Clinical trial NCT02996682
Conditions: Hepatitis C Virus Infection
Keywords: Communicable Diseases Hepatitis Hepatitis C Virus Diseases Liver Diseases Digestive System Diseases Hepatitis, Viral, Human Velpatasvir RNA Virus Infections Ribavirin Sofosbuvir Antiviral Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Anti-Infective Agents Decompensated Cirrhosis
Sponsor: Gilead Sciences
Start date: 2016-12-26; Completion date: 2018-05-08
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the antiviral efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) with or without ribavirin (RBV) for 12 weeks in adults with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis.

Detailed description:

Arms: arm 1: SOF/VEL for 12 weeks arm 2: SOF/VEL + RBV for 12 weeks
Interventions: intervention 1: SOF/VEL intervention 2: RBV
Intervention descriptions: intervention 1: 400/100 mg FDC tablet administered orally once daily intervention 2: Capsules administered orally in a divided daily dose

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Phase 3, Open-Label Study to 
Investigate the Efficacy and Safety of SofosbuvirN elpatasvir ± 
Ribavirin for 12 Weeks in Subjects with Chronic HCV fufection and 
Decompensated Cinhosis 
Gilead Sciences, Inc. 
333 Lakeside Dtive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-4019 
Gilead Study Director 
Name: 
PPD 
t-'t-'U 
PPD 
t-'t-'U 
Telephone: 
Fax: 
Email: 
Gilead Medical 
Name: 
Monitor: 
Telephone: 
Fax: 
Email: 
Protocol Version/Date: 
Original: 
Amendment 1: 
Anu Osinusi, MD, MPH 
pp 
PPD 
t-'t-'U 
03 October 2016 
17 November 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, pruiicularly unpublished data, is the prope1iy or 
lmder 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 info1mation 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 infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain info1med consent from those 
persons to whom the dmg may be administered. 


SOFNELFDC 
Protocol GS-US-342-4019 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
Final 
Amendment 1 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 11 
1. 
INTRODUCTION .............................................................................................................................................. 16 
1.1. 
Backgrotmd ............................................................................................................................................ 16 
1.1.1. 
HCV Infection in Japan ........................................................................................................ 16 
1.2. 
SofosbuvirNelpatasvir Fixed-Dose Combination ................................................................................. 17 
1.3. 
Infonnation about Ribavirin ................................................................................................................... 17 
1.4. 
Rationale for This Study ........................................................................................................................ 17 
1.5. 
Rationale for Dose Selection of SOFNEL ............................................................................................ 18 
1.6. 
Rationale for Dose Selection of Ribavirin .............................................................................................. 18 
1. 7. 
Risk/Benefit Assessn1ent for the Study .................................................................................................. 19 
1.8. 
Con1pliance ............................................................................................................................................ 19 
2. 
OBJECTIVES ..................................................................................................................................................... 20 
3. 
STUDY DESIGN ................................................................................................................................................ 21 
3.1. 
Study Design .......................................................................................................................................... 21 
3.2. 
Study Treatments ................................................................................................................................... 21 
3.3. 
Duration ofTreatment ............................................................................................................................ 21 
3 .4. 
Stopping Rules and Discontinuation Criteria ......................................................................................... 21 
3.4.1. 
Toxicity-Based Stopping Criteria ......................................................................................... 22 
3.4.2. 
Virologic Response-Based Treatment Stopping Criteria ..................................................... 23 
3.5. 
PPD 
................................................................................................... 23 
3.6. 
PPD 
............................................................................................... 24 
4. 
SUBJECT POPULATION .................................................................................................................................. 26 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 26 
4.2. 
Inclusion Criteria .................................................................................................................................... 26 
4.3. 
Exclusion Criteria ................................................................................................................................... 27 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 30 
5 .1. 
Randomization. Blinding and Treatment Codes .................................................................................... 30 
5.2. 
Description and Handling of SOFNEL FDC ........................................................................................ 30 
5.2.1. 
Fonnulation .......................................................................................................................... 30 
5.2.2. 
SOFNEL FDC Packaging and Labeling .............................................................................. 30 
5.2.3. 
SOFNELFDC Storage and Handling ................................................................................. 31 
5.2.4. 
Dosage and Administration ofSOFNEL FDC .................................................................... 31 
5.3. 
Description and Handling of Ribavirin (RBV) ...................................................................................... 31 
5.3.1. 
Fonnulation .......................................................................................................................... 31 
5.3 .2. 
RBV Packaging and Labeling .............................................................................................. 31 
5.3.3. 
RBV Storage and Handling .................................................................................................. 32 
5.3.4. 
Dosage and Administration ofRBV) ................................................................................... 32 
5.4. 
Co-adn1inistration of SOFNEL and RBV ............................................................................................. 32 
5.5. 
Study Dmg Adherence and Dmg Accmmtability ................................................................................... 33 
5.6. 
Prior and Concotnitant Medications ....................................................................................................... 33 
5.7. 
Accotmtability for Study Dntg ............................................................................................................... 35 
5.7.1. 
Study Drug Rettu11 or Disposal ............................................................................................ 35 
6. 
STUDY PROCEDURES .................................................................................................................................... 36 
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6.1.
Screening Visit.......................................................................................................................................36
6.1.1.
Day 1 Assessments...............................................................................................................38
6.2.
Study Drug Administration ....................................................................................................................39
6.3.
Close Monitoring During Early Phase of Treatment for Subjects with CPT C Cirrhosis ......................39
6.4.
Treatment Assessments (± 3 days).........................................................................................................39
6.4.1.
Weeks 1, 3, 5, 6, 7, 9, 10, and 11 (± 3 days) ........................................................................39
6.4.2.
Week 2 (± 3 days) ................................................................................................................40
6.4.3.
Weeks 4 and 8 (± 3 days) .....................................................................................................40
6.4.4.
Week 12 (± 3 days) ..............................................................................................................41
6.5.
Posttreatment Assessments (± 5 days) ...................................................................................................42
6.5.1.
Posttreatment Week 4 (± 5 days)..........................................................................................42
6.5.2.
Posttreatment Week 12 (± 5 days)........................................................................................43
6.5.3.
Posttreatment Week 24 (± 5 days)........................................................................................44
6.6.
Early Termination (ET)..........................................................................................................................44
6.7.
Unscheduled Visit ..................................................................................................................................45
6.8.
Procedures and Specifications................................................................................................................46
6.8.1.
Clinical Laboratory Analytes ...............................................................................................46
6.8.2.
Medical History....................................................................................................................46
6.8.3.
Complete Physical Examination...........................................................................................46
6.8.4.
Vital Signs............................................................................................................................47
6.8.5.
12-Lead ECG........................................................................................................................47
6.8.6.
Health Related Quality of Life (HRQoL).............................................................................47
6.8.7.
MELD and CPT Score Calculations.....................................................................................47
6.8.8.
Creatinine Clearance ............................................................................................................49
6.8.9.
Viral RNA Sequencing / Phenotyping Sample.....................................................................49
6.8.10.
HBV DNA Sample...............................................................................................................49
6.8.11.
Single Pharmacokinetic (PK) Sample ..................................................................................49
6.8.12.
Pregnancy Testing................................................................................................................50
6.8.13.
IL28B Testing ......................................................................................................................50
6.8.14.
Archive Plasma Sample........................................................................................................50
6.8.15.
Genomic Testing ..................................................................................................................50
6.9.
End of Study...........................................................................................................................................51
6.10.
Post Study Care......................................................................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................54
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Toxicity Management ............................................................................................................................56
7.5.1.
RBV Dose Adjustments .......................................................................................................56
7.6.
Special Situations Reports......................................................................................................................57
7.6.1.
Definitions of Special Situations..........................................................................................57
7.6.2.
Instructions for Reporting Special Situations.......................................................................58
8.
STATISTICAL CONSIDERATIONS................................................................................................................60
8.1.
Analysis Objectives and Endpoints........................................................................................................60


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8.1.1.
Analysis Objectives..............................................................................................................60
8.1.2.
Primary Endpoint .................................................................................................................60
8.1.3.
Secondary Endpoint .............................................................................................................61
8.1.4.
Other Endpoints of Interest ..................................................................................................61
8.2.
Analysis Conventions.............................................................................................................................61
8.2.1.
Analysis Sets ........................................................................................................................61
8.3.
Data Handling Conventions ...................................................................................................................62
8.4.
Demographic Data and Baseline Characteristics ...................................................................................63
8.5.
Efficacy Analysis ...................................................................................................................................63
8.5.1.
Primary Analysis..................................................................................................................63
8.5.2.
Secondary Analyses .............................................................................................................63
8.6.
Safety Analysis.......................................................................................................................................64
8.6.1.
Extent of Exposure...............................................................................................................64
8.6.2.
Adverse Events.....................................................................................................................64
8.6.3.
Laboratory Evaluations ........................................................................................................65
8.6.4.
Other Safety Evaluations......................................................................................................65
8.7.
Pharmacokinetic Analysis......................................................................................................................65
8.8.
Sample Size............................................................................................................................................65
8.9.
Data Monitoring Committee ..................................................................................................................66
9.
RESPONSIBILITIES..........................................................................................................................................67
9.1.
Investigator Responsibilities ..................................................................................................................67
9.1.1.
Good Clinical Practice..........................................................................................................67
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................67
9.1.3.
Informed Consent.................................................................................................................67
9.1.4.
Confidentiality......................................................................................................................68
9.1.5.
Study Files and Retention of Records ..................................................................................68
9.1.6.
Case Report Forms...............................................................................................................69
9.1.7.
Study Drug Accountability and Return ................................................................................70
9.1.8.
Inspections............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................71
9.2.1.
Protocol Modifications.........................................................................................................71
9.2.2.
Study Report and Publications .............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Access to Information for Monitoring..................................................................................71
9.3.2.
Access to Information for Auditing or Inspections ..............................................................72
9.3.3.
Study Discontinuation..........................................................................................................72
10.
REFERENCES ...................................................................................................................................................73
11.
APPENDICES ....................................................................................................................................................76
Appendix 1.
Investigator Signature Page....................................................................................................77
Appendix 2.
Study Procedures Table..........................................................................................................78
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............81
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................103


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LIST OF IN-TEXT TABLES
Table 5-1.
Dosing and Administration of RBV .......................................................................................32
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution .....................................34
Table 6-1.
Child-Pugh-Turcotte Classification of the severity of cirrhosis .............................................48
Table 7-1.
RBV Dose Reduction Recommendations...............................................................................57


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Multicenter, Randomized, Phase 3, Open-Label Study to 
Investigate the Efficacy and Safety of Sofosbuvir/Velpatasvir ± 
Ribavirin for 12 Weeks in Subjects with Chronic HCV Infection and 
Decompensated Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
Not Applicable
Not Available
Study Centers 
Planned:
Approximately 30 centers in Japan
Objectives:
The primary objectives of this study are:

To evaluate the antiviral efficacy of therapy with 
sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) 
with or without ribavirin for 12 weeks as measured by the 
proportion of subjects with sustained virologic response 12 weeks 
after cessation of treatment (SVR12) 

To evaluate the safety and tolerability of each 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 treatment (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 of treatment

To evaluate the emergence of viral resistance to SOF and VEL
during treatment and after cessation of treatment


SOFNELFDC 
Protocol GS-US-342-4019 
Gilead Sciences, Inc. 
Study Design: 
Number of Subjects 
Planned: 
Target Population: 
Duration of 
Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
The exploratoty objectives of this study are: 
• 
PD 
• 
PPD 
Final 
Amendment 1 
This is a multicenter, randomized, open-label study in subjects with 
chronic HCV infection with decompensated ci.lThosis. 
Approximately 100 subjects will be randomized (1: 1) to one of the 
following two treatment groups: 
• 
SOFIVEL (400/100 mg) for 12 weeks (n=50) 
• 
SOFIVEL (400/100 mg) with RBV for 12 weeks (n=50) 
Randomization will be stratified by Child-Pugh-Turcotte (CPT) class 
at Screening (CPT B/ CPT C) and HCV genotype (genotype 11 non-
genotype 1 ). For the purposes of randomization, a subject with non-
definitive or mixed HCV genotype results by centrallaboratoty 
analysis will be considered non-genotype 1. At least 15 subjects will 
have non-genotype 1 HCV infection. Approximately 10% of subjects 
will have CPT C (score 1 0-12) cinhosis. 
illitially only subjects with CPT B cinhosis (score 7-9) at Screening 
will be enrolled. Enrollment of subjects with CPT C cinhosis at 
Screening (score 10-12) will begin after the Data Monitoring 
Committee (DMC) has reviewed accumulated safety data from the 
first 20 subjects through 4 weeks of treatment (or early treatment 
discontinuation) and concluded that these data support enrollment of 
subjects with CPT C cinhosis. 
Approximately 100 subjects 
Adults with chronic HCV infection and decompensated cinhosis. 
Subjects will be treated for 12 weeks. 
Chronic HCV infected male and non-pregnant/non-lactating female 
subjects aged 20 years or older with decompensated ci.lThosis. 
All subjects will complete the following study visits: Screening, 
Day 1, on-treatment visits at the end of Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11, and 12, and posttreatment visits at Weeks 4, 12, and 24 after 
completion of treatment. 
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SOFNELFDC 
Protocol GS-US-342-4019 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
Screening assessments will be completed within 28 days of the Day 1 
visit. The screening window can be extended up to 42 days for 
subjects for extenuating circumstances with sponsor approval. 
Screening assessments will include obtaining infotmed consent, 
physical examination, medical histoty, height, weight, vital signs, 
12-lead electrocardiogram (ECG), adverse events (AEs) related to 
screening procedures, concomitant medications, laboratoty tests 
(including hematology, chemistry, and coagulation), calculation of 
CPT and Model for End Stage Liver Disease (MELD) scores, HCV 
RNA, HCV genotyping, serology (HIV, HCV, HBV), Fibrotest®, 
liver imaging to exclude hepatocellular carcinoma (HCC) (if 
appropriate historical results are not available), sennn ~-hCG 
(females of child beat·ing potential only), and urinalysis. 
Single 12-lead ECGs will be collected at Screening and Day 1 (prior 
to study dmg administr·ation). 
On-tr·eatinent assessments include physical examination, weight, vital 
signs, AEs, concomitant medications, review of study dmgs 
adherence and dmg accountability, safety laboratoty tests (including 
hematology, chemistty, coagulation), calculation of CPT and MELD 
scores, HCV RNA, IL28B genotyping, phmmacokinetic samples, 
health-related quality of life (HRQoL) surveys, and urine pregnancy 
tests (females of child bem·ing potential only). Subjects with CPT C 
cinhosis at Screening will lmdergo close monitoring in the early 
phase of tr·eatment. 
Posttr·eatinent assessments include physical examination, weight, vital 
signs, AEs and concomitant medications, safety laboratoty tests 
(including hematology, chemistry, coagulation), calculation of CPT 
and MELD scores, HCV RNA, HRQoL surveys, and urine pregnancy 
tests (females of childbearing potential only). 
HRQoL surveys (SF-36, CLDQ-HCV, FACIT-F, and WPAI) will be 
conducted at Day 1, on-treatment Week 12 or Early Tetmination (ET; 
if applicable), and posttreatment Week 12. 
Smnples for HCV RNA sequencing I phenotyping and HBV DNA 
will be collected at Day 1 (except HBV DNA) a11d on-treatinent 
Weeks 2, 4, 8, and 12 or ET and post-treatment Weeks 4, 12, and 24. 
Samples will be collected during on-tr·eatinent Weeks 2, 4, 8, and 
12 or ET for phatmacokinetic (PK) analysis of study dmgs. 
PPD 
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Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a
400/100 mg tablet for oral administration. Subjects will take 1 tablet 
daily with or without food. 
Ribavirin (REBETOL®, RBV) is manufactured as a 200 mg capsule. 
Subjects with CPT B cirrhosis at Screening will take weight-based 
RBV every day (600-1000 mg/day in a divided daily dose). Subjects 
with CPT C cirrhosis at Screening will take 600 mg/day in a divided 
daily dose. The subject will take the morning dose of RBV with the 
SOF/VEL tablet and with food. The evening dose of RBV will be 
taken alone with food.
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 evaluated using scheduled assessments of CPT 
and MELD scores.
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.
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all 
randomized and treated subjects. 
In the primary efficacy analysis, the SVR12 rate for subjects in each 
of the two treatment groups will be compared to the spontaneous 
clearance rate of 1% using the two-sided exact one-sample binomial 
test with Bonferroni alpha adjustment (each at significance level of 
0.025). 
Secondary endpoints include SVR4 and SVR24; proportion of 
subjects who have HCV RNA < LLOQ by visit while on study 
treatment; absolute and change from baseline in HCV RNA through 
end of treatment; virologic failure; and change from baseline in 
MELD and CPT scores.


