................59
9.1.6.
Case Report Forms...............................................................................................................60
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................61
9.1.8.
Inspections............................................................................................................................61
9.1.9.
Protocol Compliance............................................................................................................62
9.2.
Sponsor Responsibilities ........................................................................................................................62
9.2.1.
Protocol Modifications.........................................................................................................62
9.2.2.
Study Report and Publications .............................................................................................62
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................62
9.3.1.
Payment Reporting...............................................................................................................62
9.3.2.
Access to Information for Monitoring..................................................................................63
9.3.3.
Access to Information for Auditing or Inspections ..............................................................63
9.3.4.
Study Discontinuation..........................................................................................................63
10.
REFERENCES ...................................................................................................................................................64
11.
APPENDICES ....................................................................................................................................................66
Appendix 1.
Investigator Signature Page....................................................................................................67
Appendix 2.
Study Procedures Table..........................................................................................................68
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............70
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................92

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LIST OF IN-TEXT TABLES
Table 5-1.
Suggested Dose Administration of RBV................................................................................28
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution .....................................29
Table 6-1.
Child-Pugh-Turcotte Classification of the severity of cirrhosis .............................................41

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy 
and Safety of Sofosbuvir/Velpatasvir Fixed-Dose Combination and 
Ribavirin for 12 Weeks in Subjects with Chronic HCV Infection and 
Child-Pugh-Turcotte Class C Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
118605 
2016-003066-10
Not Available
Study Centers 
Planned:
Approximately 20 centers in United States and Europe
Objectives:
The primary objectives of this study are:

To evaluate the efficacy of treatment with sofosbuvir 
(SOF)/velpatasvir (VEL) fixed-dose combination (FDC) with 
ribavirin (RBV) for 12 weeks in subjects with chronic hepatitis C 
virus (HCV) infection and Child-Pugh-Turcotte (CPT) class C 
cirrhosis as measured by the proportion of subjects with sustained 
viral response 12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability of the treatment regimen 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 
24 weeks after cessation of the study treatment regimen (SVR4 
and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate therapeutic efficacy as measured by the change of
CPT score and Model for End Stage Liver Disease (MELD) score

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation treatment

To evaluate the emergence of viral resistance to SOF and VEL 
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The exploratory objectives of this study are:
 
 
Study Design:
Approximately 50 subjects with chronic HCV infection and CPT 
Class C cirrhosis will be enrolled and treated with SOF/VEL 
Fixed-Dose Combination (FDC) tablet with RBV for 12 weeks. 
Substudies and 
Registry Studies:
  
Sequence Registry Study (GS-US-248-0123)
Subjects who do not achieve SVR will be eligible for enrollment in an 
Observational Sequence Registry Study. The purpose of the Sequence
Registry Study will be to monitor the persistence of HCV resistant 
mutations. The Sequence Registry Study is described in a separate 
protocol.
Cirrhosis SVR Registry Study (GS-US-337-1431)
Cirrhotic subjects who achieve SVR will be eligible for enrollment in 
the Cirrhosis SVR Registry Study. The purpose of the Cirrhosis SVR
Registry Study will be to evaluate durability of SVR and the 
progression or regression of liver disease for up to 5 years 
posttreatment.  The Cirrhosis SVR Registry Study is described in a 
separate protocol.
Number of Subjects 
Planned:
Approximately 50 subjects
Target Population:
Adults with chronic HCV infection and CPT C cirrhosis.
Duration of 
Treatment:
12 weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic HCV infected, male and non-pregnant/non-lactating female 
subjects aged 18 years or older with CPT C cirrhosis. 
See the Sections 4.2 and 4.3 for full eligibility criteria.
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Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. The screening window can be extended to 42 days for subjects 
in extenuating circumstances with Sponsor approval.
All subjects will complete the following study visits: Screening, 
Day 1, on-treatment visits at the end of Weeks 2, 4, 8, and 12, and 
posttreatment visits at Week 4 and 12, after completion of treatment.  
Subjects who achieve SVR12 will complete the posttreatment 
Week 24 visit. 
Screening assessments will include obtaining informed consent, 
physical examination, medical history, height, weight, vital signs, 
12-lead electrocardiogram (ECG),  adverse events (AEs) related to 
screening procedures, concomitant medications, safety laboratory 
tests (including hematology, chemistry, and coagulation), calculation 
of CPT and MELD scores, HCV RNA, HCV genotyping, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c), screening for 
hepatocellular carcinoma (HCC), serum β-hCG (females of child 
bearing potential only),  IL28B genotyping, urinalysis and urine drug 
screen.
On-treatment assessments include AEs, concomitant medications, 
calculation of CPT and MELD scores, study drug pill count, physical 
examination, weight, vital signs, safety laboratory tests, HCV RNA, 
HRQoL surveys, urinalysis and urine pregnancy tests (females of 
child bearing potential only).
Single 12-lead ECGs will be collected at Screening and Day 1 (prior 
to study drug administration). At the time of ECG collection, printed 
copies (paper) will be reviewed by qualified study staff (as 
determined by the Investigator).
Posttreatment assessments include AEs, concomitant medications, 
vital signs, weight, safety laboratory tests, calculation of CPT and 
MELD scores, pregnancy prevention counseling, physical 
examination, HCV RNA, HRQoL surveys, and urine pregnancy tests 
(females of child bearing potential only).
HRQoL surveys (SF-36, CLDQ-HCV, FACIT-F, and WPAI) will be 
conducted at Day 1, on-treatment Week 12, Early Termination (ET)
(if applicable), and posttreatment Weeks 12 (if applicable).
Samples for viral RNA sequencing/phenotyping will be collected at 
Day 1 and every visit thereafter. Samples will be collected during 
on-treatment visits for pharmacokinetic (PK) analysis of study drugs. 
For subjects who are Hepatitis B core antibody positive (HBcAb+), 
HBV DNA will be measured at Day 1, on-treatment Weeks 4, 8, 12, 
and posttreatment Weeks 4, 12, and 24.

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Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL FDC is manufactured as a 400 mg/100 mg FDC tablet for 
oral administration. Subjects will take 1 tablet daily with or without 
food. 
RBV is manufactured as a 200 mg tablet for oral administration. 
Subjects will take a starting dose of 600 mg RBV with food in a 
divided daily dose. 
If the starting dose is well-tolerated, RBV can be titrated up to a 
maximum of 1000-1200 mg daily (1000 mg for subjects 
weighing < 75 kg and 1200 mg for subjects weighing 75 kg) 
divided twice daily. If the starting dose is not well tolerated, the dose 
should be reduced as necessary.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
AEs and laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep®/COBAS® TaqMan® HCV 
Quantitative Test, v2.0.
Efficacy will also be assessed based on MELD and CPT scores on-
treatment and posttreatment.
Pharmacokinetics:
A single PK blood sample will be collected at each on-treatment visit 
for all subjects. 
The PK of SOF (and metabolites), VEL and RBV may be assessed.
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Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. In the primary efficacy analysis, point estimate 
and 95% confidence interval (using the Clopper-Pearson method) of 
SVR12 will be computed.
Secondary endpoints include SVR4 and SVR24; proportion of 
subjects who have HCV RNA < LLOQ by visit while on study 
treatment; absolute and change from Day 1 in HCV RNA; virologic 
failure; and change from Day 1 in MELD and CPT scores.
With a sample size of approximately 50 subjects, a 2-sided 95% exact 
confidence interval of the SVR12 rate will extend at most 29% in 
length.
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
ACR
acute cellular rejection
AE
adverse event
AFP
alpha-fetoprotein
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
BMI
body mass index
CK
creatine kinase
CT
computed tomography
ClCr
creatinine clearance
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CPT
Child-Pugh-Turcotte 
CSA
colony stimulating agents
DAA
direct acting antiviral
DCV
daclatasvir
dL
deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form(s)
ESA
erythropoiesis stimulating agent
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
GCP
Good Clinical Practice (Guidelines)
GM-CSF
granulocyte-macrophage colony stimulating factor
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBcAb
Hepatitis B core antibody