SOF/VEL FDC
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A sample size of 50 subjects in each treatment group will provide 
over 99% power to detect at least 40% improvement in SVR12 rate 
from the assumed spontaneous rate of 1% or less using a two-sided 
exact one-sample binomial test at significance level of 0.025.
This study will be conducted in accordance with ICH Good Clinical Practice (GCP), and J-GCP 
(Ministerial Ordinance on Good Clinical Practice for Drugs), and all applicable regulatory 
requirements, including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
actual body weight
ADD
Attention deficit disorder
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
ASV
asunaprevir
AUC
area under the curve
AV
atrioventricular
BLQ
below limit of quantification
BMD
bone mineral density
BMI
body mass index
BW
body weight
CD4+
cluster of differentiation 4+
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
ClCr
creatinine clearance
CLDQ-HCV
Chronic Liver Disease Questionnaire
cm2
square centimeter
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CNS
Central nervous system
CPT
Child-Pugh-Turcotte
CRO
contract (or clinical) research organization
CSR
clinical study report
CVA
Cerebral vascular accident
DAA
direct-acting antiviral
DCV
daclatasvir
dL
Deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid 
DSPH
(Gilead) Drug Safety and Public Health
ECG
electrocardiogram


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eCRF
electronic case report form
EDC
electronic data capture
eg
example given
ER
emergency room
eSAE
electronic serious adverse event
ESLD
end stage liver disease
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FACIT-F
Fatigue Index
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed-dose combination
FEV1
forced expiratory volume in 1 second
FSH
follicle stimulating hormone
g
grams
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
giga
GMR
geometric mean  ratio
GS-7977
sofosbuvir, formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
genotype
h
hour
H2
histamine
Hb
hemoglobin 
HbA1c
hemoglobin A1c 
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high density polyethylene 
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HMG-CoA
3-hydroxy-3-methyl-glutaryl coenzyme A
HPF
high power field
HRQoL
Health Related Quality of Life
IB
investigator brochure
ICF
informed consent form 


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ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
interferon
LH
luteinizing hormone
ie
in essence
IL28B
interleukin-28B gene
IMB
intermenstrual bleeding
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio of prothrombin time
IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWRS
interactive web response system
J-GCP
Ministerial Ordinance on Good Clinical Practice for Drugs
kg
kilogram
kPA
kilopascal
L
liter
LAM
lactational amenorrhea method
LDL
low-density lipoprotein
LDV
ledipasvir
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower-level term
m2
square meter
MCV
mean corpuscular volume or mean cell volume
MELD
Model for End Stage Liver Disease
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
mg
milligram
MGB
minor groove binder
MH
Mantel-Haenszel
MHLW
Ministry of Health, Labour and Welfare
mL
milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
mmol
millimole
n
number


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NGM/EE
norgestimate/ethinyl estradiol
NS (3/4A/5A/5B)
non-structural protein
OC
hormonal contraceptive
PCR
polymerase chain reaction
Peg-IFN
pegylated interferon
P-gp
p-glycoprotein
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PPIs
proton-pump inhibitors
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time
Q1
quartile 1
Q3
quartile 3
QTc
corrected QT
RAV
resistance-associated variants
RBC
red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
Scr
serum creatinine (mg/dL)
SD
standard deviation
sec
seconds
SF-36
36-Item Short Form Health Survey
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SNP
single nucleotide polymorphism
SOC
system Organ Class
SOF
sofosbuvir, formerly GS-7977
SOP
standard operating procedure
STR
single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
SVR12
sustained virologic response 12 weeks after cessation of treatment
SVR24
sustained virologic response 24 weeks after cessation of treatment
SVR4
sustained virologic response 4 weeks after cessation of treatment
TEN
toxic epidermal necrolysis
TIPS
transjugular intrahepatic portosystemic shunt
TND
target not detected
ULN
upper limit of normal


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US
United States
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
VEL
velpatasvir
β-hCG
β-human chorionic gonadotropin
μg
microgram
μL
microliter
μmol
micromole


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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) 2016}. 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 infections are the most 
prevalent. Genotypes 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 (HCC), and death. Globally, 27% of all 
patients with cirrhosis and 25% of those who develop HCC are attributable to HCV infection 
{Perz et al 2006}. In addition to having a higher incidence of HCC, patients with chronic HCV 
infection have a higher incidence and mortality of many types of nonliver cancers including 
pancreatic, rectal, kidney, non-Hodgkin’s 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 HCC 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 direct-acting antivirals (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, Gilead Sciences International Ltd. 2016}. Sofosbuvir (SOF)-based regimens 
are the most widely prescribed treatments for HCV infection due to the efficacy, tolerability, and 
simplicity of the dosing regimens. In addition, SOF-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 SOF 
and velpatasvir (VEL), are important advancements 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}
1.1.1.
HCV Infection in Japan
With published HCV prevalence estimates from blood-donor and subgroup-based studies on the 
order of 1-1.9% in Japan {Sievert et al 2011}, it is estimated that there are approximately
1.3-2.4 million people chronically infected with HCV. The highest prevalence rates of HCV 


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antibodies in first-time blood donor studies have been reported in the 50-59 year (1.8%) and 
60-69 year (3.4%) age groups {Tanaka et al 2004}. It is estimated that approximately 15-30% of 
patients with chronic hepatitis C will go on to develop complications including liver cirrhosis, 
HCC, and end stage liver disease (ESLD) {Thein et al 2008}. In Japan, HCV genotype 1 and 
genotype 2 are the predominant genotypes which account for approximately 70% and 30% of 
chronic infections, respectively {Chung et al 2010}. 
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. 
1.2.1
General Information
Please refer to the Investigator’s Brochure (IB) for additional information on SOF/VEL, and the 
individual components, including:

InVitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Information about Ribavirin
Ribavirin (RBV) is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {MSD K.K. Kudan-kita Chiyoda-ku 2016}. RBV 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. RBV is a known teratogen. 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. A comprehensive review of RBV is contained in 
the REBETOL® package insert.
1.4.
Rationale for This Study
The GS-US-342-4019 study is a Phase 3 multicenter, open-label study evaluating 
SOF/VEL ± RBV for 12 weeks in subjects with HCV infection and Child-Pugh-Turcotte (CPT) 
class B or C cirrhosis. Approximately 100 subjects will be enrolled.
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}. Of the 87 HCV infected subjects treated with SOF/VEL 
and RBV for 12 weeks in the ASTRAL-4 study, 82 (94%) achieved SVR12 (ranging from 


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85% in GT3 to 100% in GT2 and GT4). In GT1, the SVR12 rates were 94% and 100% in GT1a 
and GT1b, respectively.
Of the 90 subjects treated with SOF/VEL for 12 weeks, 75 (83%) achieved SVR12 (ranging 
from 50% in GT3 to 100% in GT2 and GT4 subjects). The majority of subjects were GT1 with 
SVR rates of 88% in GT1a and 89% in GT1b. The majority of Japanese patients with chronic 
HCV are elderly (average age ~ 70 years), are more likely to be treatment-experienced, and have 
progressive liver disease. Comorbid conditions (e.g., diabetes and cardiovascular disease) are 
common in this population and pose challenges to the use of RBV therapy. Therefore, SOF/VEL 
will be evaluated both with and without RBV.
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 infected 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 the use of different starting doses of RBV 
based on subject’s CPT class at Screening so that subjects with CPT B cirrhosis will start at 
600-1000 mg daily based on weight, whereas subjects with CPT C cirrhosis will start at 600 mg
daily.
The SOLAR-1 and SOLAR -2 studies evaluated ledipasvir (LDV)/SOF and RBV 600mg for 
12 or 24 weeks in pre and posttransplant subjects with advanced liver disease including subjects 
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-1 and SOLAR-2
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}.
The ASTRAL-4 study evaluated the safety and efficacy of SOF/VEL with and without RBV 
(1000-1200 mg daily weight-based, per the RBV US PI and SmPC) per the RBV US PI and 


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SmPC 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.
1.7.
Risk/Benefit Assessment for the Study
This study will provide information of the safety and efficacy of the combination of SOF/VEL 
with or without RBV for 12 weeks in Japanese patients with 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. 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 and a 
Data Monitoring Committee (DMC) will meet to review safety data.
In summary, safety and efficacy of SOF/VEL with and without RBV for 12 weeks has been 
evaluated in subjects with CPT B cirrhosis in overseas studies. This study will be the first to 
evaluate SOF/VEL with and without RBV in Japanese patients with decompensated cirrhosis. 
1.8.
Compliance
This study will be conducted in accordance with ICH Good Clinical Practice (GCP), and J-GCP 
(Ministerial Ordinance on Good Clinical Practice for Drugs), and all applicable regulatory 
requirements, including archiving of essential documents.


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OBJECTIVES 
The primaty objectives of this study are: 
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• 
To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOFNEL) 
fixed-dose combination (FDC) with or without ribavirin for 12 weeks as measured by the 
propotiion of subjects with sustained virologic response 12 weeks after cessation of fl·eatment 
(SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondaty objectives of this study are: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion 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 aft.er cessation of 
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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• 
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3.
STUDY DESIGN
3.1.
Study Design
This is a multicenter, randomized, open-label study evaluating the efficacy and safety of 
SOF/VEL ± RBV for 12 weeks in subjects with chronic HCV infection with decompensated 
cirrhosis.
Initially only subjects with CPT B cirrhosis at Screening (score 7-9) will be enrolled. Enrollment 
of subjects with CPT C cirrhosis at Screening (score 10-12) will begin after the DMC has 
reviewed accumulated safety data from the first 20 subjects through 4 weeks of treatment 
(or early treatment discontinuation) and concluded that these data support enrollment of subjects 
with CPT C cirrhosis.
3.2.
Study Treatments
Approximately 100 subjects will be randomized (1:1) to one of the following two treatment
groups:

SOF/VEL (400/100 mg) for 12 weeks (n=50)

SOF/VEL (400/100 mg) with RBV for 12 weeks (n=50)
Randomization will be stratified by Child-Pugh-Turcotte (CPT) class at Screening 
(CPT B/ CPT C) and HCV genotype (genotype 1/ non-genotype 1). For the purposes of 
randomization, a subject with non-definitive or mixed HCV genotype results by central 
laboratory analysis will be considered non-genotype 1. At least 15 subjects will have 
non-genotype 1 HCV infection. Approximately 10% of subjects will have CPT C (score 10-12) 
decompensated cirrhosis.
3.3.
Duration of Treatment
Subjects will be treated for 12 weeks.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those
requiring an extension of the Screening period):

28 days (4 weeks) screening period 

12 weeks study treatment period

24 weeks posttreatment period
3.4.
Stopping Rules and 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 


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study-related follow-up procedures (see Section 6.5). 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. If SOF/VEL is withheld due to toxicity, the 
subject must also discontinue RBV treatment (if applicable). 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.
Subjects who permanently discontinue SOF/VEL should complete an Early Termination (ET)
visit.  For subjects who have completed an ET visit, the posttreatment Week 4, 12, and 24 visits 
will be completed after the last dose of any of the study drugs. When medically feasible, the 
medical monitor must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 3.4.1, or toxicity that, in the judgment of the
investigator, compromises the ability to continue study-specific procedures or is considered 
to not be in the subject’s best interest

It is expected that some subjects will have progression of their liver disease during the study. 
The decision to continue such subjects on treatment will be made by the investigator based 
on assessment of the risk/benefit for the individual patient

Virologic failure (as defined in Section 3.4.2)

Pregnancy of female subject (refer to Appendix 4)

In the event that the female partner of a male subject receiving SOF/VEL+RBV 
becomes pregnant, the subject must discontinue RBV but may continue treatment 
with SOF/VEL (refer to Section 7.5.1)

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)
3.4.1.
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


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• 
Any Grade 3 or greater rash associated with constitutional symptoms 
• 
Any Grade 4 adverse event assessed as related to administration of SOFNEL 
3.4.2. 
Virologic Response-Based Treatment Stopping Criteria 
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The following on-treatment Virologic Response-based Treatment Stopping Criteria will be 
utilized: 
• 
Confi1med HCV RNA ~ LLOQ after 2 consecutive HCV RNA < LLOQ 
• 
Confirmed > 1 log10 increase in HCV RNA from nadir 
• 
HCV RNA~ LLOQ through 8 weeks of treatment 
Confi1mation should be pe1f01med as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the on-treatment phase. 
3.5. 
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I 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 chronic HCV infected, male and non-pregnant female subjects, ages 20 years 
or older with CPT class B or C cirrhosis at Screening 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 enrollment at any site or study-wide at any time.
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) Male or female, age 20 years at Screening
3) Body weight ≥40 kg at Screening
4) Quantifiable HCV RNA at Screening
5) Chronic HCV infection (≥ 6 months prior to Screening) documented by prior medical history 
or liver biopsy
6) Confirmation of cirrhosis by any one of the following methods:
a) Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score 5)
b) Fibroscan showing cirrhosis or results > 12.5 kPa
c) FibroTest® score of  > 0.75 (only in the absence of liver biopsy or availability of 
Fibroscan)
7) CPT score 7 to 12, inclusive, at Screening as determined using laboratory values from the 
central laboratory, and at Day 1 (before dosing) using laboratory values from the local 
laboratory
8) Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) performed 
within 4 months of Day 1 to exclude hepatocellular carcinoma (HCC)
9) If treatment-experienced, the most recent HCV treatment must have been completed at least 
8 weeks prior to Screening
10) If listed for liver transplant, Day 1 is expected to be at least 12 weeks prior to transplant.