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HBcAb+
Hepatitis B core antibody positive
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBsAg+
Hepatitis B surface antigen positive
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
HRQoL
Health-Related Quality of Life
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
kilogram
L
liter
LDV
ledipasvir, GS-5885
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End Stage Liver Disease
mg
milligram
mL
milliliter
min
minute
mmHg
millimeters mercury
MRI
magnetic resonance imaging
NS (3/4A/5A/5B)
non-structural protein
PBMC
peripheral blood mononuclear cell(s)
P-gp
P-glycoprotein
PK
pharmacokinetic
PPI
proton pump inhibitor
RBC
red blood cell count
RBV
ribavirin
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RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SmPC
Summaries of Product Characteristics
SOC
System Organ Class
SOF
sofosbuvir, GS-7977
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
TIPS
transjugular intrahepatic portosystemic shunt
ULN
upper limit of the normal range
US
United States
US PI
United States Package Insert
VEL
velpatasvir, GS-5816
WBC
white blood cell 

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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus infection is a global health challenge with the estimated number of persons 
infected ranging from 80 to 150 million worldwide {Gower et al 2014, World Health 
Organization (WHO) 2014}. Hepatitis C virus has significant genetic (RNA sequence) 
variability and is classified on this basis into at least 6 genotypes. There is significant 
geographical variation in the distribution of HCV genotypes. In North America and Europe, 
genotype 1 HCV infection predominates. In Asia, genotype 1 and 3 HCV infection are the most 
prevalent. Genotype 4, 5 and 6 are highly prevalent in Northern Africa, Southern Africa, and 
Southeast Asia, respectively. 
The disease burden of HCV infection is due to progression of chronic liver disease, which can 
lead to cirrhosis, liver failure, hepatocellular carcinoma, and death. Globally, 27% of all patients 
with cirrhosis and 25% of those who develop hepatocellular carcinoma are attributable to HCV 
infection {Perz et al 2006}. In addition to having a higher incidence of hepatocellular carcinoma, 
patients with chronic HCV infection have a higher incidence and mortality of many types of 
nonliver cancers including pancreatic, rectal, kidney, non-Hodgkin lymphoma and lung cancers, 
compared with the general population {Allison et al 2015}. Curing HCV infection is associated 
with numerous health benefits including more than 70% reduction in the risk of hepatocellular 
carcinoma and a 90% reduction in the risk of liver-related mortality and liver transplantation 
{Morgan et al 2013, Poynard et al 2002, van der Meer et al 2012, Veldt et al 2007}.
Recently, there has been a transformation in the treatment of HCV infection with the 
development of DAAs targeting viral proteins essential to viral replication. DAA based treatment 
regimens are generally well tolerated and result in high rates of sustained virologic response at 
12 weeks following completion of all treatment (SVR12) across most patient populations 
{Gilead Sciences Inc 2013, Gilead Sciences Inc 2016a, Gilead Sciences Inc 2016b}. 
Sofosbuvir-based regimens (Sovaldi® and Harvoni®) are the most widely prescribed treatments 
for HCV infection due to the efficacy, tolerability, and simplicity of the dosing regimens. In 
addition, sofosbuvir-based regimens offer the advantages of having relatively few drug-drug 
interactions, strong concordance between clinical trial and “real world” data, and absence of a 
requirement for baseline NS5A polymorphism testing{Ioannou et al 2016} The recent approvals 
in the US and EU of Epclusa®, a fixed dose combination of sofosbuvir and velpatasvir is an 
important advance in HCV drug development as Epclusa® is highly efficacious across all HCV 
genotypes whereas previously approved regimens were HCV genotype specific {Arias et al 
2016, Gilead Sciences Inc 2013, Gilead Sciences Inc 2016a, Gilead Sciences International Ltd 
2016, Ioannou et al 2016}. 
Despite the progress made in the development of effective treatments for HCV infection, many 
challenges remain. These include the evaluation of DAA based regimens in patient populations 
not evaluated in registration clinical studies, such as patients with advanced hepatic disease, or 
advanced renal disease and pediatric populations. In addition, the treatment of populations with 
high HCV prevalence such as the incarcerated or injection drug users will require the 

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development of treatment models tailored to these specific populations. Finally, as the highest 
prevalence of HCV infection occurs in low and middle income countries, the development of 
treatment algorithms that can be implemented in resource limited settings will be necessary to 
decrease the global prevalence and burden of HCV.
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination
Sofosbuvir (SOF) is a nucleotide analog HCV NS5B polymerase inhibitor. Velpatasvir (VEL) is 
a pangenotypic HCV NS5A inhibitor. SOF/VEL (Epclusa®) is a co-formulation of SOF 400 mg 
and VEL 100 mg that is approved in the US, EU and other regions for the treatment of HCV 
infection in adults.
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
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {Roche Laboratories Inc. 2010, Roche Products Limited 2010}. 
Ribavirin monotherapy has little or no effect on the replication of HCV in vivo but can result in
normalization of serum ALT activity and improvement in liver histology. 
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment, and in the case of males, impregnating a female while on RBV and up 
to 7 months following completion of therapy.
A comprehensive review of RBV is contained in the US PI or SmPC.
1.4.
Rationale for This Study
The GS-US-342-4022 study is a Phase 2 multicenter, open-label study evaluating 
SOF/VEL +RBV for 12 weeks in subjects with HCV infection and Child-Pugh-Turcotte (CPT) 
class C (CPT C) cirrhosis. Approximately 50 subjects will be enrolled.

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SOF/VEL with RBV for 12 weeks is approved in the US and EU (as Epclusa®) for the treatment 
of HCV infection in patients with decompensated cirrhosis based on the results of the ASTRAL-
4 study {Curry et al 2015}. However, of the 87 HCV infected subjects treated with SOF/VEL 
and RBV for 12 weeks in the ASTRAL-4 study, 77 (89%) had CPT B cirrhosis and only 4 (5%) 
had CPT C cirrhosis at baseline. The regimen was efficacious with all 4 subjects with CPT C 
cirrhosis achieving SVR12. However 3 of 4 subjects with CPT C cirrhosis required dose 
reduction of RBV suggesting that weight-based dosing of RBV may not be appropriate for 
subjects with CPT C cirrhosis. An additional limitation of the ASTRAL-4 study was that 
subjects who had received a liver transplant were not eligible.
Given the small number of subjects with CPT C cirrhosis evaluated with SOF/VEL+RBV in the 
ASTRAL-4 study, this study will more comprehensively evaluate the safety and efficacy of 
SOF/VEL+RBV in subjects with CPT C cirrhosis including patients who have received a liver 
transplant. 
1.5.
Rationale for Dose Selection of SOF/VEL
Subjects in this study will be administered SOF/VEL, a co-formulation of SOF 400 mg and VEL 
100 mg that is approved in the US, EU and other regions as Epclusa® for the treatment of HCV 
infection in adults. 
In the Phase 3 ASTRAL 1-3 studies, treatment of HCV infected subjects without cirrhosis or 
with compensated cirrhosis for 12 weeks with SOF/VEL was well tolerated and resulted in high 
SVR12 rates. In the ASTRAL-4 study, treatment of HCV infected subjects with decompensated 
Child Pugh Turcotte class B cirrhosis with SOF/VEL and ribavirin for 12 weeks was well 
tolerated and resulted in high SVR12 rates across all HCV genotypes evaluated. 
Based on these data, the results of Phase 1 studies in subjects with hepatic impairment and 
population PK analyses from studies of HCV infected subjects, no dose adjustment of SOF/VEL 
is recommended in patients with CPT C cirrhosis. Refer to the SOF/VEL Investigator’s Brochure 
for additional information.
1.6.
Rationale for Dose Selection of Ribavirin
Data from the ASTRAL-4 and SOLAR studies support a starting dose of RBV 600 mg in 
combination with SOF/VEL  for  subjects with CPT C cirrhosis in this study.
The ASTRAL-4 study evaluated the safety and efficacy of SOF/VEL with and without weight 
based RBV (1000-1200 mg) for 12 weeks and SOF/VEL for 24 weeks in patients with 
decompensated cirrhosis. Of 87 subjects treated with SOF/VEL and RBV for 12 weeks, 
77 (89%) had CPT B cirrhosis and 4 (5%) had CPT C cirrhosis at baseline. RBV dose reduction 
was required by approximately one third of subjects with CPT B cirrhosis compared with 3 of 
4 subjects with CPT C cirrhosis suggesting that weight based (1000-1200 mg) RBV dosing was 
less tolerated in patients with CPT C cirrhosis compared with patients with CPT B cirrhosis.

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The SOLAR-1 and SOLAR -2 studies evaluated ledipasvir (LDV) /SOF and RBV 600mg for 
12 or 24 weeks in pre- and posttransplant patients including patients with decompensated 
cirrhosis{Charlton et al 2015, Manns et al 2016}. In these studies, treatment of subjects with 
CPT C cirrhosis with LDV/SOF and RBV 600mg for 12 or 24 weeks was well tolerated and 
resulted in high SVR12 rates. Based on the SOLAR data, the US PI and EU SmPC for Harvoni 
recommended a 600 mg starting dose of RBV in HCV infected patients with decompensated 
cirrhosis {Gilead Sciences Inc 2016b, Gilead Sciences International Ltd. 2016}.
1.7.
Risk/Benefit Assessment for the Study
This study will provide information of the safety and efficacy of the combination of SOF/VEL 
plus RBV for 12 weeks in patients with CPT C decompensated cirrhosis.
The safety profile of SOF/VEL has been established in 3126 subjects, including 1558 subjects in 
the Phase 3 studies, 802 in the Phase 2 studies, 499 in the Phase 1 studies, and 267 subjects with 
decompensated cirrhosis in the Phase 3 Study GS-US-342-1137 (ASTRAL-4). No clinical safety 
issues specifically related to the combination of 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}. Overall, SOF/VEL plus RBV for 12 weeks was safe and well tolerated in patients with 
CPT B cirrhosis.  
During the conduct of the study, the sponsor will perform ongoing safety review.
In summary, safety and efficacy of SOF/VEL plus RBV for 12 weeks has been evaluated in 
subjects with CPT B decompensated cirrhosis. This study will evaluate this regimen in patients 
with more advanced liver disease.
1.8.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the efficacy of treatment with sofosbuvir (SOF)/velpatasvir (VEL) fixed-dose 
combination (FDC) with ribavirin (RBV) for 12 weeks  in subjects with chronic HCV 
infection and Child-Pugh-Turcotte (CPT) class C cirrhosis as measured by the proportion of 
subjects with sustained viral response 12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability of the treatment regimen 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
the study treatment regimen (SVR4 and SVR24) 

To evaluate the proportion of subjects with virologic failure

To evaluate therapeutic efficacy as measured by the change of CPT score and MELD score

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation 
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment
The exploratory objectives of this study are:
 
 
 
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3.
STUDY DESIGN
3.1.
Study Design
This is a multicenter, open-label study evaluating the efficacy and safety of SOF/VEL and RBV 
for 12 weeks in chronic HCV infected subjects with CPT C cirrhosis.
3.2.
Visit Schedule
Screening assessments will be completed within 28 days of the Day 1 visit.  The screening 
window can be extended to 42 days for extenuating circumstance with Sponsor approval.
All subjects will complete the following study visits: Screening, Day 1, on-treatment visits at the 
end of Weeks 2, 4, 8, and 12, and posttreatment visits at Week 4 and 12, after completion of 
treatment.  Subjects who achieve SVR12 will also complete the posttreatment Week 24 visit.
3.3.
Duration of Treatment
Approximately 50 subjects will be enrolled and treated with SOF/VEL tablet once daily and 
600-1200 mg RBV in a divided daily dose with food.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those 
requiring extension of the Screening period):

28 days (4 week) screening period (or 42 days for extenuating circumstances)

12 week study treatment period

24 week posttreatment period
3.4.
Treatment Discontinuation 
3.4.1.
Treatment Discontinuation Criteria
If a subject discontinues study dosing (for example, as a result of an adverse event [AE]), every 
attempt should be made to keep the subject in the study and continue to perform the required 
study-related follow-up procedures (see Section 6.4). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study.
There is no option for SOF/VEL dose reduction due to toxicity. If SOF/VEL is withheld due to 
toxicity, the subject must discontinue treatment and complete an Early Termination (ET) visit. 
Subjects that require discontinuation of only RBV for RBV-related events should continue with 
SOF/VEL for the remainder of the treatment period and complete all scheduled study visits. 

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For subjects who have completed an ET visit, the posttreatment Week 4, and 12 visits will be 
completed after the last dose of the study drug. Subjects who achieve SVR12 will complete a 
posttreatment Week 24 visit.  
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. 
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 3.4.2, or toxicity that in the opinion of the 
investigator compromises that ability of the subject to participate in the study or is considered 
to not be in the best interest of the subject

Virologic failure (as defined in Section 3.5)

Pregnancy of female subject or female partner of male subject 

Significant protocol violation including non-compliance with study assessments

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)
3.4.2.
Toxicity-Based Stopping Criteria
Subjects who meet any of the following laboratory or adverse event criteria must stop treatment 
with SOF/VEL:

Confirmed total bilirubin > 3x Day 1 or nadir and ALT and/or AST > 3x Day 1 or nadir

Elevation of alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) > 10x Day 1 or nadir, confirmed by immediate repeat testing

Elevation of ALT >15x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any non-laboratory Grade 4 event assessed as related to administration of SOF/VEL, study 
drugs should be discontinued immediately
3.5.
Virologic Response-Based Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

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
Confirmed >1 log10  increase from on-treatment nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
3.6.
Substudies and Registry Studies
 
 
 
 
 