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11) 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 
randomization.
12) 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.
13) Female subjects must agree to refrain from egg donation and in vitro fertilization during 
treatment until at least 6 months after the last dose of RBV or 30 days after the last dose 
SOF/VEL, whichever occurs last.
14) Male subjects must agree to refrain from sperm donation from the date of screening until at 
least 6 months after the last dose of RBV or 30 days after the last dose SOF/VEL, whichever 
occurs last.
15) Lactating females must agree to discontinue nursing before the study drugs are administered
and through at least 12 weeks after the last dose of any study drug.
16) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments, including all required posttreatment 
visits.
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 illness or 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 major medical disorder that may interfere 
with subject treatment, assessment or compliance with the protocol.  
b) Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drugs
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
d) Solid organ transplantation
e) Significant pulmonary disease 
f)
Unstable cardiac disease or significant cardiac event within one year prior to Screening
g) Porphyria


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h) Clinically significant hemoglobinopathy (e.g., thalassemia, sickle cell anemia)
i)
Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 2 years prior to Screening
j)
Malignancy, other than hepatocellular carcinoma, 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. 
k) Hepatocellular carcinoma within 2 years prior to Screening. Subjects with a history of 
HCC that was curatively treated with either surgical resection or radiofrequency ablation 
(RFA), with the end of treatment occurring at least 2 years prior to Screening, are eligible 
for enrollment.
l)
Recurrence of hepatocellular carcinoma after curative treatment
m) Significant drug allergy (such as anaphylaxis or hepatotoxicity)
n) Hepatopulmonary syndrome
o) Hepatorenal syndrome
2) Infection with human immunodeficiency virus (HIV) at Screening
3) Hepatitis B virus (HBV) surface antigen positive at Screening
4) Screening ECG with clinically significant abnormalities
5) Prior exposure to any HCV NS5A inhibitor
6) Use of GM-CSF, epoetin alfa or other hematopoietic stimulating agents within 2 weeks of 
Screening
7) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, autoimmune hepatitis, 
Wilson’s disease, α-1-antitrypsin deficiency, alcoholic liver disease, non-alcoholic 
steatohepatitis, or toxin exposures)
8) Pregnant or nursing female or male with pregnant female partner
9) Women who wish to become pregnant or males with female partners who wish to become 
pregnant during study treatment and through 6 months after the last dose of RBV or 30 days 
after the last dose SOF/VEL whichever comes last
10) Chronic use of systemically administered immunosuppressive agents (eg, prednisone 
equivalent > 10 mg/day)
11) Active spontaneous bacterial peritonitis at Screening


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12) Infection requiring systemic antibiotics at the time of Screening
13) Evidence of fibrosing cholestatic hepatitis 
14) Life threatening SAE during Screening
15) Active variceal bleeding within 6 months of Screening
16) Prior placement of a portosystemic shunt (such as TIPS)
17) Subjects with any of the following laboratory parameters at Screening:
a) Hemoglobin (Hb) < 11 g/dL for female subjects; Hb < 12 g/dL for male subjects
b) Platelets < 50,000/mm3
c) Neutrophils <1000/mm3
d) ALT, AST, or alkaline phosphatase ≥ 10 x ULN 
e) Sodium <125 mEq/L
f)
Total bilirubin > 10 mg/dL 
g) Creatinine clearance (CLcr) < 50 mL/min as calculated by the Cockcroft-Gault equation 
using actual body weight {Cockcroft et al 1976}; ideal body weight may be used on a 
case-by-case basis when approved by the Medical Monitor.
18) Donation or loss of more than 400 mL of blood within 2 months prior to Day 1
19) Participation in a clinical study with an investigational drug or biologic within 1 month prior 
to Screening
20) Any contraindication to RBV therapy, per the approved package insert, with the exception of 
serious hepatic dysfunction
21) Any prohibited medications as described in Section 5.6
22) Known hypersensitivity to ribavirin, velpatasvir, sofosbuvir, or the metabolites or 
formulation excipients
23) Known contraindication to sofosbuvir per the approved package insert


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a multicenter, randomized, open-label study in subjects with chronic HCV infection with 
decompensated cirrhosis. No blinding is required.
Approximately 100 subjects will be randomized (1:1) to one of the following two groups:

SOF/VEL (400/100 mg) for 12 weeks (n=50)

SOF/VEL (400/100 mg) with RBV for 12 weeks (n=50)
Randomization will be stratified by Child-Pugh-Turcotte (CPT) class (CPT B/ CPT C) at 
Screening and HCV genotype (genotype 1/ non-genotype 1). Any non-definitive or mixed HCV 
genotype results will be considered non-genotype 1 for randomization purposes. At least 
15 subjects will have non-genotype 1 HCV infection. Approximately 10% of subjects will have 
CPT C (score 10-12) decompensated cirrhosis.
Initially only subjects with CPT B cirrhosis at Screening (score 7-9) will be enrolled. Enrollment 
of subjects with CPT C cirrhosis at Screening (score 10-12) will begin after the DMC has 
reviewed accumulated safety data from the first 20 subjects through 4 weeks of treatment (or 
early treatment discontinuation) and concluded that these data support enrollment of subjects 
with CPT C cirrhosis.
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.
SOF/VEL FDC 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 Japan shall be labeled for clinical use to meet 
applicable requirements of the J-GCP (Ministerial Ordinance on Good Clinical Practice for 
Drugs).


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5.2.3.
SOF/VEL FDC Storage and Handling
SOF/VEL FDC tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77 F); excursions are permitted 
between 15C and 30C (59F to 86F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drugs and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL tablets.
Sufficient quantities of SOF/VEL FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from the Gilead Clinical Supply Management Team (or its 
designee).
5.2.4.
Dosage and Administration of SOF/VEL FDC 
SOF/VEL tablet is to be administered once daily with or without food. Each subject must be 
given instructions to maintain approximately the same daily dosing interval between study drugs
doses.
If a subject does not take the SOF/VEL FDC dose at the usual time, it may be taken up to 
18 hours later; however, no more than one tablet should be taken on any calendar day. The 
subject should resume the standing dosing schedule on the next day.
Study drugs should not be cut or split.  SOF/VEL FDC tablets will be provided by 
Gilead Sciences for all subjects.
5.3.
Description and Handling of Ribavirin (RBV)
5.3.1.
Formulation
RBV will be provided in the course of this study as REBETOLcapsules (MSD K.K.). 
REBETOLcapsules are white opaque hard capsules. Each capsule contains 200 mg of 
ribavirin. Information regarding commercially available REBETOLcapsules can be found in 
the current prescribing information {MSD K.K. Kudan-kita Chiyoda-ku 2016}.
5.3.2.
RBV Packaging and Labeling
REBETOLcapsules are packaged in blister packaging of 140 capsules. The RBV package shall 
be labeled for clinical use to meet all applicable requirements of the J-GCP (Ministerial 
Ordinance on Good Clinical Practice for Drugs).


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5.3.3.
RBV Storage and Handling
Information regarding commercially available REBETOLcapsules can be found in the current 
prescribing information.
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.
5.3.4.
Dosage and Administration of RBV  
For subjects with CPT B cirrhosis at Screening, RBV dosage will be based on weight. Subjects 
with CPT C cirrhosis at Screening will be administered 600 mg in a divided daily dose. See 
Table 5-1 below.
Table 5-1.
Dosing and Administration of RBV 
CPT Class
Body Weight at 
Day 1
Ribavirin dosage
Daily dosage
After morning 
meal
After evening meal
CPT B
60 kg
600 mg
200 mg
400 mg
> 60 kg to 80 kg
800 mg
400 mg
400 mg
> 80 kg
1,000 mg
400 mg
600 mg
CPT C
-
600 mg
200 mg
400 mg
Recommendations for RBV dose modification or discontinuation are in Section 7.5.1.
RBV should be dosed with food and SOF/VEL when appropriate.
RBV capsule (200 mg) will be supplied by Gilead Sciences for all applicable subjects.
5.4.
Co-administration of SOF/VEL and RBV 
For morning doses, subjects will be instructed to take study drugs with food as follows:

One SOF/VEL FDC Tablet: contains 400 mg  of SOF and 100 mg of VEL

RBV as per Table 5-1


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For evening doses, subjects will be instructed to take study drug with food as follows:

RBV as per Table 5-1
If a subject does not take the SOF/VEL dose at the usual time, it may be taken up to 18 hours 
later; however, no more than one tablet should be taken on any calendar day. The subject should 
resume the standing dosing schedule on the next day.
RBV should be administered as a divided daily dose (i.e., morning and evening) per Table 5-1.
If the subject misses a dose of RBV and remembers the same day, the missed dose should be 
taken as soon as possible. However, if the subject missed taking the morning dose with lunch or 
if more than 6 hours have passed since the usual morning dose time, the subject should only take 
the prescribed evening dose of RBV.  Subjects should be instructed not to take his/her morning 
and evening doses of RBV at the same time.
Study drugs should not be cut or split.  No food restrictions apply to SOF/VEL; however, 
SOF/VEL should be taken with the morning dose of RBV which is taken with food.
5.5.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all study drug(s) in the original container at every study
visit after Day 1 through the end of treatment.
Study drug(s) will be reconciled using medication pill count at every post-Day 1 visit by the 
investigator or designee (ie, pharmacist) in order to monitor the subject’s adherence with the 
study drug(s).
5.6.
Prior and Concomitant Medications
All 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 eCRF
(including all blood products).  In addition, records of concomitant medications for ascites and 
hepatic encephalopathy taken through posttreatment Week 24 will be collected in the eCRF.  
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.


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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, Rifapentineg
Cardiac Medicationsc
Amiodaroned
Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day) f, Atorvastatin
Other
Bosentanb, Modafinil b, Sulfasalazinec, , 
Methotrexatec
a
Proton pump inhibitor (PPI) doses comparable with omeprazole 20mg can be administered with SOF/VEL when SOF/VEL 
is administered with food. H2-receptor antagonists must not exceed a dose of 40 mg famotidine or equivalent and can be 
taken simultaneously with SOF/VEL and/or staggered by 12 hours. Antacids that directly neutralize stomach acid 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 HMG-CoA Reductase Inhibitor, rosuvastatin. Monitor 
for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
g
Unapproved in Japan
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.
Colony Stimulating Agents
Potential subjects may not be treated with colony stimulating agents (CSA) within 2 weeks prior 
to Screening and through Day 1 to elevate hematology laboratory parameters to facilitate entry 
into the study. Use during the study is allowed as clinically indicated. 


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5.7.
Accountability for Study Drug 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drugs. This includes acknowledgement of receipt of each shipment 
of study drugs (quantity and condition). All used and unused study drugs dispensed to subjects 
must be returned to the site.
SOF/VEL and RBV accountability records will be provided to each study site to:

Record the lot number, expiration date (if necessary)

Record the date received and quantity of study drugs kits 

Record the date, subject number, the study drugs kit number dispensed

Record the date, quantity of used and unused study drugs returned, along with the initials of 
the person recording the information.
5.7.1.
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 
Final 
Amendment 1 
The study procedures to be conducted for each subject emolled in the study are presented in 
tabula!' fonn in Appendix 2 and described in the text that follows 
The investigator must docmnent any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Screening Visit 
Screening assessments will be completed within 28 days of the Day 1 visit. The screening 
window can be extended up to 42 days for subjects for extenuating circmnstances with sponsor 
approval. A single retest of screening labs is permitted only if there is reason to believe the 
retest value will be within accepted parameters if the initial value was either due to a sample 
processing enor or due to an extenuating circumstance such as intercunent infection. 
The following procedmes will be performed and documented: 
• 
Obtain written infmmed consent 
PD 
• 
Determine inclusion and exclusion eligibility 
• 
Obtain medical histmy (refer to Section 6.8.2), including: 
-
Hepatitis C treatment histmy, if applicable 
• 
Regimen( s) 
• 
Dates of previous treatment(s) 
• 
Response to previous treatment (ie, nomesponder, relapse, discontinuation including 
reason) 
• 
Perfmm complete physical examination (refer to Section 6.8.3) 
• 
Obtain height and weight 
• 
Obtain vital signs (refer to Section 6.8.4) 
• 
Perfmm 12-Lead ECG (refer to Section 6.8.5) 
• 
Record any serious adverse events and all adverse events related to protocol mandated 
procedmes occmTing after signing of the consent form 
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
Obtain details of concomitant medications

Liver Disease Assessment
Liver biopsy and/or Fibroscan results (if available)
Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer 
to Section 6.8.7)
Diagnostic imaging (eg, ultrasound or CT scan, at the discretion of the investigator) 
should be performed to exclude the presence of hepatocellular carcinoma (HCC). 
Imaging must have been performed within 4 months of Day 1.

Obtain blood samples for tests (approximately 30 mL of blood will be drawn):
Hematology
Chemistry
Coagulation tests
HCV RNA
Serum β-hCG pregnancy test for females of childbearing potential only
HCV Genotype
HCV antibody, HIV antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb)
Fibrotest®

Obtain urine sample for:
Urinalysis
A CPT Score Confirmation Form will be required to be submitted and reviewed by the Medical 
Monitor prior to randomization on Day 1. Subjects meeting all of the inclusion criteria and none 
of the exclusion criteria will return to the clinic for randomization into the study, upon 
confirmation of CPT score.
From the time of obtaining informed consent through the first administration of study drugs, 
record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF).  All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF.  See Section 7
Adverse Events and Toxicity Management for additional details.