3.6.2.
Sequence Registry Study (GS-US-248-0123)
Subjects who do not achieve SVR will be eligible for enrollment in an observational Sequence 
Registry Study. The purpose of the Sequence Registry Study will be to monitor the persistence of 
HCV resistant mutations. The Sequence Registry Study is described in a separate protocol.
3.6.3.
Cirrhosis SVR Registry Study (GS-US-337-1431)
Cirrhotic subjects who achieve SVR will be eligible for enrollment in the Cirrhosis SVR 
Registry Study. The purpose of the Cirrhosis SVR Registry Study will be to evaluate durability 
of SVR and the progression or regression of liver disease for up to 5 years posttreatment. The 
Cirrhosis SVR Registry Study is described in a separate protocol.
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects will be enrolled in this study.  
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 or study-wide 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
2) Males and females, age  ≥ 18 years old
3) A body mass index (BMI) of ≥ 18 kg/m2
4) Chronic HCV infection (≥ 6 months) as documented by either prior medical history or liver 
biopsy
5) Quantifiable HCV RNA at Screening
6) Subjects may be non-transplanted or with recurrent HCV post-liver transplant. 
a.
If listed for liver transplant, then the projected date of transplant must be ≥12 weeks 
after Day1 of treatment 
b. If post-liver transplant, then Day1 must be ≥ 6 months from date of transplant
7) CPT score of 10 to 12, inclusive, as determined at Screening
8) Liver imaging within 6 months of Day 1 to exclude HCC
9) If treatment-experienced, the most recent HCV treatment must have been completed at least 
8 weeks prior to Screening
10) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to 
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11) 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
12) Female subjects must agree to refrain from egg donation and in vitro fertilization during 
treatment until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose 
of RBV, whichever occurs last
13) Lactating females must agree to discontinue nursing before the study drugs are administered
14) Male subjects must agree to refrain from sperm donation from the date of Screening until at 
least 7 months after the last dose of RBV or 30 days after the last dose of SOF/VEL, 
whichever occurs last
15) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically significant medical or psychiatric illness or subjects is currently under 
evaluation for a potentially clinically significant illness (other than HCV or 
co-morbidities associated with advanced liver disease except as noted below) or any other 
medical or psychiatric disorder that may interfere with subject treatment, assessment or 
compliance with the protocol  
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug 
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy
d) Significant pulmonary disease, significant cardiac disease or porphyria
e) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc.).  Subjects under 
evaluation for possible malignancy are not eligible
f)
Significant drug allergy (such as anaphylaxis or hepatotoxicity) 
2) Any history of organ transplant other than liver or kidney
3) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 
antitrypsin deficiency, cholangitis)

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4) Inability to exclude HCC by imaging within 6 months of Day 1 (including indeterminate 
hepatic nodule meeting OPTN Class 5 criteria, defined by arterial enhancement with washout 
on portal venous/delayed phase OR rate of growth maximum diameter increase in the 
absence of ablative therapy by 50% or more documented on serial magnetic resonance 
imaging (MRI) or computed tomography (CT) obtained <6 month apart)
5) Alpha-fetoprotein (AFP) > 50 unless negative imaging for hepatic masses within the last
6 months or during screening
6) Active spontaneous bacterial peritonitis at Screening
7) Infection requiring systemic antibiotics at the time of Screening
8) Evidence of fibrosing cholestatic hepatitis at Screening
9) Life threatening SAE during Screening
10) Active variceal bleeding within 6 months of Screening
11) Prior placement of a portosystemic shunt (such as TIPS)
12) ECG with clinically significant abnormalities
13) Laboratory parameters at Screening: 
a) Hemoglobin < 10 g/dL
b) Platelets < 30,000/L
c) ALT > 10 the upper limit of normal  (ULN)
d) AST > 10 ULN
e) Alkaline phosphatase > 10 x ULN
f)
Sodium <125 mEq/L
g) Total bilirubin > 10 mg/dL
h) Creatinine clearance (CLcr) < 30 mL /min, as calculated by the Cockcroft-Gault equation 
{Cockcroft et al 1976} using actual body weight
14) Hepatitis B surface antigen positive (HBsAg+) at Screening
15) Infection with human immunodeficiency virus (HIV)

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16) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the Investigator.
17) Prior exposure to any HCV NS5A inhibitor
18) Current use of corticosteroids at any dose >10 mg of prednisone/day (or equivalent dose of 
corticosteroid)
19) Use of any prohibited concomitant medications as described in Section 5.5
20) Use of GM-CSF, epoetin alfa or other hematopoietic stimulating agents within 2 weeks of 
Screening.
21) Male with pregnant female partner. 
22) History of clinically significant hemoglobinopathy (eg, sickle cell disease, thalassemia)
23) Contraindications to RBV therapy
24) Known hypersensitivity to VEL, RBV, SOF, the metabolites, or formulation excipients
25) Participation in a clinical study with an investigational drug or biologic within 3 months prior 
to Day 1
Exclusion criteria that are specific to subjects who have not had a liver transplant
26) Medical justification for any MELD exception points (such as for HCC, current 
hepatopulmonary syndrome, intractable encephalopathy, or any other reason)
27) History of hepatopulmonary syndrome
Exclusion criteria that are specific to subjects who have had a liver transplant
28) Recipient of ABO incompatible organ
29) Histological evidence of unresolved rejection of liver transplant
30) Patients who had evidence of HCC at time of transplant must be 5 years posttransplant with 
no evidence of recurrence at Screening
31) Use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents or
cyclosporine >300mg/day, or use of any prohibited medications listed in Section 5.4

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a multicenter, open label study.  All subjects enrolled will receive SOF/VEL and RBV for 
12 weeks.  There will be no randomization or blinding.
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL (400/100 mg) 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.
5.2.2.
Packaging and Labeling
SOF/VEL (400/100 mg) 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.
5.2.3.
Storage and Handling
SOF/VEL 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 to complete the entire study will be shipped to the investigator 
or qualified designee from the Gilead Supply Management Team (or its designee).

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5.3.
Description and Handling of Ribavirin (RBV)
5.3.1.
Formulation
RBV tablets, 200 mg, are light blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. See package insert for further information.
The RBV tablets being supplied by Gilead Sciences are a US marketed formulation of RBV.
5.3.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. 
All RBV bottles to be distributed to centers in the participating countries and shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA), EU Guideline 
to Good Manufacturing Practices- Annex 13 (Investigational Medicinal Products), and/or other 
local regulations as applicable.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.
5.3.3.
Storage and Handling
RBV tablets should be stored at 25 °C (77 °F); excursions are permitted between 15 and 30 °C 
(59 and 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 RBV.
5.4.
Dosage and Administration of SOF/VEL and RBV
SOF/VEL 400/100 mg tablets will be administered once daily. RBV 200 mg tablets will be 
administered twice daily at a starting dose of 600 mg. RBV should be taken in a divided daily 
dose with food (Table 5-1). If the starting dose is well-tolerated and the subject maintains a 
hemoglobin level above 10 g/dL without the need for significant growth factor support, the dose 
can be titrated up to a maximum of 1000-1200 mg daily (1000 mg for subjects weighing <75 kg 
and 1200 mg for subjects weighing ≥75 kg). If the starting dose is not well-tolerated, the dose 
should be reduced as necessary.