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6.1.1.
Day 1 Assessments
The following Day 1 tests and procedures must be performed prior to enrollment and 
dosing/dispensation of study drugs:

Determine inclusion and exclusion eligibility (refer to Sections 4.1 and 4.2)
Confirm CPT score is 7-12 using laboratory data from the local laboratory (refer to 
Section 6.8.7) 

Subject completes Health Related Quality of Life (HRQoL) surveys (refer to Section 6.8.6)

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Perform 12-Lead ECG (refer to Section 6.8.5)

Obtain blood samples for tests (approximately 30 mL of blood will be drawn for required 
tests):
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
IL28B Genotype
Archive plasma sample (for subjects who have consented) (an additional 12 mL of blood 
will be drawn)
Single genomic sample (for subjects who have consented) (an additional 6 mL of blood 
will be drawn)

Obtain urine sample for:
Pregnancy test for females of childbearing potential only


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6.2.
Study Drug Administration
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment, 
randomization, and treatment assignment. Randomization stratification factors are described in 
Section 5.1.
When ready to administer study drugs to the subject:

Dispense study drugs as directed by the IWRS

Instruct the subject on the packaging, storage, and administration of study drugs

Instruct the subject on how to complete the subject diary

Observe the subject taking the first dose of study drugs. The subject should take the study 
drugs with food.
6.3.
Close Monitoring During Early Phase of Treatment for Subjects with CPT C 
Cirrhosis
Subjects with CPT C cirrhosis at Screening should be monitored closely during treatment with 
SOF/VEL ± RBV. The extent and duration of monitoring is at the discretion of the Investigator, 
based on assessment of each individual subject, but may include daily contact with subject (or 
subject’s family) or in-patient hospitalization.  Proximity of subject’s residence to the 
investigator’s institution should be taken into consideration. The objective of this close 
monitoring is to facilitate prompt communication and response to adverse events that may occur.
6.4.
Treatment Assessments (± 3 days)
On-treatment visits will be performed at the end of Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 
12 for all subjects.
Study drugs will be reconciled at every post-Day 1 visit by the investigator or designee 
(ie pharmacist) in order to monitor the subject’s adherence with the study drugs.
6.4.1.
Weeks 1, 3, 5, 6, 7, 9, 10, and 11 (± 3 days)
The following procedures/assessments are to be completed at the end of Weeks 1, 3, 5, 6, 7, 9, 
10, and 11:

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess adherence with study drug dosing regimen including pill count


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6.4.2.
Week 2 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 2:

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess adherence with study drug dosing regimen including pill count

Obtain blood samples for tests (approximately 40 mL of blood will be drawn total):
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample
Single PK sample
6.4.3.
Weeks 4 and 8 (± 3 days)
The following procedures/assessments are to be completed at the end of Weeks 4 and 8:

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Pregnancy prevention counseling


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
Assess adherence with study drug dosing regimen including pill count

Dispense study drugs as directed by the IWRS

Obtain blood samples for tests (approximately 40 mL of blood will be drawn for required 
tests):
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample
HBV DNA Sample
Single PK sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.4.4.
Week 12 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 12:

Subject completes Health Related Quality of Life (HRQoL) surveys (refer to Section 6.8.6)

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Conduct pregnancy prevention counseling

Assess adherence with study drug dosing regimen including pill count

Collect any remaining study drug from the subject 


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
Obtain blood samples for tests (approximately 40 mL of blood will be drawn for all required 
tests):
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample
Single PK sample
Archive plasma sample (for subjects who have consented) (an additional 12 mL of blood 
will be drawn)

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.5.
Posttreatment Assessments (± 5 days)
The posttreatment Week 4, 12, and 24 visits should be timed from the date of last administration 
of any study drugs for all subjects, regardless of whether they are a virologic failure or 
discontinued study drugs early.
6.5.1.
Posttreatment Week 4 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 4 weeks after taking 
the last dose of study drug:

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Conduct pregnancy prevention counseling


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
Obtain blood samples for tests (approximately 35 mL of blood will be drawn total):
Hematology
Chemistry
Coagulation Tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only (refer to Section 6.8.12)
6.5.2.
Posttreatment Week 12 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 12 weeks after taking 
the last dose of study drug:

Subject completes Health Related Quality of Life (HRQoL) surveys (refer to Section 6.8.6)

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section6.8.4)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Conduct pregnancy prevention counseling (only for females of childbearing potential and 
males with female partners of childbearing potential in the treatment group receiving RBV)

Obtain blood samples for tests (approximately 35 mL of blood will be drawn total):
Hematology
Chemistry
Coagulation Tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample

Obtain urine sample for:


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Pregnancy test for females of childbearing potential in the treatment group receiving 
RBV only (refer to Section 6.8.12)
6.5.3.
Posttreatment Week 24 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 24 weeks after taking 
the last dose of study drug:

Perform complete physical examination (refer to Section 6.8.3)

Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Obtain blood samples for tests (approximately 35 mL of blood will be drawn total):
Hematology
Chemistry
Coagulation Tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential in the treatment group receiving 
RBV only (refer to Section 6.8.12)
6.6.
Early Termination (ET)
For subjects who have completed an ET visit, the posttreatment Week 4, 12, and 24 follow-up 
visits will be scheduled after the last dose of the study drugs.  
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
The following procedures/assessments are to be completed at an Early Termination visit:

Subject completes Health Related Quality of Life (HRQoL) surveys (refer to Section 6.8.6)

Perform complete physical examination (refer to Section 6.8.3)


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
Obtain weight

Obtain vital signs (refer to Section 6.8.4)

Assessment of AEs and concomitant medications

Assess presence and severity of ascites and hepatic encephalopathy for CPT score (refer to 
Section 6.8.7)

Conduct pregnancy prevention counseling

Assess adherence with study drug dosing regimen including pill count.  Collect any 
remaining study drug from the subject

Obtain blood samples for tests (approximately 40 mL of blood will be drawn for required 
tests):
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
HBV DNA Sample
Single PK sample
Archive plasma sample (for subjects who have consented) (an additional 12 mL of blood 
will be drawn)

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.7.
Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion as clinically indicated, but the investigator should, 
at a minimum, collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a sample for a viral RNA 
sequencing/phenotyping must be collected.  


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6.8.
Procedures and Specifications
6.8.1.
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, and Basophils, Reticulocyte count and 
mean corpuscular volume (MCV).
Coagulation: INR, Prothrombin Activation %, Prothrombin time (PT), Activated partial 
thromboplastin time (aPTT)
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase, Creatinine, Direct Bilirubin, Total Bilirubin, 
Glucose, Lipase, Potassium, Sodium, phosphate, uric acid, FibroTest® (at Screening only).
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 (reflex testing done when 
ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening).  Serology 
and/or antigen testing for HIV, including reflex testing as necessary. HCV RNA will be 
measured using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 
2.0. HCV genotype and subtype will be determined using the Siemens VERSANT® HCV 
Genotype INNO-LiPA2.0 Assay.  Gilead reserves the right to use alternate assays for HCV RNA 
and HCV genotype should the above assays become unavailable or are not definitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG (if positive, requires immediate confirmation 
with Serum β-hCG).
6.8.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
6.8.3.
Complete Physical Examination
A 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.


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6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.8.5.
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. 
6.8.6.
Health Related Quality of Life (HRQoL)
Health Related Quality of Life surveys (HRQoL) included in this study are the SF-36, Chronic 
Liver Disease Questionnaire (CLDQ-HCV), Fatigue Index (FACIT-F), and Work Productivity 
and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: Hepatitis C).
The Health Related Quality of Life surveys (HRQoL) will only be administered to subjects if 
available at Day 1. The subject should read the questionnaire by himself/herself and record the 
answers by himself/herself.
6.8.7.
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 eCRF. Besides calculating the CPT score at screening 
(using central laboratory values) and Day 1 (using local laboratory values) to determine 
eligibility, sites will not need to calculate these scores for subsequent visits.
6.8.7.1.
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.


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* 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.
6.8.7.2.
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
Measure
1 point
2 points
3 points
Total bilirubin, mg/dL, 
(μmol/L) 
<2, (<34)
2-3, (34-50)
>3, (>50)
Serum albumin, g/dL
>3.5
2.8-3.5
<2.8
Coagulationa
INR
< 1.7
1.7-2.3
> 2.3
Prothrombin
Activation 
%
>70%
40-70%
<40%
Ascitesb
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
Hepatic encephalopathyc
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 
hepatic encephalopathy
Medication-Refractory
Marked confusion/incoherent, 
rousable but sleeping unless 
aroused or comatosed
a
For coagulation, use either INR or Prothrombin activation %
b
{Moore et al 2003}
c
{Vilstrup et al 2014}
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 taken within 30 days 
of Screening through posttreatment Week 24 will be collected in the eCRF.  


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6.8.8.
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using
actual body weight (ABW).
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)
For determination of eligibility, ideal body weight (IBW) may be used on a case-by-case basis 
when approved by the Medical Monitor.
6.8.9.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and at on-treatment visits at Weeks 2, 4, 8, and 12 or 
early termination and all posttreatment visits and may be archived for viral sequence analysis. At 
any unscheduled visit initiated for the purpose of confirming virologic breakthrough, a viral 
sequence analysis plasma sample must be collected.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.8.10.
HBV DNA Sample
A sample for HBV DNA testing will be collected at on-treatment visits at Weeks 2, 4, 8, and 12 
or early termination and all posttreatment visits.  HBV DNA will only be tested when ALT > 2x 
Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.  
6.8.11.
Single Pharmacokinetic (PK) Sample
Single PK blood samples will be collected for all subjects at on-treatment visits at Weeks 2, 4, 8, 
and 12 or early termination and archived for PK analysis of SOF, its metabolites, VEL, and RBV 
(if appropriate). Approximately 6 mL of whole blood will be collected for each sample (which is 
included in the total blood volume amounts in Section 6.3).  The exact time the study drugs were
taken and whether or not the study drugs were taken with food on PK assessment days will be 
recorded in the source documents and eCRF.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.


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Pregnancy Testing 
Final 
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All females of childbearing potential will have a semm pregnancy test at Screening. Urine 
pregnancy testing will occur at Day 1 and eve1y 4 weeks through posttreatment 4. 
Females of childbearing potential in the treatment group receiving RBV will have additional 
urine pregnancy testing eve1y 4 weeks for a minimum of 6 months following last dose ofRBV. 
If required by local regulations, additional pregnancy tests beyond 6 months may be added. In 
the event of a positive urine pregnancy result, subjects will be instmcted to retum to the clinic as 
soon as possible for a semm pregnancy test. Pregnancy test kits will be dispensed to female 
subjects of childbearing potential after the posttreatment Week 4 visit. The subject will be 
contacted by telephone monthly to confmn that urine pregnancy testing has been perfonned 
posttreatment and to record the outcome. Altematively, if required by local regulations or 
prefened by the investigator or subject, the subject may retum to the clinic for m'ine pregnancy 
tests. 
6.8.13. 
IL28B Testing 
A blood sample will be obtained at Day 1 for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 
6.8.14. 
Archive Plasma Sample 
For subjects who provide consent, an archive plasma san1ple (non-genetic) will be collected at 
Day 1 and Week 12 or ET (if applicable) visits. Approximately 12 mL of whole blood will be 
collected for each sample. The specimens collected will be used to increase our knowledge and 
understanding of the biology pathogenesis, progression and/or treatment outcomes, including 
efficacy, AEs, and the processes of dmg absorption and disposition. These specimens may be 
used for retesting of the amount of HCV in the blood, clinicallaborat01y testing to provide 
additional clinical data and to develop non-genetic biomarker or diagnostic assays and establish 
the perf01mance chal'acteristics of these assays. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. At the conclusion of this study, these samples may be retained in storage by 
Gilead Sciences, Inc. for a period up to 15 years after the end of the study. These samples will 
be destroyed by intemationally accepted means ( eg, incineration). 
6.8.15. 
Genomic Testing 
PD 
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6.9. 
End of Study 
Final 
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Subjects al'e considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment dmation or early temlination of study dmgs. 
6.10. 
Post Study Care 
No poststudy ongoing care will be provided. 
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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, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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


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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 or CRO
Requirements for collection prior to study drug(s) initiation:
After informed consent, but prior to initiation of study drug(s), the following types of events 
should be reported on the case report form (eCRF): all SAEs, and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study drug(s), collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study and report to the eCRF database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
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 


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and the event is deemed relevant to the use of study drugs, he/she should promptly document and 
report the event to Gilead DSPH.
Prior treatment history is collected as part of the study entry criteria and evaluation of individual 
patient characteristics and will not be generating lack of effect reports as this is outside the scope 
of the present clinical study. However, investigators should report any cases of lack of effect that 
they feel appropriate regarding the previous treatment regimen as spontaneous reports to the 
relevant authorities or marketing authorisation holders.

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 as described above.
Gilead DSPH:
Fax: +1 (650) 522-5477
Email: Safety_FC@gilead.com

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 eCRF and the event description section of the SAE form.


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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(s). 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.
RBV Dose Adjustments 
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. Information on RBV dose reduction is provided in 
Table 7-1. 
In the event a female partner of a male subject becomes pregnant, the male subject must 
permanently discontinue RBV, however they can continue SOF/VEL FDC.


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Table 7-1.
RBV Dose Reduction Recommendations
Test items
Value
Ribavirin
Neutrophil count
< 500 /mm3
Discontinue
Platelet count
<50,000/mm3
Discontinue
<25,000/mm3
Discontinue (resumption of dosing not 
allowed)
Hemoglobin level
(No cardiac disease or history of 
cardiac disease)
< 11 g/dL at Week 1 to 4 after start 
of administration
Reduce dose
600 mg/day → 200 mg/day
800 mg/day → 400 mg/day
1,000 mg/day → 400 mg/day
< 10 g/dL at Week 5 to 12 after 
start of administration
< 8.5 g/dL
Discontinue
Hemoglobin level
(Cardiac disease or history of 
cardiac disease present)
< 11 g/dL at Week 1 to 4 after start 
of administration or during 
administration, reduction of 2 g/dL 
or more relative to Day 1 persists 
for 4 weeks
Reduce dose
600 mg/day → 200 mg/day
800 mg/day → 400 mg/day
1,000 mg/day → 400 mg/day
< 10 g/dL at Week 5 to 12 after 
start of administration or during 
administration, reduction of 2 g/dL 
or more relative to baseline persists 
for 4 weeks
< 8.5 g/dL, or after dose reduction, 
less than 12 g/dL even after 4 
weeks
Discontinue
Once RBV has been withheld due to either a laboratory abnormality or clinical manifestation, an 
attempt may be made to restart RBV at a lower daily dose with subsequent step-wise increase in 
the daily dose as clinically indicated. However, it is not recommended that the RBV daily dose 
be increased to the original assigned dose.
Subjects that require discontinuation of RBV for RBV-related events should continue with 
SOF/VEL for the remainder of the treatment period and complete all scheduled study visits.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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.


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug(s) and throughout the study, including the post study drug(s) follow-up 
period, to Gilead DSPH by transmitting electronically and also by sending paper pregnancy 
report form within 24 hours of becoming aware of the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 


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Pregnancies of female partners of male study subjects exposed to 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 
+1 650 522-5477 or email Safety_FC@gilead.com. 
Clinical staff should also report any pregnancies to the Pregnancy Registry at 1 800-593-2214 
(see also http://www.ribavirinpregnancyregistry.com). Refer to Appendix 4 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on electronic special situations report form 
and transmitted to Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. If for any reason it is not possible to record the special situation report (SSR) 
information electronically, ie, the eCRF database is not functioning, record the SSR on the paper 
special situation reporting form and submit within 24 hours to:
Gilead DSPH: Fax: +1 (650) 522-5477
Email: Safety_FC@gilead.com
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
These reports must consist of situations that involve study drug(s) and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are: 
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• 
To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOFNEL) 
fixed-dose combination (FDC) with or without ribavirin for 12 weeks as measured by the 
propmtion of subjects with sustained virologic response 12 weeks after cessation of treatment 
(SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondmy objectives of this study are: 
• 
To detennine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the propmtion 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 of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
The exploratmy objectives of this study are: 
• 
~PD 
• 
PPD 
8.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of 
treatment) in the Full Analysis Set (F AS) population. 
The prima1y safety endpoint is any AE leading to pe1manent discontinuation of study mugs. 
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8.1.3.
Secondary Endpoint
The secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

Proportion of subjects who have HCV RNA < LLOQ by visit while on  treatment

MELD and CPT score changes from Baseline

HCV RNA change from Baseline

The proportion of subjects with virologic failure
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include the health related quality of life endpoints. 
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 include SOF/VEL FDC and RBV. Last dose of study drugs refers 
to the last dose of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of SVR 
at various post treatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is defined as the Full Analysis Set (FAS) which 
includes all randomized subjects who took at least 1 dose of study drug(s). 
8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who took at least 1 dose of 
study drug(s). Treatment-emergent data will be analyzed and defined as data collected from the 
first dose of study drugs through the date of last dose of study drugs plus 30 days.
8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of the 
study drugs and have at least 1 nonmissing concentration value for the corresponding analyte in 


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plasma. The analyte of interest may include SOF, GS-566500, GS-331007, VEL, and RBV (if 
appropriate). The PK analysis set will be used for analyses of general PK. 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the 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 (i.e., ≥ LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be termed a failure (i.e., ≥ LLOQ detected) except for 
SVR24, which will be imputed according to the SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints.
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 drugs, 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 pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment safety laboratory value 
is available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) in the 
summary of graded laboratory abnormalities. Values for missing vital signs data will not be 
imputed; however, a missing baseline 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 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.


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For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
For PK plasma/blood concentrations and analysis of PK parameters natural logarithmic 
transformation will be used. 
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic data will include age, sex, self-identified race and ethnicity. Baseline characteristic 
data will include body mass index, HCV RNA level (log10 IU/mL), genotype of HCV infection, 
IL28B genotype, CPT, MELD scores and additional endpoints as necessary.
8.5.
Efficacy Analysis
8.5.1.
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 treatment. The primary analysis will 
be performed after all randomized and treated subjects have been followed through 12 weeks 
posttreatment or discontinued from study.
A point estimate with a two-sided 95% exact confidence interval using the binomial distribution
(Clopper-Pearson method) will be constructed for the SVR12 rate by treatment group.
In the primary efficacy analysis, the SVR12 rate in each of the 2 treatment groups will be 
compared to the spontaneous clearance rate of 1% using two-sided exact one-sample binomial 
test with Bonferroni alpha adjustment (each at significance level 0.025): ie, for each treatment 
group the hypothesis for superiority is as follows:
H0: SVR12 rate = 1%,
H1: SVR12 rate ≠ 1%
This 1% spontaneous rate was assumed in the statistical test of treatment benefit because there 
are no currently available treatment options for these subjects and non-treatment rarely results in 
spontaneous cure.
8.5.2.
Secondary Analyses
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) 
will be presented in tabular and graphical form. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
HCV RNA values and change from baseline through end of treatment, MELD and CPT scores 
and change from Baseline, and subjects who experience virologic failure.


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Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
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Safety will be evaluated by assessment of clinicallaborat01y tests, physical examinations, and 
vital signs measurements and AEs will be docmnented at various time points during the study. 
All safety data collected, on or after the first dose of study dtugs adtninistration up to 30 days 
after the last dose of study dt11gs will be summarized by treatment group according to the study 
dt11gs received. 
8.6.1. 
Extent of Exposure 
A subject's extent of exposure to the study dmg will be generated from the study dt11g 
adtninistration page of eCRF. Exposure data will be smnmarized by treatment group. 
8.6.2. 
Adverse Events 
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulat01y Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm 
(HLGT), High-Level Tenn (HLT), Prefened Te1m (PT), and Lower-Level Te1m (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 AE with an onset date on or after the study dtugs strut date 
atld no later than 30 days after pennanent discontinuation of the study dt11gs; or any AE leading 
to premature discontinuation of the study dt11gs. 
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-
emergent adverse events (by SOC, and PT) will be provided by treatment group 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 
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
All SAEs

All treatment-related SAEs

AEs leading to premature discontinuation of  any study drugs

AEs leading to modification or interruption of any study drugs
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined in Appendix 3 of this protocol. The 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 the date of last dose of study drugs plus 30 days will be summarized. 
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 (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. If 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.
8.6.4.
Other Safety Evaluations
Individual data for vital signs measurements will be listed by subject and summarized by 
treatment group by descriptive statistical summaries (n, mean, SD, median, Q1, Q3, minimum, 
and maximum), as appropriate. 
8.7.
Pharmacokinetic Analysis
In the PK analysis set, concentrations of SOF, its metabolites GS-566500 and GS-331007, VEL, 
and RBV (if appropriate) in plasma may be determined using validated bioanalytical assays and 
listed. Details of the analyses will be provided in the pharmacokinetic reporting and analysis 
plan.
8.8.
Sample Size
A sample size of 50 subjects in each treatment group will provide over 99% power to detect at 
least 40% improvement in SVR12 rate from the assumed spontaneous rate of 1% or less using a 
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8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will perform a review of
accumulated safety data from the first 20 subjects with CPT B cirrhosis at Screening enrolled 
through 4 weeks of treatment (or treatment discontinuation) and provide a recommendation to 
Gilead on whether these data support enrollment of subjects with CPT C cirrhosis at Screening. 
The DMC may also provide recommendations as needed regarding study design, conduct, and 
the need for additional meetings.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (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.
This protocol is to be conducted in accordance with the guidance stipulated in Article 14, 
Paragraph 3 and Article 80-2 of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs 
and Medical Devices, “MHLW Ordinance on Good Clinical Practice” {Ministry of Health and 
Welfare 2013}.
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 or IEC.  The investigator will not begin any study subject activities 
until approval from the IRB or 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 or IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial 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 approved consent form for documenting written informed 
consent. Each informed consent will be appropriately signed and dated by the subject and the 
person conducting the consent discussion, and also by an impartial witness if required by local 
requirements. The consent form will inform subjects about genomic testing and sample retention.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law), and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drugs, 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, and governmental approval 
with correspondence, informed consent, drug records, staff curriculum vitae and authorization 
forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;


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


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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.
Study Drug Accountability and Return
Gilead recommends that used and unused study drugs supplies be returned to the shipping 
facility from which it came for eventual destruction. The study monitor will provide instructions 
for return. If return is not possible, the study monitor will evaluate each study center’s study 
drugs disposal procedures and provide appropriate instruction for destruction of unused study 
drugs supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead, the site may destroy used (empty or partially empty) and 
unused study drugs 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 drugs are destroyed on site, the investigator or designee (ie, pharmacist) must maintain 
accurate records for all study drugs destroyed. Records must show the identification and quantity 
of each unit destroyed, the method of destruction, and the person who disposed of the study 
drugs. Upon study completion, originals of the study drugs accountability records must be filed 
at the site. A copy will be returned to Gilead.
The study monitor will review study drugs 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/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC
in accordance with local requirements and receive documented approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see 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.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the accuracy of 
the data recorded in the eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 


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verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.2.
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 Gilead or the CRO 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.
9.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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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 
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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).  
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Gilead Sciences International Ltd. HARVONI (ledipasvir/sofosbuvir) 90 mg/400 mg Film-
Coated Tablets. Summary of Product Characteristics. Cambridge, UK. Revised 
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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.


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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.
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.
MELD/PELD. Calculator Documentation. 28 January.  2009:
Ministry of Health and Welfare. Ministerial Ordinance on Good Clinical Practice for Drugs. 
Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997 (As 
last amended by the Ordinance of Ministry of Health, Labour and Welfare No. 
161 of December 28, 2012). Provisional Translation as of March 2013.
Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The management of ascites 
in cirrhosis: report on the consensus conference of the International Ascites Club. 
Hepatology 2003;38 (1):258-66.
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)).
MSD K.K. Kudan-kita Chiyoda-ku. REBETOL® (ribavirin) Capsules 200 mg. Japan Prescribing 
Information [English]. Tokyo, Japan. Revised January.  2016:
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.
Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of 
hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31 
Suppl 2:61-80.
Tanaka J, Kumagai J, Katayama K, Komiya Y, Mizui M, Yamanaka R, et al. Sex- and age-
specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence 
in the 3,485,648 first-time blood donors during 1995-2000. Intervirology 2004;47 
(1):32-40.


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Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in 
chronic hepatitis C virus infection: a meta-analysis and meta-regression. 
Hepatology 2008;48 (2):418-31.
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.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy 
in chronic liver disease: 2014 Practice Guideline by the American Association for 
the Study of Liver Diseases and the European Association for the Study of the 
Liver. Hepatology 2014;60 (2):715-35.
World Health Organization (WHO). Media Centre : Hepatitis C - Fact Sheet. Updated July.  
2016.


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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


SOFIVEL FDC 
Protocol GS·US·342·4019 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEl\tiENT 
A Multicenter, Randomized, Phase 3, Open-Label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/Velpatasvir ± Ribavirin for 12 Weeks in Subjects with Chronic HCV Infection and 
Decompensated Cirrhosis 
GS-US-342-4019, Protocol Amendment 1, 17 November 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
pp 
Anu Osinusi, MD, MPH (Printed) 
Signature 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
l will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 77 
17 November 2016 


SOF/VEL FDC
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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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17 November 2016
Appendix 2.
Study Procedures Table
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment 
Week (5 days)
1
2
3
4
5
6
7
8
9
10
11
12/ETb
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Verification of CPT scorec
X
Medical History
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGe
X
X
Adverse Events and Concomitant 
Medicationsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
X
Health Related Quality of Lifeg
X
X
X
Assessment of ascites and hepatic 
encephalopathy 
X
X
X
X
X
X
X
X
Imaging for HCCh
X
Review of Study Drug Adherence and Drug 
Accountabilityi
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensingj
X
X
X
Close Monitoring of Subjects with CPT C 
Cirrhosisk
X


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 79
17 November 2016
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment 
Week (5 days)
1
2
3
4
5
6
7
8
9
10
11
12/ETb
4
12
24
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
Coagulation (Prothrombin activation %, PT, 
aPTT and INR)
X
X
X
X
X
X
X
X
X
Urinalysis
X
HCV RNA
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing / Phenotyping
X
X
X
X
X
X
X
X
HBV DNA samplel
X
X
X
X
X
X
X
Single PK
X
X
X
X
Serum or Urine Pregnancy Testm
X
X
X
X
X
X
X
X
HCV Genotyping
X
IL28B Genotype
X
HCV Ab, HIV Ab, HBsAg, HBsAb, HBcAb
X
FibroTest®
X
Archive Plasma samplen
X
X
Single Genomic sampleo
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = early termination.
c
Prior to randomization on Day 1, CPT score should be calculated using laboratory values from the local lab to verify that it is between 7-12; however, randomization will be 
based on CPT score at Screening.
d
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
e
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. 
f
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drugs.  In addition, records of Concomitant Medications for ascites 
and hepatic encephalopathy taken through posttreatment Week 24 will be collected in the eCRF.  
g
Health Related Quality of Life (HRQoL) Surveys (eg, SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1.


SOF/VEL FDC
Protocol GS-US-342-4019
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Gilead Sciences, Inc. 
Amendment 1
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h
Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all subjects 
within 4 months of Day 1.
i
Study drugs will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the study drugs.  Subjects must be instructed to 
bring back all bottles of study drugs in the original container at every post- Day 1 visit through the end of treatment.
j
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
k
Subjects with CPT C cirrhosis at Screening should be monitored closely during treatment with SOF/VEL ± RBV. The extent and duration of monitoring is at the discretion of 
the Investigator, based on assessment of each individual subject, but may include daily contact with subject (or subject’s family) or in-patient hospitalization.  Proximity of 
subject’s residence to the investigator’s institution should be taken into consideration. The objective of this close monitoring is to facilitate prompt communication and 
response to adverse events that may occur.
l
Reflex testing done only when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
m
All females of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment 
Week 4. In addition, females of childbearing potential in the treatment group receiving RBV will have additional urine pregnancy testing every 4 weeks for a minimum of 6
months following last dose of RBV.  If required by local regulations, additional pregnancy tests beyond 6 months may be added.  In the event of a positive urine pregnancy 
result, subjects will be instructed to return to the clinic as soon as possible for a serum pregnancy test.  The subject will be contacted by telephone monthly to confirm that 
urine pregnancy testing has been performed posttreatment and to record the outcome. Alternatively, if required by local regulations or preferred by the investigator or subject, 
the subject may return to the clinic for urine pregnancy tests.
n
Only for subjects who have provided separate consent for this sample and testing
o
Only for subjects who have provided separate consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1.


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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17 November 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
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


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 82
17 November 2016
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.  


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 83
17 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 84
17 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


SOF/VEL FDC
Protocol GS-US-342-4019
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 85
17 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
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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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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Protocol GS-US-342-4019
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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 (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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Amendment 1
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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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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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


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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 101
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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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Amendment 1
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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


SOF/VEL FDC
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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
a) Ribavirin Warnings for Pregnancy 
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 6 months following 
completion of treatment. Please refer to the latest version of the REBETOL® product insert for 
additional information
2) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
3) Study Drug Effect 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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Amendment 1
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4) 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 first dose of study drug.  Pregnancy 
testing will occur at regular intervals throughout the duration of the trial.  In the event of a 
delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy.  This is even true for women of childbearing potential with 
infrequent or irregular periods.  They must also agree to one of the following from Screening 
until 30 days after 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 used 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 (unapproved in Japan)
Vasectomy in the male partner 
Barrier methods 
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
(unapproved in Japan)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone (unapproved in Japan)
■
Implants of levonorgestrel or etonorgestrel (unapproved in Japan)
■
Transdermal contraceptive patch (unapproved in Japan)


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Amendment 1
CONFIDENTIAL
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■
Contraceptive vaginal ring (unapproved in Japan)
Female subjects must also refrain from egg donation and in vitro fertilization during study 
treatment and until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose 
of RBV, whichever occurs last.
5) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms until 30 days after the last dose of SOF/VEL treatment or 6 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 6 months after last dose of RBV, whichever comes last.
Male subjects must also refrain from sperm donation during treatment and until at least 30 days 
after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever comes last.
6) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
7) 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, if they become pregnant within 30 days of last dose of SOF/VEL, or if they become 
pregnant within 6 months of the last dose of RBV. Subjects who become pregnant or who 
suspect that they are pregnant during the study must report the information to the investigator 
and discontinue study drug immediately. Subjects whose partner has become pregnant or 
suspects she is pregnant within 30 days of the last dose of SOF/VEL or 6 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.