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Table 5-1.
Suggested Dose Administration of RBV
Total Daily RBV dose
AM dose
PM dose
200 mg
1 tablet
--
400 mg
1 tablet
1 tablet
600 mg
1 tablet
2 tablets
800 mg
2 tablets
2 tablets
1000 mg
2 tablets
3 tablets
1200 mg
3 tablets
3 tablets
All subjects should be instructed to maintain approximately the same daily dosing interval 
between study drug doses. To aid compliance, it is suggested that SOF/VEL is administered with 
either the morning or evening dose of RBV with food.
For missed dose(s) of SOF/VEL, subjects should be instructed to take the missed dose of study 
drug as soon as possible during the same day.  Subjects should be cautioned never to double the 
next dose of SOF/VEL with a missed dose under any circumstances.  
For missed dose(s) of RBV, subjects should be instructed to take the missed dose(s) of study 
drug as soon as possible, unless more than 6 hours has elapsed since the scheduled time of the 
missed dose. In this case, the subject should be instructed to wait and take the next dose at the 
regularly scheduled time. No more than the daily dose of RBV should be taken on any calendar 
day. Subjects should be cautioned never to double the next dose with a missed dose of study drug 
under any circumstances. 
No food restrictions apply to SOF/VEL. However as RBV must be taken with food hence it is 
suggested that when SOF/VEL is taken with RBV, both drugs should be taken together and with 
food for optimal adherence.
5.5.
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 drug, need to be recorded in the source documents and eCRFs 
(including all blood products).
For subjects on a calcineurin inhibitor (eg, tacrolimus, sirolimus, everolimus) for posttransplant 
immunosuppression, drug levels should be measured as per the standard schedule (or as 
clinically indicated) for dose management at the clinical site, and processed at the local
laboratory. Management of the immunosuppression is not part of the clinical protocol, but levels
and resulting dose adjustments will be recorded to assess whether the regimens required
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Chronic use of corticosteroids at any dose > 10mg of prednisone/day (or equivalent dose of
corticosteroid) for maintenance of immunosuppression is prohibited from 28 days prior to the 
Day 1 visit through the end of study drug dosing. Use of steroids for the short term treatment of 
Acute Cellular Rejection (ACR) or other reasons is up to the discretion of the Investigator.
Investigational agents or devices for any indication are prohibited from 28 days prior to the 
Day 1 visit through the end of study drug dosing.
Concomitant use of certain medications or herbal/natural supplements (such as moderate to 
potent inducers of drug transporters or metabolizing enzymes, eg, P-gp, CYP2B6, CYP2C8, 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 5-2 below contains examples of medications that are prohibited from 21 days prior to 
Day 1 through the end of treatment and those medications which may be used with caution. The 
use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment.
Additionally, Investigators should refer to the product/package inserts of other medications for 
age-related recommendations or contraindications related to their use.
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton Pump Inhibitors, H2-Receptor
Antagonists, Antacids
Anticonvulsantsb
Phenytoin, Carbamazepine, Phenobarbital, 
Oxcarbazepine
Antimycobacterialsb
Rifampicin, Rifabutin, Rifapentine
Cardiac Medications
Amiodaroned
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), Atorvastatin
Other
Bosentanb, Modafinil b, Sulfasalazinec, 
Methotrexatec
a
Co-administration with proton pump inhibitors (PPIs) is not recommended. If it is considered necessary to co-administer, 
then SOF/VEL should be administered with food and taken 4 hours before PPI at max doses comparable to omeprazole 
20 mg. 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 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 rosuvastatin Titrate rosuvastatin dose carefully and use 
the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. Use atorvastatin with caution and at the lowest necessary 
dose. Monitor for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis

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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.
Subjects may not take any approved HCV medications during their participation in the study 
period.
5.5.1
Colony Stimulating Agents
Potential subjects may not be treated with colony stimulating agents (CSA) within 2 weeks of 
Screening to elevate hematology laboratory parameters to facilitate entry into the study. Use 
during the study is allowed as clinically indicated. Use should be captured as a concomitant 
medication.
If erythropoiesis-stimulating agents (ESAs) are used during the study, the following guidelines 
should be adhered to:

ESAs should not be initiated until the hemoglobin falls below 10 g/dL,

Iron studies should be obtained prior to and during treatment with ESA,

Iron supplementation should be initiated for deficient patients and to maintain transferrin 
saturation at a level that will support erythropoiesis,

Once an ESA is initiated, hemoglobin levels and blood pressure must be monitored weekly 
until the hemoglobin level stabilizes,

Treatment should target a hemoglobin level sufficient to avoid transfusion.

ESA dose should be titrated to treatment response,

ESA dose should be reduced if the hemoglobin increases by more than 1 g/dL in a 2 week 
period,

ESA dose should not exceed those recommended for currently approved indications,

ESAs should not be used in patients at increased risk for thromboembolic events, 
cardiovascular events, including those with inadequately controlled hypertension, and in 
patients diagnosed with malignancies.

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5.6.
Accountability for SOF/VEL+RBV
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles. This includes acknowledgement of receipt of each shipment of study drug (quantity 
and condition). All used and unused study drug bottles dispensed to subjects must be returned to 
the site.
SOF/VEL + RBV accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug kits returned, along with the initials 
of the person recording the information.
5.6.1.
Study Drug Return or Disposal
Refer to Section 9.1.7 for information on return and disposal of study drugs.

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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. 
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
This is an open-label study.  An Interactive Web Response System (IWRS) will be employed to 
manage subject screening, subject enrollment, and study drug dispensation and resupply.  
6.1.1.
Screening Visit (Day -28 to Day 0)
Subjects will be screened within 28 days prior to enrollment to determine eligibility for 
participation in the study. The screening window can be extended to 42 days with Sponsor
approval for subjects with extenuating circumstances. The following will be performed and 
documented at screening:

Obtain written informed consent
 

Determine inclusion and exclusion eligibility

Obtain medical history, including:
Hepatitis C treatment history:
■
Regimen(s)
■
Dates of previous treatment(s)
■
Response to previous treatment (eg, nonresponder, relapse, discontinuation including 
reason)
Liver transplant history

Perform 12-lead ECG

Liver Disease Assessment
Liver biopsy and/or Fibroscan results (if available)
PPD

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Assess presence and severity of ascites and hepatic encephalopathy for CPT score
Diagnostic imaging (eg, ultrasound or CT scan) should be performed to exclude the 
presence of HCC

Perform complete physical examination 

Vital signs

Body weight and height

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Review of concomitant medications

Pregnancy prevention counseling 

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of genotype and subtype of HCV infection
Serum -hCG pregnancy test for females of childbearing potential only
HCV antibody, HIV 1/2 antibody, HBsAg, HBcAb, and Hepatitis B surface antibody
(HBsAb)
HbA1c
IL28B
Fibrotest®

Obtain urine sample for:
Urinalysis
Urine Drug Screen

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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after screening for enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/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 CRF/eCRF.  
See Section 7 Adverse Events and Toxicity Management for additional details.
Retests of Screening labs are permitted only if the initial exclusionary value was either due to a
sample processing error or due to extenuating circumstances such as intercurrent illness.
6.2.
Treatment Phase: Treatment Assessments
6.2.1.
Day 1 Assessments
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed on Day 1 prior to enrollment and dosing/dispensing:

Confirm eligibility

Perform complete physical examination 

Vital signs 

Body weight 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling 

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Perform 12-lead ECG

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests

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HCV RNA
Viral sequencing
 
HBV DNA (only in subjects who are HBcAb+ at Screening)

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test for females of childbearing potential only
6.2.2.
Study Drug Administration

Dispense study drugs as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Observe the subject taking the first dose of study drugs and record the time of first dose and 
whether it was taken with or without food 
6.2.3.
Week 2 (3 days)
The following procedures/assessments are to be completed at this visit:

Vital signs

Body Weight

Assessment of AEs and concomitant medications

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Obtain blood samples for:
Hematology
Chemistry
Coagulation
PPD
PPD

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HCV RNA
Viral sequencing 
Single PK 