SAP_001.pdf: 
Study Title: 
Name of Test Drug: 
Study N um her: 
Protocol Version (Date): 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
(r'J GILEAU 
STATISTICAL ANALYSIS PLAN 
A Multicenter, Randomized, Phase 3, Open-Label Study to 
Investigate the Efficacy and Safety of SofosbuvirN elpatasvir ± 
Ribavirin for 12 Weeks in Subjects with Cluonic HCV Infection 
and Decompensated Cinhosis 
SOFNEL Fixed Dose Combination (FDC) 
GS-US-342-4019 
Amendment 1: 17 November 2016 
S VR 12 and Final Analysis 
Version 1.0 
27 Febmary 2018 
PPD 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 2
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1.
Data Monitoring Committee ....................................................................................................................8
2.2.
Interim Analysis.......................................................................................................................................8
2.2.1.
Posttreatment Week 4 Analysis..............................................................................................8
2.2.2.
Posttreatment Week 12 Analysis............................................................................................8
2.3.
Final Analysis ..........................................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1.
Analysis Sets............................................................................................................................................9
3.1.1.
All Randomized Analysis Set.................................................................................................9
3.1.2.
Full Analysis Set ....................................................................................................................9
3.1.3.
Safety Analysis Set.................................................................................................................9
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................10
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Strata and Covariates..............................................................................................................................10
3.4.
Examination of Subject Subsets.............................................................................................................10
3.5.
Multiple Comparisons............................................................................................................................11
3.6.
Missing Data and Outliers......................................................................................................................11
3.6.1.
Missing Data ........................................................................................................................11
3.6.2.
Outliers.................................................................................................................................12
3.7.
Data Handling Conventions and Transformations .................................................................................12
3.8.
Visit Windows........................................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Windows................................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................18
4.1.
Subject Enrollment and Disposition.......................................................................................................18
4.2.
Extent of Exposure.................................................................................................................................19
4.2.1.
Duration of Exposure to Study Drug....................................................................................19
4.2.2.
Adherence to Study Drug.....................................................................................................20
4.2.3.
Ribavirin Dosing Summary..................................................................................................21
4.3.
Protocol Deviations................................................................................................................................21
5.
BASELINE CHARACTERISTICS....................................................................................................................22
5.1.
Demographics ........................................................................................................................................22
5.2.
Other Baseline Characteristics ...............................................................................................................22
5.3.
Medical History......................................................................................................................................23
6.
EFFICACY ANALYSES ...................................................................................................................................24


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6.1.
Primary Efficacy Endpoint.....................................................................................................................24
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................24
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................24
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint ............................................................24
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................24
6.2.
Secondary Efficacy Endpoints ...............................................................................................................25
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................25
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................26
6.3.
Exploratory Efficacy Endpoints.............................................................................................................29
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................29
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................29
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................30
7.
SAFETY ANALYSES........................................................................................................................................31
7.1.
Adverse Events and Deaths....................................................................................................................31
7.1.1.
Adverse Event Dictionary ....................................................................................................31
7.1.2.
Adverse Event Severity........................................................................................................31
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................31
7.1.4.
Serious Adverse Events........................................................................................................31
7.1.5.
Treatment-Emergent Adverse Events...................................................................................31
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................32
7.2.
Laboratory Evaluations ..........................................................................................................................34
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................35
7.2.2.
Graded Laboratory Values ...................................................................................................35
7.3.
Body Weight, Height, and Vital Signs...................................................................................................36
7.4.
Prior and Concomitant Medications.......................................................................................................37
7.5.
Electrocardiogram Results .....................................................................................................................38
7.6.
Other Safety Measures ...........................................................................................................................38
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................38
8.
PHARMACOKINETIC ANALYSES ................................................................................................................39
9.
REFERENCES ...................................................................................................................................................40
10.
SOFTWARE.......................................................................................................................................................41
11.
APPENDICES ....................................................................................................................................................42
Appendix 1.
Study Procedures Table..........................................................................................................43
Appendix 2.
QOL Score Calculation Algorithm.........................................................................................46
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for On-Treatment HCV RNA and Safety Laboratory Data.....................15
Table 3-2.
Analysis Windows for On-Treatment MELD and CPT Data.................................................15
Table 3-3.
Analysis Windows for On-Treatment Vital Signsa and Weight Data.....................................15
Table 3-4.
Analysis Windows for Posttreatment HCV RNA, CPT, MELD, Vital Signs, and 
Safety Laboratory Data...........................................................................................................16
Table 6-1.
Child-Pugh-Turcotte Scoring of the Severity of Cirrhosis .....................................................27


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Statistical Analysis Plan
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CONFIDENTIAL
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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
BMI
body mass index
CI
confidence interval
CPT
Child-Pugh-Turcotte
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT
end of treatment
FAS
full analysis set
FDC
fixed dose combination
FU
follow-up
HCV
hepatitis C virus
HLGT
high level group term
HLT
high level term
ID
Identification
INR
International normalized ratio
IWRS
Interactive Web Response System
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PT
preferred term
PT%
Prothrombin Activation %
Q1
first quartile
Q3
third quartile
RBV
ribavirin
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
SOF
sofosbuvir (Sovaldi®)
SVR
sustained virologic response


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SVRx
sustained virologic response x weeks after stopping study drug
TE
treatment-emergent
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of the normal range
VEL
velpatasvir
WBC
white blood cell
WHO
World Health Organization


SOFNELFDC 
GS-US-342-4019 
Statistical Analysis Plan 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study rep01t (CSR) 
for Study GS-US-342-4019. This SAP is based on the study protocol amendment I dated 
17 November 2016 and the electronic case report f01m (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
1.1. 
Study Objectives 
The primaty objectives of this study are as follows: 
• 
To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOFNEL) 
fixed-dose combination (FDC) with or without ribavirin for 12 weeks as measured by the 
prop01tion of subjects with sustained virologic. response 12 weeks after cessation of treatment 
(SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondruy objectives of this study ru·e as follows: 
• 
To detetmine the prop01tion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failure 
• 
To evaluate therapeutic efficacy as measured by the change of Child-Pugh-Turcotte (CPT) 
score and Model for End Stage Liver Disease (MELD) score 
• 
To evaluate the kinetics of circulating HCV RNA during treatment ru1d after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are as follows: 
• 
PPD 
• 
PPD 
CONFIDENTIAL 
Page 6 
1 March2018 


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1.2.
Study Design
This multicenter, randomized, open-label study evaluates the efficacy and safety of 
SOF/VEL ± RBV for 12 weeks in subjects with chronic HCV infection with decompensated 
cirrhosis.
Initially only subjects with CPT B cirrhosis at screening (score 7-9) will be enrolled. Enrollment 
of subjects with CPT C cirrhosis at screening (score 10-12) will begin after the data monitoring 
committee (DMC) has reviewed accumulated safety data when the first 20 subjects enrolled have 
completed 4 weeks of treatment (or early treatment discontinuation) and concluded that these 
data support enrollment of subjects with CPT C cirrhosis.
Approximately 100 subjects will be randomized (1:1) to 1 of the following 2 treatment groups:

SOF/VEL (400/100 mg) for 12 weeks (n=50)

SOF/VEL (400/100 mg) with RBV for 12 weeks (n=50)
Randomization will be stratified by CPT class at screening (CPT B/CPT C) and HCV genotype 
(genotype 1/nongenotype 1). CPT class for randomization will be based on the site’s calculation 
of CPT score. For the purposes of randomization, a subject with nondefinitive or mixed HCV 
genotype results by central laboratory analysis will be considered nongenotype 1. At least 
15 subjects will have nongenotype 1 HCV infection. Approximately 10% of subjects will have 
CPT C (score 10-12) decompensated cirrhosis.
Subjects will be treated with SOF/VEL or SOF/VEL+RBV for 12 weeks. The total time to 
complete all study visits is approximately 40 weeks (42 weeks for those requiring an extension 
of the screening period):

28-day (4-week) screening period

12-week study treatment period

24-week posttreatment period
1.3.
Sample Size and Power
A sample size of 50 subjects in each treatment group will provide over 99% power to detect at 
least 40% improvement in SVR12 rate from the assumed spontaneous rate of 1% or less using a 
2-sided exact 1-sample binomial test at significance level of 0.025.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
An external multidisciplinary DMC will perform a review of accumulated safety data when the 
first 20 subjects with CPT B cirrhosis at screening enrolled have completed 4 weeks of treatment 
(or treatment discontinuation) and provide a recommendation to Gilead on whether these data 
support enrollment of subjects with CPT C cirrhosis. The DMC may also provide 
recommendations as needed regarding study design, conduct, and the need for additional 
meetings.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the
DMC’s membership, conduct, and meeting schedule.
2.2.
Interim Analysis
2.2.1.
Posttreatment Week 4 Analysis
A posttreatment Week 4 analysis will be conducted for administrative purposes after all subjects 
complete the posttreatment Week 4 visit or prematurely discontinue from study. All safety and 
efficacy data through the posttreatment Week 4 visit will be included. The results will be 
restricted to a limited group of individuals within Gilead. There will be no changes to the study 
design, study conduct, or the sample size as a result of this administrative analysis. 
2.2.2.
Posttreatment Week 12 Analysis
The analysis for the primary endpoint SVR12 will occur after all subjects complete the 
posttreatment Week 12 visit or prematurely discontinue from study. All safety and efficacy data 
through the posttreatment Week 12 visit will be cleaned, finalized, and included for the analysis.
2.3.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved, and the 
database has been cleaned and finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects [n], mean, standard deviation [SD] or standard error [SE], median, first 
quartile [Q1], third quartile [Q3], minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level, unless otherwise 
specified.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified.
For screening, CPT scores can be assessed using prothrombin activation % (PT%) or 
international normalized ratio (INR) for the coagulation parameter. In the clinical database, all 
CPT scores will be assessed using PT% unless otherwise specified. 
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from each analysis set will be summarized or provided in 
a by-subject listing with reasons for exclusion by treatment group. 
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects randomized in the study after screening. 
All analyses based on the All Randomized Analysis Set will be performed according to the 
treatment subjects randomized.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized into the study and 
received at least 1 dose of study drug. The study drugs in this study are SOF/VEL and RBV. 
Subjects are grouped within the FAS by the treatment group to which they were randomized. 
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug. Subjects 
are grouped according to the treatment they actually received. 
This is the primary analysis set for safety analyses.


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3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all subjects who were randomized into the 
study, received at least 1 dose of the study drugs and had at least 1 nonmissing concentration 
value for the corresponding analyte in plasma. The analyte of interest may include SOF, 
GS-566500, GS-331007, or VEL. The PK Analysis Set will be used for analyses of general PK. 
3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Set or FAS, subjects will be grouped 
according to the treatment to which they were randomized. For analyses based on other analysis 
sets, such as the Safety Analysis Set, subjects will be grouped according to the actual treatment 
received. The actual treatment received is defined as the randomized treatment except for 
subjects who received treatment that differs from the randomized treatment for the entire 
treatment duration. In this case, the actual treatment received is defined as the treatment received 
for the entire treatment duration. 
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) in a 1:1 ratio using a stratified randomization schedule. Stratification will be based on 
the following variables: 

CPT class at screening (CPT B/CPT C) calculated by sites

HCV genotype (genotype 1/nongenotype 1). For the purposes of randomization, a subject 
with nondefinitive or mixed HCV genotype results by central laboratory analysis will be 
considered nongenotype 1
If there are discrepancies in stratification factor values between the IWRS and the clinical 
database, the values recorded in the clinical database will be used for analyses unless otherwise 
specified. 
3.4.
Examination of Subject Subsets
Subgroup analyses will be explored by HCV genotype (genotype 1/nongenotype 1) and/or by 
CPT class at baseline in clinical database. 
Other subject subsets will also be explored for the primary efficacy endpoint (SVR12), including 
the following:

age (< 65 years, 65 years)

sex (male, female)

baseline BMI (< 25 kg/m2 , ≥ 25 kg/m2) 


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
HCV genotype and subtype (if applicable)

IL28B genotype (CC, non-CC; with non-CC further broken down to CT, TT)

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL and < 5 log10 IU/mL, 
≥5 log10 IU/mL)

baseline CPT class (CPT A [5-6], CPT B [7-9], or CPT C [10-15])

baseline MELD score category (<10, 10-15, 16-20, 21-25, >25)

baseline alanine aminotransferase (ALT) (≤1.5 × upper limit of normal [ULN], 
> 1.5 × ULN)

prior HCV treatment experience (treatment naive, treatment experienced)

study treatment status (completed study treatment, discontinued study treatment)

adherence to study regimen (<80%, ≥ 80%)

adherence to SOF/VEL (<80%, ≥ 80%)

adherence to RBV (Group 2 only) (< 80%, ≥ 80%)
3.5.
Multiple Comparisons
In the primary efficacy analysis, the SVR12 rate in each of the 2 treatment groups will be 
compared with the spontaneous clearance rate of 1% using 2-sided exact 1-sample binomial test 
with Bonferroni alpha adjustment (each at significance level 0.025).
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.8.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2 and for prior and concomitant medications in Section 7.4.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the last 
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is missing, the value will be imputed. If the study day associated with the last dosing date is less 
than the lower bound of a visit window, the on-treatment value at that visit will remain missing. 
If an HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantitation (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) except for SVR24, which will be imputed according to 
SVR12 status. Success for SVR12 who have no further HCV RNA measurements collected will 
be counted as a success for SVR24 due to the high correlation between these 2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ - 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
For health-related quality of life (HRQoL) data including 36-Item Short Form Health Survey 
(SF-36), Chronic Liver Disease Questionnaire (CLDQ-HCV), Fatigue Index (FACIT-F), and 
Work Productivity and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: Hepatitis
C), missing data will not be imputed.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable), unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order for each subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug, then the date the informed consent was signed will be 
used instead of first dose date of study drug. 


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Data that are continuous in nature but are less than the lower limit of quantitation or above the 
upper limit of quantitation will be imputed as follows:

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 
0.9 or 0.09 will be used for calculation of summary statistics.

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0 was used to 
determine HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, the result will be 
reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document as 
the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “target not detected” will also be set to 
14 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).


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3.8.
Visit Windows
3.8.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date 
The last dose date for an individual study drug will be the end date on study drug administration 
eCRF for the record where the “subject permanently withdrawn” flag is ‘Yes’. The last dose date 
will be defined as the maximum of the last dose dates of individual study drugs in a treatment 
group.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.8.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, CPT, MELD, vital signs, and safety laboratory data collected up to the last dose date 
+ 3 days are considered to be on-treatment data and HCV RNA, CPT, MELD, vital signs, and 
safety laboratory data collected after the last dose date + 3 days are considered posttreatment 
data. The analysis windows for on-treatment HCV RNA and safety laboratory data; MELD and 
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Table 3-1.
Analysis Windows for On-Treatment HCV RNA and Safety 
Laboratory Data
Nominal Visit
HCV RNA and Safety Laboratory Data
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 2
14
2
21
Week 4
28
22
42
Week 8
56
43
70
Week 12
84
71
≥85
Table 3-2.
Analysis Windows for On-Treatment MELD and CPT Data
Nominal Visit
MELD and CPT Data
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
≥85
Table 3-3.
Analysis Windows for On-Treatment Vital Signsa and Weight Data
Nominal Visit
Vital Signs and Weight Data
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
11
Week 2
14
12
18
Week 3
21
19
25
Week 4
28
26
32
Week 5
35
33
39
Week 6
42
40
46
Week 7
49
47
53
Week 8
56
54
60
Week 9
63
61
67
Week 10
70
68
74
Week 11
77
75
81
Week 12
84
82
≥85
a
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature.


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HCV RNA, CPT, MELD, vital signs, and safety laboratory data collected after the last dose date
+ 3 days will be assigned to the posttreatment follow-up (FU) visits. Visit windows will be 
calculated from the last dose date (ie, FU Day = collection date minus the last dose date) as 
shown in Table 3-4. 
Table 3-4.
Analysis Windows for Posttreatment HCV RNA, CPT, MELD, Vital 
Signs, and Safety Laboratory Data
Nominal FU a
Visit
HCV RNA, CPT and MELD data
Vital Signs and Safety Laboratory Data b
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
4
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Vital signs and safety labs will only be summarized for the posttreatment Week 4 (FU-4) visit (up to 30 days after last dose).
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. If multiple ECG 
measurements occur on the same day prior to first dose of any study drug, the average will be 
used as baseline value for continuous data, regardless of the timing of these multiple ECG 
measurements.

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected.  
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.


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
If multiple valid nonmissing categorical observations exist in a window, records will be 
selected as follows:
For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on 
the same day, the value with the lowest severity will be selected (eg, normal will be 
selected over abnormal). If multiple ECG measurements occur on the same day prior to 
the first dose of any study drug, the value with the lowest severity will be selected 
regardless of the timing of these multiple ECG measurements.
For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most 
conservative value will be selected (eg, abnormal will be selected over normal).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each investigator within Japan by 
treatment group and overall. The summary will present the number and percentage of subjects in 
the Safety Analysis Set. For each column, the denominator for the percentage calculation will be 
the total number of subjects analyzed for that column. 
A similar enrollment table will be provided by CPT class at baseline and HCV genotype for each 
treatment group and overall. The denominator for the percentage of subjects in the category will 
be the total number of subjects in the Safety Analysis Set within that category for each treatment 
group and overall. A listing of discrepancies between IWRS and database values in CPT class 
and HCV genotype at screening will also be provided. A summary of reasons for screen failure
will be provided. A by-subject listing will be provided for subjects randomized and treated who 
did not meet eligibility criteria.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and overall. Two 
additional summaries will be provided, one by CPT class at baseline (CPT B, CPT C, total) and 
one by HCV genotype (genotype 1, nongenotype 1, total) within each treatment group and 
overall. The summaries will present the number of subjects screened, the number of subjects not 
randomized, the number of subjects randomized, the number of subjects randomized but never 
treated, and the number of subjects in each of the categories listed below:

In Safety Analysis Set

In FAS

In PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study

Did not complete the study with reasons for premature discontinuation of study
For the percentage of subjects who completed or did not complete study treatment or study, the 
denominator for the percentage calculation will be the total number of subjects in the Safety 
Analysis Set. Among subjects who completed study treatment and who discontinued study 
treatment, the number of subjects will be summarized for:

Subjects who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
and thereafter)

Subjects who had HCV posttreatment Week 4 assessment, but no HCV posttreatment Week 
12 assessment and thereafter (With HCV FU-4 but No FU-12 and thereafter)


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If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.
In addition, the total number of subjects who were randomized and the number of subjects in 
each of the disposition categories listed above will be depicted by a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition for subjects who completed study treatment and study

Disposition for subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study treatment and/or study 

Lot number and kit ID (if applicable) 
4.2.
Extent of Exposure 
Extent of exposure to study drug will be examined by assessing the total duration of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol. 
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
The total duration of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and the number (ie, cumulative 
counts) and percentage of subjects exposed through  the following time periods: baseline 
(Day 1), Week1 (Day 7), Week 2 (Day 14), Week 3 (Day 21), Week 4 (Day 28), Week 5 
(Day 35), Week 6 (Day 42), Week 7 (Day 49), Week 8 (Day 56), Week 9 (Day 63), Week 10 
(Day 70), Week 11 (Day 77), and Week 12 (Day 84). A 3-day window will be applied to the last 
planned on-treatment visit to match with the protocol-specified visit window (ie, the number of 
subjects exposed through Week 12 will be calculated as the number of subjects who were 
exposed to study drug for at least 81 days). Summaries will be provided by treatment group for 
the Safety Analysis Set. 


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4.2.2.
Adherence to Study Drug
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:







returned
Tablets
of
No.
 Dispensed
Tablets
of
No.
ed
Administer
 Doses
of
Number 
Total
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed at baseline. 
The level of adherence will be expressed in percentage using the following formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In the SOF/VEL 12 Week group, the total amount of SOF/VEL (400 mg/100 mg) prescribed for 
12 weeks would require 84 tablets.
In the SOF/VEL+RBV 12 Week group, the total amount of SOF/VEL (400 mg/100 mg) 
prescribed for 12 weeks would require 84 tablets. For subjects with CPT B cirrhosis at screening
as recorded in IWRS, weight-based RBV (200 mg) prescribed for 12 weeks would require 
252 tablets (3 tablets/day) for baseline weight ≤ 60 kg, 336 tablets (4 tablets/day) for baseline 
weight > 60 kg to ≤ 80 kg, or 420 tablets (5 tablets/day) for baseline weight > 80 kg. For subjects
with CPT C cirrhosis at screening as recorded in IWRS, 252 tablets (3 tablets/day) of RBV 
would be required. Subjects who prematurely discontinued study drug for lack of efficacy 
(ie, virologic failure) will have the total amount of study drug prescribed calculated up to the first 
date when virologic failure criteria were met. For virologic failure confirmed by 2 consecutive 
measurements the date of the first measurement will be used. If there were study drug bottles 
dispensed on or after the subject first met virologic failure criteria, these bottles will not be 
included in the calculation of adherence. If a bottle was dispensed and the bottle was returned 
empty, then the number of tablets returned will be entered as zero. If a bottle was dispensed but 
not returned (missing), the number of tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(eg, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by treatment group for the Safety Analysis 
Set. Categorical displays will be provided for the number of subjects who are at least 
80% adherent to their study drug regimen (ie, adherence is ≥ 80% for each of the study drugs).


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No inferential statistics will be provided for duration of exposure and adherence to study drug. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
4.2.3.
Ribavirin Dosing Summary
This analysis will only be performed on subjects in Group 2 and by CPT class at baseline (CPT 
B, CPT C, total).Average RBV daily dose and average weight-based RBV daily dose will be 
calculated for each subject as follows (and then summarized for the treatment group):
Average RBV Daily Dose = (RBV [mg] taken during the study) ÷ (Days on any RBV)
Average Weight-based RBV dose = (Average RBV Daily Dose) ÷ (Weight [kg] at baseline)
where,
Days on RBV = Sum of number of days that the subject took a non-zero dose of RBV from the 
log form study drug administration page.
RBV (mg) taken during the study= Sum of all RBV entries on EX eCRF for: (RBV last dose 
date – RBV first dose date + 1) x (# RBV tablets per day x 200 mg). 
The number and percentage of subjects who prematurely discontinued RBV dosing will be 
presented. Premature discontinuation will be defined by:
subjects will be considered prematurely d/c from RBV if total days on RBV (ie, last dose date of 
RBV – first dose date of RBV +1) is < 81 days. 
The number and percentage of subjects who interrupted (ie, zero dose, or a gap of ≥ 3 days 
between RBV stop date of one entry and start date of the next entry) or decreased their RBV 
dose (ie, for at least 3 consecutive days) while on study drug will be presented. Subjects will be 
counted once for each category.
4.3.
Protocol Deviations 
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.
Subjects who received study drug other than their randomized treatment assignment will be 
listed with the start and stop dates that they received incorrect study drug.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment 
group and overall. Two additional summaries will be provided, one by CPT class at baseline 
(CPT B, CPT C, total) and one by HCV genotype (genotype 1, nongenotype 1, total) within each 
treatment group using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for age and using the numbers and percentages of subjects for age categories 
(< 65 years, ≥65 years), sex, race, and ethnicity. Age is calculated in years at the date of initial 
study drug administration. If a subject did not receive study drug after randomization/enrollment, 
the subject’s age will be calculated from the date that the subject signed the informed consent 
form. The summary of demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing, which includes the date the informed consent was signed, will
be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include the following: 

body mass index (BMI; in kg/m2) as a continuous variable and as categories (< 25 kg/m2, 
≥25 kg/m2) 

HCV genotype and subtype (if applicable)

IL28B genotype (CC, non-CC; with non-CC further broken down to CT, TT) 

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥ 800,000 IU/mL and < 5 log10 IU/mL, ≥ 5 log10 IU/mL) 

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 ULN, > 1.5 ULN)

baseline CPT score and category (CPT A [5-6], CPT B [7-9], CPT C [10-15])      

baseline MELD score and category (<10, 10-15, 16-20, 21-25, >25)

baseline ascites (none, mild/moderate, severe)

baseline hepatic encephalopathy (none, medication-controlled, medication-refractory)

prior HCV treatment experience (treatment-naive, treatment-experienced)

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eGFR will be calculated by the Cockcroft-Gault method: eGFRCG (mL/min) = [(140 – age (yrs)) 
× weight (kg) × (0.85 if female)] / (serum creatinine (mg/dL) × 72), where weight is total body 
mass in kilograms.
These baseline characteristics will be summarized by treatment group and overall. Two 
additional summaries will be provided, one by CPT class at baseline (CPT B, CPTC, total) and 
one by HCV genotype (genotype 1, nongenotype 1, total) within each treatment group using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous 
variables and using the numbers and percentages of subjects for categorical variables. The 
summary of baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order. 
A separate by-subject data listing for cirrhosis determination and prior HCV treatment and 
response will be provided for all subjects at screening.
5.3.
Medical History
A by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history (in chronological order).


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with SVR12, defined as HCV RNA 
< LLOQ (ie, < 15 IU/mL) 12 weeks after cessation of treatment. The primary analysis will be 
performed after all randomized subjects have been followed through 12 weeks posttreatment or 
discontinued from study. The COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, 
v2.0 will be used to measure HCV RNA.
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
In the primary efficacy analysis, the SVR12 rate in each of the 2 treatment groups will be 
compared with the spontaneous clearance rate of 1% using 2-sided exact 1-sample binomial test 
with Bonferroni alpha adjustment (each at significance level 0.025) and, for each treatment 
group, the hypothesis for superiority is as follows:
H0: SVR12 rate = 1%,
H1: SVR12 rate ≠ 1%
This 1% spontaneous rate was assumed in the statistical test of treatment benefit because there 
are no currently available treatment options for these subjects and nontreatment rarely results in 
spontaneous cure.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The 2-sided exact 1-sample binomial test will be used to test the statistical hypotheses described
above for each treatment group. 
A point estimate with a 2-sided 95% exact confidence interval using the binomial distribution
(Clopper-Pearson method) will be constructed for the SVR12 rate by treatment group (Clopper 
and Pearson 1934).
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint
Point estimates and 95% exact CIs of the SVR12 rates will be displayed by treatment group and 
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6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

Proportion of subjects who have HCV RNA < LLOQ by visit while on treatment

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT) 

MELD and CPT score changes from baseline

The proportion of subjects with virologic failure as the following:
On-treatment virologic failure
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can be 
posttreatment), or last available on-treatment measurement with no subsequent follow-up 
values (ie, breakthrough)
1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment),  or last 
available on-treatment measurement with no subsequent follow-up values (ie, rebound)
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse 
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy 
with SOF/VEL and SOF/VEL+RBV


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
6.2.2.1.
Analysis Methods for Efficacy Endpoints – Viral Kinetics
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.8.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.6.1. The 2-sided 95% exact confidence interval based on 
Clopper-Pearson method will be provided by HCV genotype (genotype 1, nongenotype 1, total) 
for the percentage of subjects with HCV RNA < LLOQ at each visit in each treatment group. 
The overall category for “HCV RNA < LLOQ” will be split into the following 2 subcategories: 
“< LLOQ TND” for subjects with target not detected and “< LLOQ detected” for subjects 
with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed by HCV genotype (genotype 1, nongenotype 1, total).
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by HCV genotype (genotype 1, nongenotype 1, total) and by visit through EOT. 
Imputation rules described in Section 3.6.1 will be used to assign HCV RNA values for missing 
values at a visit that are bracketed by “< LLOQ TND” and/or “< LLOQ detected”. Otherwise, a 
missing = excluded analysis will be performed. Plots of the mean ± SD and median (Q1, Q3) of 
absolute values and changes from baseline in HCV RNA through EOT will be presented by 
HCV genotype (genotype 1, nongenotype 1, total).
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created by HCV genotype (genotype 1, 
nongenotype 1, total) for each treatment group. All subjects who achieve SVR12 will be 
categorized as SVR12. Virologic failure will be descriptively summarized as “on-treatment 
virologic failure” and relapse (which will be broken down by study drug completed yes/no). 
Subjects who do not achieve SVR12 and do not meet criteria for VF will be categorized as 
“Other”. The denominator for relapse will be the number of subjects who had HCV 
RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS. This summary table will also be 
provided by CPT class at baseline (CPT B, CPT C) and by HCV genotype (genotype 1, 
nongenotype 1, total) for each treatment group.
For subjects with virologic failure, a summary table of the point estimates and 95% exact CIs 
based on Clopper-Pearson method of the rate of virologic failure within each treatment group 
will be displayed by HCV genotype (genotype 1, nongenotype 1, total).
A concordance table between SVR12 and SVR24 will be provided for each treatment group and 
HCV genotype (genotype 1, nongenotype 1, total). Subjects with both observed SVR12 and 
observed SVR24 data will be included for this analysis.
In addition, a summary table of the number and percentage of subjects with HCV RNA < LLOQ 
and ≥ LLOQ at the posttreatment follow-up visit (observed and imputed, with reasons for 
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posttreatment follow-up visit. 95% Clopper-Pearson exact CIs will be presented for the overall 
proportion of subjects with HCV RNA < LLOQ.
Drug resistant substitutions will be analyzed as part of the Virology Study Report.
6.2.2.2.
Analysis Methods for Other Efficacy Endpoints – CPT and MELD Scores
Analyses of CPT and MELD scores will be presented separately for the subset of subjects in the 
FAS who achieved SVR12 for the SVR12 analysis or SVR24 for the final analysis. 
6.2.2.2.1.
Child-Pugh-Turcotte Score
In the clinical database, CPT score will be assessed using prothrombin activation % for the 
coagulation parameter as described in Table 6-1. CPT score calculated by sites at 
screening/randomization can be assessed using either INR or PT% for coagulation parameter. 
CPT scores will be calculated as: the sum of the scores related to the 5 items in the table below 
(if any of the components are missing, the score will not be calculated):
Table 6-1.
Child-Pugh-Turcotte Scoring of the Severity of Cirrhosis
Measure
1 point
2 points
3 points
Total bilirubin, mg/dL, 
(μmol/L) 
<2, (<34)
2-3, (34-50)
>3, (>50)
Serum albumin, g/dL
>3.5
2.8-3.5
<2.8
Coagulationa
INR
<1.7
1.7-2.3
> 2.3
Prothrombin
Activation
%
>70%
40-70%
<40%
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
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
hepatic encephalopathy
Medication-Refractory
Marked confusion/incoherent,
rousable but sleeping unless
aroused or comatosed
a
For coagulation, either INR or prothrombin activation % will be used