Assess adherence with the study drug dosing regimen including pill count
6.2.4.
Weeks 4 and 8 (3 days)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Vital signs

Body Weight

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
Hematology
Chemistry
Coagulation
HCV RNA
Viral sequencing
Single PK 
HBV DNA (only in subjects who are HBcAb+ at Screening)

Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only

Review study drug compliance with subject (subject should return all study drug at these 
visits)

Dispense study drug as directed by the IWRS

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6.2.5.
Week 12 (3 days) or Early Termination

Perform complete physical examination 

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Vital signs

Body weight 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling 

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing
Single PK 
HBV DNA (only in subjects who are HBcAb+ at Screening)

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test for females of childbearing potential only

Review study drug compliance

Subjects should return all bottles of study drug at the Week 12 Visit
PPD

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6.3.
Posttreatment Assessments
6.3.1.
4-Week Posttreatment Visit (5 days)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Vital signs

Body Weight

Assessment of AEs and concomitant medications

Pregnancy prevention counseling 

Obtain blood samples for: 
Hematology
Chemistry
Coagulation
HCV RNA
Viral sequencing
HBV DNA (only in subjects who are HBcAb+ at Screening)

Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only
6.3.2.
12 & 24 Week Posttreatment Visit (5 days)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score

Vital signs

Body Weight

Perform symptom-directed physical examination

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV,
FACIT-F, and WPAI at posttreatment Week 12 only

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
Obtain blood samples for:
Hematology
Chemistry
Coagulation
HCV RNA
Viral sequencing
HBV DNA (only in subjects who are HBcAb+ at Screening)

Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only
6.4.
Assessments for Premature Discontinuation from Study
If a subject discontinues study drug (for example, as a result of an AE), 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 3.4.1, Criteria for Discontinuation of Study Treatment). If this is 
not possible or acceptable to the subject or Investigator, the subject may be withdrawn from the 
study.
6.5.
Procedures and Specifications
6.5.1.
Clinical 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 mean corpuscular volume 
(MCV).
Coagulation: International normalized ratio (INR), prothrombin time (PT), activated partial 
thromboplastin time (APTT) 
Chemistry: Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
albumin, alkaline phosphatase, creatinine, total bilirubin and direct bilirubin, glucose, lipase, 
potassium, sodium, phosphate, uric acid, and creatine kinase (CK), 
Urinalysis: blood, glucose, leukocyte esterase, pH, protein, urobilinogen. Reflex to microscopic 
urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. HBV DNA (only in subjects who are 
HBcAb+ at Screening). Serology and/or antigen testing for HIV (including reflex testing) as 

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necessary, HCV RNA will be measured using the COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test, v2.0 for Use with the High Pure System. 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 the results are inconclusive.
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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine drug screen (for amphetamines, cocaine, methadone, opiates), 
hemoglobin A1c (HbA1c), Fibrotest.
6.5.2.
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. Obtain HCV treatment history as per Section 4.
6.5.3.
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. 
6.5.4.
Height & Weight Measurement
Height will be collected at Screening. Weight measurement will be collected at each study visit. 
The difference in body weight measurements between Day 1 and End of Treatment will be 
calculated. 
6.5.5.
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.

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6.5.6.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.5.7.
MELD and CPT Score Calculations
MELD score and CPT score will be calculated from the central laboratory values attained at each 
visit. Assessment of ascites and hepatic encephalopathy will be determined by the site as in 
below table and will be entered into the CRF. Besides calculating the CPT score at Screening 
(using central laboratory values) to determine eligibility, sites will not need to calculate these 
scores for subsequent visits.
6.5.7.1.
MELD Score
The MELD score is calculated using the following formula {MELD/PELD 2009}:
MELD = 3.8[serum bilirubin (mg/dL)] + 11.2[INR] + 9.57[serum creatinine* (mg/dL)] + 6.43
Round to the nearest whole number. Laboratory values less than 1.0 are set to 1.0 for the 
purposes of the MELD score calculation.
* If subject has had dialysis twice within a week prior to the serum creatinine measurement, or is 
within 24 hours of continuous venovenous hemodiafiltration, then default to 4 mg/dL for serum 
creatinine value in MELD calculation.
6.5.7.2.
CPT Score
Child-Pugh-Turcotte score should be assessed at all visits per Table 6-1.  
Table 6-1.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
1
2
3
Hepatic Encephalopathy
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject is receiving 
medical therapy for HE  
Medication-Refractory
Marked 
confusion/incoherent, 
rousable but sleeping 
unless aroused or 
comatosed
Ascites
None
No ascites and not on 
treatment for ascites
Mild/Moderate
Cross sectional imaging 
showing ascites
   
Abdominal distension 
  
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3

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CPT score is obtained by adding the score for each parameter.
CPT class: 
A = 5-6 points
B = 7-9 points
C = 10-15 points
Records of concomitant medications for ascites and hepatic encephalopathy will be collected in 
the CRF.  
6.5.8.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976}.
Male:
CLCr (mL/min) = [140 −age (years)] BW(kg)
72 SCr
Female:
CLCr (mL/min) = [140 −age (years)] BW(kg) 0.85
72 SCr
SCr = serum creatinine (mg/dL)
Actual body weight will be used for the CLCr.
6.5.9.
12-Lead ECG
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.
6.5.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confirming HCV virologic breakthrough, 
HCV viral sequencing/phenotype plasma sample must also be collected.  Unused samples may 
be archived.
6.5.11.
Single Pharmacokinetic (PK) Sample
Single PK blood samples will be collected for all subjects at each on-treatment visit and archived
for PK analysis of SOF (and metabolites) VEL and RBV.
6.5.12.
HBV DNA Sample
A sample for HBV DNA testing will be collected at on-treatment visits at Day 1 and at Weeks 4, 
8, and 12 or Early Termination and all posttreatment visits.  HBV DNA will only be tested in 
subjects who are HBcAb+ at Screening to monitor for HBV re-activation.  

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6.5.13.
IL28B Testing
A blood sample will be obtained at Screening for specific genetic analysis of the rs12979860 
(IL28B) genetic variant.
6.5.14.
Archive Plasma Sample
 
 
 
 
 
 
 
 
 
 
  
 
 
 
6.5.16.
Pregnancy Testing
Female subjects of childbearing potential should be provided with Urine Pregnancy test kits, 
instructed on their use, and requested to continue to self-monitor for pregnancy between 
scheduled study visits, every 4 weeks, for 6 months after their last dose of RBV.  If required by 
regulations, additional pregnancy tests beyond 6 months may be added.  The subject will be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject will be asked to return to the clinic for a 
confirmatory serum pregnancy test. 
6.5.17.
Health Related Quality of Life Survey
A health related quality of life survey, SF-36, CLDQ-HCV, FACIT-F, and WPAI, will be 
completed by patients at Day 1, Week 12 and posttreatment Week 12, and Early Termination (if 
appropriate).  The subject should read the questionnaire by himself/herself and write/mark 
answers directly onto the questionnaire.
PPD
PPD

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

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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. 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 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure

Yes: The adverse event occurred as a result of protocol procedures (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events 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 drug, the following types of events should 
be reported on the case report form (CRF/eCRF): all SAEs, regardless of cause or relationship,
and adverse events related to protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug and report to the CRF/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.
7.3.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported to the 
CRF/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 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period;
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically (ie, the eCRF 
database is not functioning) record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead Sciences, DSPH:
Fax:
E-mail:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
Medical Monitor contact information is as follows:
Gilead Medical Monitor:
Telephone:
Fax:
Email:
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management
7.5.1.
Dose Adjustments
There is no option of SOF/VEL dose reduction due to toxicity.  If SOF/VEL is withheld due to 
toxicity, the subject must discontinue treatment and complete an Early Termination (ET) visit.
Dose reduction or discontinuation of RBV due to toxicity is allowed at the discretion of the 
investigator. Once discontinued or reduced, the RBV dosing may be restarted or increased to the 
starting dose at the discretion of the investigator. RBV may be permanently discontinued due to 
toxicity without stopping SOF/VEL FDC.
7.5.2.
Management of Rejection
The diagnosis of ACR, based on liver biopsy, and the decision to treat are important concerns 
due to the potential interactions between immunosuppression and the success of HCV treatment. 
It is expected that this will not be a common occurrence in this study, given that subjects must be 
stable and at least 6 months from transplant at study entry. Sites will be asked to follow their 
institutional guidelines for the management of organ rejection, but to also give consideration to 
the following issues as related to this study protocol. (This information is provided for guidance 
and consistency across subjects, but variations will not be considered protocol violations if the 
treatment is consistent with the guidelines of the institution).

It is important to use standard criteria for diagnosis of rejection, to avoid over-treatment of 
milder grades of rejection with corticosteroids whenever possible, and to standardize the 
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
Episodes of rejection will be recorded on the CRF and severity will be graded (grading by 
Banff criteria, Appendix 3)

It is preferred that mild ACR is to be treated with upward adjustment of maintenance 
immunosuppression rather than the addition of corticosteroids

Cases of moderate or severe ACR may require treatment with corticosteroids

Cases of presumptive rejection should be confirmed by liver biopsy (as per standard practice) 
if more than one dose of corticosteroid is required

Subjects with steroid-resistant ACR should be discontinued from the study so that 
management of their organ rejection can be the primary focus of treatment.
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, occupational exposure with an AE, 
pregnancy reports regardless of an associated AE and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
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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 drug and throughout the study, including the post study drug follow-up period, 
to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
 or email 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Requirements for Liver Transplant and Complications of Liver 
Transplant
If the liver transplant procedure occurs within the AE collection window (30 days after the last 
dose of study drug), due to the nature of the subject population and the inclusion criteria, events 
that are clearly related to liver transplant should not be collected as an AE or SAE.  In addition, 
these events will be exempt from global expedited reporting requirements for the duration of the 
study. These include:
a) The liver transplant procedure itself (and related hospitalization)
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b) Events that are direct sequelae of the liver transplant (such as surgical complications) or 
peri-operative care (central line insertions, etc.)
c) 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 were not an 
anticipated or predictable part of the transplant process or procedure. 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.
7.6.2.3.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to or Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study drug and/or Gilead 
concomitant medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/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 CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the efficacy of treatment with sofosbuvir (SOF)/velpatasvir (VEL) fixed-dose 
combination (FDC) with ribavirin (RBV) for 12 weeks  in subjects with chronic HCV 
infection and Child-Pugh-Turcotte (CPT) class C cirrhosis as measured by the proportion of 
subjects with sustained viral response 12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability of the treatment regimen 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
the study treatment regimen (SVR4 and SVR24) 

To evaluate the proportion of subjects with virologic failure

To evaluate therapeutic efficacy as measured by the change of CPT score and MELD score

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation 
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment
The exploratory objectives of this study are:
 
 
 
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of study 
treatment regimen) in the Full Analysis Set (FAS).
The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
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8.1.3.
Secondary Endpoint
The secondary efficacy endpoints include the proportion of subjects who attain sustained 
virologic response at 4 and 24 weeks after cessation of the study treatment regimen (SVR4 and 
SVR24); the proportion of subjects who have HCV RNA < LLOQ by visit while on study 
treatment; CPT and MELD score changes from Day 1; absolute and change from Day 1 in HCV 
RNA through Week 12; and the proportion of subjects with virologic failure.
8.1.4.
Other Endpoints of Interest
Other endpoints of interest may include ALT normalization and change in HRQoL parameters.
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 drugs in this study are SOF/VEL + RBV. Last dose of the study drug refers to the last 
dose of SOF/VEL and RBV and will be used in the definition of treatment-emergent AEs and 
laboratory abnormalities as well as the efficacy endpoints of SVR at various posttreatment
timepoints.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy Analysis Set
The analysis set for antiviral activity analyses is defined as the Full Analysis Set (FAS) which 
includes all enrolled subjects who received at least 1 dose of the study drug.
8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will be Safety Analysis Set which includes all
subjects who took at least 1 dose of the study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of the 
study drug through the date of the last dose of the study drug plus 30 days.
8.2.1.3.
Pharmacokinetics Analysis Sets
The Pharmacokinetic (PK) Analysis Set includes all enrolled subjects who took at least 1 dose of 
study drug and have at least 1 nonmissing postdose concentration value for the corresponding 
analyte in plasma. The analytes of interest may include SOF (and its metabolites GS-566500 and 
GS-331007), VEL, and RBV. The PK Analysis Set will be used for analysis of general PK.

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8.2.2.
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 analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have 
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed 
up to the time of the last dose.
If a 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).
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs according to the treatment received; otherwise, if the subject is not dosed, then they will 
be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Day 1 result will be 
replaced with a 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 values and the change from Day 1 
values by study visit. 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 
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8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic data will include sex, self-identified race/ethnicity.
Baseline characteristic data will include body mass index, HCV RNA level (log10 IU/mL), 
genotype of HCV infection, IL28B genotype, CPT score, MELD score and additional endpoints 
as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint for this study will be the proportion of subjects with SVR12, 
defined as HCV RNA < LLOQ 12 weeks after cessation of the study treatment regimen in the 
FAS population.  Point estimate and 95% confidence interval (using the Clopper-Pearson 
method) of SVR12 will be computed.
8.4.2.
Secondary Analyses
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR4 and 
SVR24) will be presented in tabular and graphical form. Descriptive summaries and listings will 
be provided for additional efficacy evaluations of the proportion of subjects who experience 
virologic failure, serum HCV RNA actual values and change from baseline, and other endpoint
of interest including ALT normalization.
 
 
 
 
Details on efficacy analyses will be described in the statistical analysis plan.
8.5.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital
signs measurements and AEs which will be documented at various time points during the study.
All safety data collected on or after the first dose of the study drug administration up to 30 days 
after the last dose of the study drug will be summarized.
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8.5.1.
Extent of Exposure
A subject’s extent of exposure to the study drug will be generated from the study drug 
administration page of eCRF. Exposure data will be summarized. 
8.5.2.
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 the study drug or any 
adverse event leading to premature discontinuation of the study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and PT) will be provided for:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of the study drug

Deaths
All AEs collected during the study will be presented in the data listings
8.5.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) by study visit along with the corresponding change from 
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Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined in Appendix 3.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase by at 
least one toxicity grade from baseline at any time post baseline up to and including the date of 
last dose of study drug plus 30 days will be summarized.
Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the baseline value will be assumed to be normal (ie, no grade 
[Grade 0]) for the summary of graded laboratory abnormalities. If Baseline/Day 1 data are 
missing, then any post-baseline graded abnormality (ie, at least Grade 1) will be considered 
treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.5.4.
Other Safety Evaluations
Individual data and change from baseline for vital signs measurements will be listed by subject 
and summarized by descriptive statistical summaries (n, mean, SD, median, Q1, Q3, minimum, 
and maximum).
8.6.
Pharmacokinetic Analysis
Concentrations of SOF (and its metabolites GS-566500 and GS-331007), VEL, and RBV in 
plasma may be determined using validated bioanalytical assays and listed.
8.7.
Sample Size
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size. The sample size is selected for practical reasons.
With a sample size of approximately 50 subjects, a 2-sided 95% exact confidence interval of the 
SVR12 rate will extend at most 29% in length.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. 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 

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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 or 
local requirements.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, 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 or in accordance 
with local regulations. 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, CRF/eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, [ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)];
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
Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, 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 

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eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF 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
Where possible, study drug should be destroyed at the site.  If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and Gilead 
Sciences (or Gilead Sciences’ representative) for returned or unused study drug supplies. The 
study monitor will provide instructions for return.  
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead 
QA, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. Refer to the Pharmacy Binder for study drug disposal/return.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, or to regulatory authority or health authority 
inspectors.