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CPT class will be assigned as:
CPT class: 
A = 5-6 points
B = 7-9 points
C = 10-15 points
CPT class will be analyzed for subjects who achieve SVR12 and SVR24 respectively by 
treatment group and overall:

Shift table of baseline CPT class vs. posttreatment week 12 CPT classes

Shift table of baseline CPT class vs. posttreatment week 24 CPT classes (for final analysis)
A by-subject listing of CPT score based on INR and %PT and change from baseline will be 
provided for all subjects in Safety Analysis Set.
6.2.2.2.2.
MELD Score
MELD score will be assessed as follows:
MELD = 0.957 x Loge (serum creatinine mg/dL)
+ 0.378 x Loge (Total bilirubin mg/dL)
+1.120 x Loge (INR)
+0.643
Multiple the score by 10 and 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 has 
received 24 hours of continuous venovenous hemodiafiltration within the prior week, then serum 
creatinine will be set to 4.0 mg/dL in the above formula.
The following analyses of MELD scores will be performed by treatment group and overall for 
subjects who achieved SVR12 at the posttreatment Week 12 analysis and those who achieved 
SVR24 at the final analysis:

The number and percentage of subjects with “no change”, “increase”, and “decrease” 
between baseline and posttreatment Week 12 and 24 visits will be presented. “No change” 
will be assigned for differences (posttreatment visits MELD score minus baseline MELD 
score) of -1, 0 or 1; “decrease” will be assigned for differences that are ≤ -2; and “increase” 
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Safety Analysis Set. 
6.3. 
Exploratory Efficacy Endpoints 
I 
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Changes From Protocol-Specified Efficacy Analyses 
There are no planned changes from protocol-specified efficacy analyses. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
eCRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Drug Safety and Public 
Health Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both 
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the first 
dose date of study drug.

The AE onset date is the same as or before the month and year (or year) of the 30th day after 
the date of the last dose of study drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by treatment group and by the number 
and percentage of subjects who had the following: any AE, any AE of Grade 3 or above, any AE 
of Grade 2 or above, any treatment-related AE, any treatment-related AE of Grade 3 or above,
any treatment-related AE of Grade 2 or above, any SAE, any treatment-related SAE, any AE 
leading to premature discontinuation of any study drug, any AE leading to premature 
discontinuation of SOF/VEL, any AE leading to premature discontinuation of RBV, any AE 
leading to premature discontinuation of all study drugs, any AE leading to modification or 
interruption of any study drug, any AE leading to interruption of SOF/VEL, any AE leading to 
modification or interruption of RBV, any AE leading to modification or interruption of all study
drugs. All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized and included in this table.
A brief summary of TEAEs by age group (ie, <65 years, ≥65 years, total) and by CPT class at 
baseline (CPT B, CPT C, total) will also be explored. Each brief summary will be presented by 
treatment group.
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, by treatment group, by CPT class at baseline (CPT B, CPT C, total) within each 
treatment group based on the Safety Analysis Set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs


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
Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

AEs leading to premature discontinuation of any study drug

AEs leading to premature discontinuation of SOF/VEL

AEs leading to premature discontinuation of RBV

AEs leading to premature discontinuation of all study drugs

AEs leading to modification or interruption of any study drug

AEs leading to interruption of SOF/VEL

AEs leading to modification or interruption of RBV

AEs leading to modification or interruption of all study drugs
Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed for each treatment first in alphabetic order of SOC and then by PT in 
order of descending incidence of the pooled treatment groups within each SOC. In summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence within pooled treatment groups for:

AEs that occurred in at least 5% of subjects within any treatment group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of any study drug

AEs leading to premature discontinuation of SOF/VEL

AEs leading to premature discontinuation of RBV


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
AEs leading to premature discontinuation of all study drugs

AEs leading to modification or interruption of any study drug

AEs leading to interruption of SOF/VEL

AEs leading to modification or interruption of RBV

AEs leading to modification or interruption of all study drugs
In addition to the by-treatment summaries described above, data listings will be provided for the 
following:

All AEs 

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of any study drug

AEs leading to modification or interruption of any study drug

AE with changes other than resolution dates between the SVR12 and SVR24 analyses 
(provided only at the final analysis)
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug or all available data at the time of the 
database snapshot for subjects those who were ongoing at the time of an interim analysis. The 
analysis will be based on values reported in conventional units. When values are below the limit 
of quantitation, they will be listed as such, and the closest imputed value will be used for the 
purpose of calculating summary statistics. For example, if “< 0.2” was recorded, a value of 
0.1 will be used for the purpose of calculating summary statistics; if “< 0.1” was recorded, a 
value of 0.09 will be used for the purpose of calculating summary statistics. Hemolyzed test 
results will not be included in the analysis, but they will be listed in by-subject laboratory 
listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
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Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline 
phosphatase, hemoglobin, reticulocytes, red blood cell (RBC), white blood cell (WBC), 
neutrophils, lymphocytes, platelets, albumin, INR, prothrombin activation %, creatinine, eGFR, 
and creatine kinase as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1. 
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, RBC, WBC, lymphocytes, platelets, and albumin will be plotted 
using a line plot by treatment group and visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3 (Selection of Data in the Event of Multiple Records in a Window). 
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visit (up 
to 30 days after the last dose of any study drug) will be summarized by treatment group and by 
CPT class at baseline (CPT  B, CPT  C, total) within each treatment group. A by-subject listing 
will be provided for subjects with postbaseline hemoglobin < 10 g/dL and < 8.5 g/dL.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1 (mild) , 
Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening). Grade 0 includes 
all values that do not meet the criteria for an abnormality of at least Grade 1. Some laboratory 
tests have laboratory toxicity criteria for both increased and decreased levels; analyses for each 
direction (ie, increased, decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug.
If the relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 will 
be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of treatment-emergent laboratory abnormalities, the denominator will be the 
number of subjects with nonmissing postbaseline values up to 30 days after last dose of study 
drug for the laboratory parameter of interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
7.3.
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment 
group. The baseline value will be defined as the last available value collected on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [oC]) will be provided by subject ID 
number and visit in chronological order. In the same manner, a by-subject listing of body weight, 
height, and BMI will be provided separately.


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7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior, concomitant, or both using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications initially taken on or after the initial study drug 
dosing date and within the study drug treatment period (including the study drug therapeutic 
reach)
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug 
class Level 2, and preferred name using the number and percentage of subjects for each 
treatment group and overall. A subject reporting the same medication more than once will be 
counted only once when calculating the number and percentage of subjects who received that 
medication. The summary of concomitant medications will be ordered by descending active 
treatment group frequency of ATC drug classes and then preferred names within an ATC 
medical class. For drugs with the same frequency, sorting will be done alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated.
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year 
(if day and month are missing) after the study drug stop date will be excluded from the 
concomitant medication summary. Medications with completely missing dates will be included 
in the concomitant medication summary. 
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
In addition, use of concomitant blood products and epoetin medication while the subject is taking 
study drug will be summarized (number and percentage of subjects) by treatment group, WHO 
drug class, and WHO generic name. Multiple drug use (by generic name) will be counted once 
only per subject. The summary will be sorted alphabetically by drug class and then by decreasing 
total frequency of generic name within a class. This subset analysis will be performed by 
selecting for the following generic terms: HUMAN RED BLOOD CELLS; BLOOD CELLS, 
PACKED HUMAN; RED BLOOD CELLS, CONCENTRATED; PLATELETS, HUMAN 
BLOOD; PLASMA; EPOETIN ALFA, ERYTHROPOIETIN, DARBEPOETIN ALFA. A listing 
of subjects with use of prior and concomitant blood products and epoetin medication while 
taking study drug will be provided. 


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Similarly, use of concomitant ascites and hepatic encephalopathy medication will be 
summarized. A listing of subjects with use of prior and concomitant medications for ascites and 
hepatic encephalopathy will be provided.
A listing of subjects with treatment for most recent prior hepatocellular carcinoma will also be 
provided. 
7.5.
Electrocardiogram Results
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. A by-subject listing for subjects with clinically significant abnormalities 
from ECG assessment results will also be provided by subject ID number and visit in 
chronological order. 
7.6.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
For the PK analysis set, plasma concentrations of SOF (and its metabolites GS-566500 and 
GS-331007) and VEL in plasma will be determined using validated bioanalytical assays. 
Population PK models for SOF, GS-331007 and VEL, previously developed for the Phase 2/3 
SOF/VEL US NDA population analyses, will be applied to the data from all PK samples 
collected in this study. Details of the population PK analysis will be provided in a separate 
population PK analysis plan. Plasma PK sampling details and PK concentrations will be 
provided in a listing.


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9.
REFERENCES
Clopper, C. J. and E. S. Pearson (1934). "The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Dec." Biometrika 26(4): pp. 404-413.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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11.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
QOL Score Calculation Algorithm


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Appendix 1.
Study Procedures Table
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment 
Week  (5 days)
1
2
3
4
5
6
7
8
9
10
11
12/ETb
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Verification of CPT scorec
X
Medical History
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGe
X
X
Adverse Events and Concomitant 
Medicationsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
X
Health Related Quality of Lifeg
X
X
X
Assessment of ascites and hepatic 
encephalopathy 
X
X
X
X
X
X
X
X
Imaging for HCCh
X
Review of Study Drug Adherence and Drug 
Accountabilityi
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensingj
X
X
X


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Screening
Day 1a
Treatment Week
(3 days)
Posttreatment 
Week  (5 days)
1
2
3
4
5
6
7
8
9
10
11
12/ETb
4
12
24
Close Monitoring of Subjects with CPT C 
Cirrhosisk
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
Coagulation (Prothrombin activation %, PT,
aPTT and INR)
X
X
X
X
X
X
X
X
X
Urinalysis
X
HCV RNA
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing / Phenotyping
X
X
X
X
X
X
X
X
HBV DNA samplel
X
X
X
X
X
X
X
Single PK
X
X
X
X
Serum or Urine Pregnancy Testm
X
X
X
X
X
X
X
X
HCV Genotyping
X
IL28B Genotype
X
HCV Ab, HIV Ab, HBsAg, HBsAb, HBcAb
X
FibroTest®
X
Archive Plasma samplen
X
X
Single Genomic sampleo
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = early termination.
c
Prior to randomization on Day 1, CPT score should be calculated using laboratory values from the local lab to verify that it is between 7-12; however, randomization will be 
based on CPT score at Screening.
d
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
e
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.


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f
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drugs. In addition, records of Concomitant Medications for ascites 
and hepatic encephalopathy taken through posttreatment Week 24 will be collected in the eCRF.
g
Health Related Quality of Life (HRQoL) Surveys (eg, SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1.
h
Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all subjects 
within 4 months of Day 1.
i
Study drugs will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the study drugs. Subjects must be instructed to 
bring back all bottles of study drugs in the original container at every post- Day 1 visit through the end of treatment.
j
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
k
Subjects with CPT C cirrhosis at Screening should be monitored closely during treatment with SOF/VEL ± RBV. The extent and duration of monitoring is at the discretion of 
the Investigator, based on assessment of each individual subject, but may include daily contact with subject (or subject’s family) or in-patient hospitalization. Proximity of 
subject’s residence to the investigator’s institution should be taken into consideration. The objective of this close monitoring is to facilitate prompt communication and 
response to adverse events that may occur.
l
Reflex testing done only when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
m
All females of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment 
Week 4. In addition, females of childbearing potential in the treatment group receiving RBV will have additional urine pregnancy testing every 4 weeks for a minimum of 6 
months following last dose of RBV. If required by local regulations, additional pregnancy tests beyond 6 months may be added. In the event of a positive urine pregnancy 
result, subjects will be instructed to return to the clinic as soon as possible for a serum pregnancy test. The subject will be contacted by telephone monthly to confirm that 
urine pregnancy testing has been performed posttreatment and to record the outcome. Alternatively, if required by local regulations or preferred by the investigator or subject, 
the subject may return to the clinic for urine pregnancy tests.
n
Only for subjects who have provided separate consent for this sample and testing 
o
Only for subjects who have provided separate consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1.


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Appendix 2.
QOL Score Calculation Algorithm
CLDQ – HCV
CLDQ-HCV scores are calculated using subject responses to 29 questions in the questionnaire. If 
Ri is the score for the patient’s response to the item i, for i=1, 2, …., 29 then the 4 domain scores 
are calculated as follows:

Activity/Energy (AE) = Mean of {R1, R3, R4, R5, R7, R18}

Emotion (EM) = Mean of {R6, R8, R9, R11, R16, R23, R24, R27, R28}

Worry (WO) = Mean of {R14, R15, R17, R19, R20, R21, R22, R29}

Systemic (SY) = Mean of {R2, R10, R12, R13, R25, R26}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is calculated 
only if at least half of corresponding items are not missing. Otherwise, the score will be missing.
Over all CLDQ-HCV score is calculated by taking the mean of 4 domain scores AE, EM, WO, 
SY.
FACIT-F
Patient responses to 40 questions in FACIT-F questionnaire are rated in 0-4 score.
If less than 50% of responses in the corresponding domain are missing, the subscales for five 
domains are calculated as follows:

Physical Well-Being (PWB) = 7 × Mean of {of GP1-GP7}

Social/Family Well-Being (SWB) = 7 × Mean of {GS1-GS7}

Emotional Well-Being (EWB) = 6 × Mean of {GE1-GE6}

Functional Well-Being (FWB) = 7 × Mean of {GF1-GF7}

Fatigue Subscale (FS) = 13 × Mean of {HI7, HI12, An1-An5, An7, An8 An12, An14-An16}
and

FACIT-F Trial Outcome Index (TOI) = PWB+FWB+FS
If less than 20% of all items included are not missing,  

TACIT-F Total Score = PWB+SWB+EWB+FWB+FS 


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WAPI: Hepatitis C
The response to Question 1 of this questionnaire provides the binary endpoint whether or not the 
subject had been in a paid employment during the week prior to assessment.
If the subject had been in a paid employment (Response to Q1 is “Yes”) at the visit when 
questionnaire was given, then following three scores are derived:

Percent work time missed due to hepatitis C = 100×Q2/(Q2+Q4)

Percent impairment while working due to hepatitis C = 100×Q5/10

Percent overall work impairment due to hepatitis C = 


















10
5
)
4
2
2
1
)
4
2
(
2
100
Q
Q
Q
Q
Q
Q
Q
Question 6 is applicable to all subjects:

Percent activity impairment due to hepatitis C = 100×Q6/10.