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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
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 

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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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Medical Monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory 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
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
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.
Allison RD, Tong X, Moorman AC, Ly KN, Rupp L, Xu F, et al. Increased Incidence of Cancer 
and Cancer-related Mortality Among Persons with Chronic Hepatitis C Infection, 
2006-2010. J Hepatol 2015.
Arias A, Aguilera A, Soriano V, Benitez-Gutierrez L, Lledo G, Navarro D, et al. Rate and 
predictors of treatment failure to all-oral HCV regimens outside clinical trials. 
Antivir Ther 2016.
Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown Jr RS, et al. Ledipasvir and 
Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with 
Advanced Liver Disease. Gastroenterology 2015:649-59.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and 
Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med 
2015.
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Gilead Sciences Inc. EPCLUSA® (sofosbuvir and velpatasvir) tablets, for oral use. US 
Prescribing Information. Foster City, CA. Revised June.  2016a:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. U.S. 
Prescribing Information. Foster City, CA.  Revised June.  2016b:
Gilead Sciences International Ltd. Epclusa 400 mg/100 mg film-coated tablets (SmPC).  
2016:41. 
Gilead Sciences International Ltd. HARVONI (ledipasvir/sofosbuvir) 90 mg/400 mg Film-
Coated Tablets. Summary of Product Characteristics. Cambridge, UK. Revised 
April.  2016:
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.
Ioannou GN, Beste LA, Chang MF, Green PK, Lowey E, Tsui JI, et al. Effectiveness of 
Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and 
Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans 
Affairs National Healthcare System [Accepted Manuscript]. Gastroenterology 
2016;151:457-71.

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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.
Manns M, Samuel D, Gane EJ, Mutimer D, McCaughan G, Buti M, et al. Ledipasvir and 
sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus 
infection and advanced liver disease: a multicentre, open-label, randomised, phase 
2 trial. Lancet Infect Dis 2016;16:685-97.
MELD/PELD. Calculator Documentation. 28 January.  2009:
Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of Hepatitis C 
Virus Infection and the Development of Hepatocellular Carcinoma. Ann Intern 
Med 2013;158 (5 (Part I)).
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus 
and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J 
Hepatol 2006;45 (4):529-38.
Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of 
pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic 
hepatitis C. Gastroenterology 2002;122 (5):1303-13.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association 
between sustained virological response and all-cause mortality among patients 
with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308 
(24):2584-93.
Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained 
virologic response and clinical outcomes in patients with chronic hepatitis C and 
advanced fibrosis. Ann Intern Med 2007;147 (10):677-84.
World Health Organization (WHO). Hepatitis C Fact Sheet No. 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed 20 June 2014:1-
7.

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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

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Appendix l. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of 
Sofosbuvir/Velpatasvir Fixed-Dose Combination and Ribavirin for 12 Weeks in Subjects 
with Chronic HCV Infection and Child-Pugh-Turcotte Class C Cirrhosis 
GS-US-342-4022, Protocol Amendment 1, 22 November 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
(Printed) 
Date 
INVESTIGATOR STATEMENT 
[have read the protocol, including all appendices, and r 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 wiU 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 
mformation 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) 
Date 
CONFIDENT'lAL 
' 
\ 
Signature 
Site Number 
Page 67 
22 November 20) 6 

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Appendix 2.
Study Procedures Table
Screen
Day 1a
On-treatment Study Week (± 3 days)
Posttreatment Study Week (± 5 days)
2
4
8
12/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
Assess ascites and hepatic 
encephalopathy
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
AEs 
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
X
X
Health Related Quality of 
Lifec
X
X
X
Study Drug Dispensingd
X
X
X
Review of Study 
Drug Compliancee
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X

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Screen
Day 1a
On-treatment Study Week (± 3 days)
Posttreatment Study Week (± 5 days)
2
4
8
12/ET
4
12
24
HCV RNA
X
X
X
X
X
X
X
X
X
HBV DNAf
X
X
X
X
X
X
X
Viral Sequencing  
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
Serum β-hCG or Urine 
Pregnancy Testg
X
X
X
X
X
X
X
X
Urine Drug Screen
X
HbA1c
X
HCV & IL28B 
Genotyping 
X
HCV, HIV, HBV 
Serology
X
Fibrotest®
X
a
Day 1 assessments must be performed prior to dosing.
b
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
There are four Health Related Quality of Life surveys to provide to subjects: SF-36, CLDQ-HCV, FACIT-F, and WPAI.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
e
Instruct the subject to bring back all study drugs and study drug containers (used/unused).
f
Only for subjects who are HBcAb+ at Screening
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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
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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  

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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 mmol/L
2.0 to 2.5 mEq/L
2.0 to <2.5 mmol/L
2.0 mEq/L 
<2.0 mmol/L
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

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Amendment 1
CONFIDENTIAL
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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 mmol/L
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmol/L
< 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

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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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
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

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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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.  

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Amendment 1
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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

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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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 (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.

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Amendment 1
CONFIDENTIAL
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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

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Amendment 1
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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

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Amendment 1
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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)

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Amendment 1
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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
Pruritus (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritus 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

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Amendment 1
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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

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Amendment 1
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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)

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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 

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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)
Pruritus Associated with 
Injection 
See also Skin: Pruritus
(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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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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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 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial
treatment indicated OR 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Systemic antimicrobial 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.

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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment for female subjects and 7 months following completion of 
treatment for male subjects. Please refer to the latest version of the prescribing information for 
additional information. 
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 VEL 
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.

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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 Day 1 visit prior to enrollment.  Pregnancy tests will be 
performed at monthly intervals thereafter.  They must also agree to one of the following from 
Screening until 30 days of the last dose of SOF/VEL or 6 months after the last dose of RBV, 
whichever occurs last.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of Screening until 
30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever 
occurs last.
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Tubal sterilization
Essure micro-insert system
Vasectomy in the male partner 
Barrier methods 
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonogestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring

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Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, 
whichever occurs last.
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 or 7 months after the last dose of RBV, 
whichever comes last, 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 or 7 months after last dose of RBV, whichever comes last.
Male subjects must agree to refrain from sperm donation until 30 days after the last dose of
SOF/VEL or 7 months after the last dose of RBV, whichever comes last.
5) Unacceptable Methods of Contraception
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
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 or if they 
become pregnant within 6 months (7 months for partners of male subjects) of the last dose of 
RBV. 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 within 30 days of the last dose of SOF/VEL or 
7 months after the last dose of RBV, whichever occurs last must report the information to the 
investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.1.