Conditions: Hepatitis C Virus Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 239
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the antiviral efficacy of therapy with ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) and to evaluate the safety and tolerability of LDV/SOF FDC and sofosbuvir (SOF) + ribavirin (RBV) in participants with chronic genotype 2 hepatitis C virus (HCV) infection.

Detailed description:

Arms:
arm 1: LDV/SOF FDC for 12 weeks arm 2: SOF+RBV for 12 weeks arm 3: Participants who are ineligible for or intolerant to RBV therapy will receive LDV/SOF FDC for 12 weeks.

Interventions: intervention 1: LDV/SOF intervention 2: SOF intervention 3: RBV
Intervention descriptions: intervention 1: 90/400 mg FDC tablet administered orally once daily intervention 2: 400 mg tablet administered orally once daily intervention 3: Capsules administered orally in a divided daily dose according to package insert weight-based dosing recommendations (≤ 60 kg = 600 mg, \> 60 kg to ≤ 80 kg = 800 mg, and \> 80 kg = 1000 mg)

Protocol document:
Prot_005.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety ofLedipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-337-1903 
Gilead Study Director: 
Natne: 
PD 
PPD 
PPD 
PPD 
Telephone: 
Fax: 
Email: 
Gilead Medical 
Natne: 
Monitor: 
Telephone: 
Fax: 
Email: 
Protocol Version/Date: 
Original: 
22 December 2015 
Amendment 1: 27 Januruy2016 
CONFIDENTIALITY STATEMENT 
The inf01m ation contained in this document, patiiculru·ly lmpublished data, is the prope1iy or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review 
Boru·d or Independent Ethics Committee. The infonnation is only to be used by you in connection 
with authorized clinical studies of the investigational dmg described in the protocol. You will not 
disclose any of the infonnation to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessaty to obtain inf01m ed consent from those persons to whom the dmg may 
be administered. 


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS...............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION...............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.1.1.
HCV Infection in Japan........................................................................................................14
1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC ..........................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study ...............................15
1.3.
Information about Ribavirin...................................................................................................................16
1.4.
Rationale for This Study.........................................................................................................................17
1.5.
Risk/Benefit Assessment for the Study ..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES .....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Study Design ..........................................................................................................................................19
3.2.
Study Treatments....................................................................................................................................19
3.3.
Duration of Treatment............................................................................................................................19
3.4.
Stopping Rules and Discontinuation Criteria .........................................................................................19
3.4.1.
Virologic Response-Based Treatment Stopping Criteria......................................................20
3.5.
Samples for Optional Genomic Research...............................................................................................20
4.
SUBJECT POPULATION..................................................................................................................................22
4.1.
Number of Subjects and Subject Selection.............................................................................................22
4.2.
Inclusion Criteria....................................................................................................................................22
4.3.
Exclusion Criteria...................................................................................................................................24
5.
INVESTIGATIONAL MEDICINAL PRODUCTS............................................................................................27
5.1.
Randomization, Blinding and Treatment Codes.....................................................................................27
5.2.
Description and Handling of LDV/SOF FDC ........................................................................................27
5.2.1.
Formulation ..........................................................................................................................27
5.2.2.
LDV/SOF FDC Packaging and Labeling .............................................................................27
5.2.3.
LDV/SOF FDC Storage and Handling.................................................................................27
5.2.4.
Dosage and Administration of LDV/SOF FDC....................................................................28
5.3.
Description and Handling of Sofosbuvir (SOF) .....................................................................................28
5.3.1.
Formulation ..........................................................................................................................28
5.3.2.
SOF Packaging and Labeling ...............................................................................................28
5.3.3.
SOF Storage and Handling...................................................................................................28
5.3.4.
Dosage and Administration of SOF......................................................................................29
5.4.
Description and Handling of Ribavirin (RBV).......................................................................................29
5.4.1.
Formulation ..........................................................................................................................29
5.4.2.
RBV Packaging and Labeling ..............................................................................................29
5.4.3.
RBV Storage and Handling..................................................................................................29
5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in 
the SOF + RBV Treatment Group) ......................................................................................30
5.5.
Co-administration of SOF and RBV ......................................................................................................30
5.6.
Study Drug Adherence and Drug Accountability...................................................................................31
5.7.
Prior and Concomitant Medications.......................................................................................................31


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5.8.
Accountability for Investigational Medicinal Product (IMP).................................................................32
6.
STUDY PROCEDURES.....................................................................................................................................33
6.1.
Screening Visit .......................................................................................................................................33
6.2.
Randomization/Enrollment ....................................................................................................................33
6.2.1.
Day 1 Assessments...............................................................................................................33
6.3.
Treatment Assessments (3 days)..........................................................................................................34
6.4.
Posttreatment Assessments (5 days).....................................................................................................34
6.5.
Early Termination (ET)..........................................................................................................................34
6.6.
Unscheduled Visit ..................................................................................................................................34
6.7.
Procedures and Specifications................................................................................................................34
6.7.1.
Clinical Laboratory Analytes................................................................................................34
6.7.2.
Medical History....................................................................................................................35
6.7.3.
Complete Physical Examination...........................................................................................35
6.7.4.
Vital Signs............................................................................................................................35
6.7.5.
12-Lead ECGs ......................................................................................................................35
6.7.6.
Health Related Quality of Life (HRQoL).............................................................................36
6.7.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................36
6.7.8.
Pregnancy Testing ................................................................................................................36
6.7.9.
IL28B Testing.......................................................................................................................36
6.7.10.
Archive Plasma Sample........................................................................................................36
6.7.11.
Genomic Testing ..................................................................................................................37
6.7.12.
Creatinine Clearance ............................................................................................................38
6.8.
End of Study...........................................................................................................................................38
6.9.
Poststudy Care........................................................................................................................................38
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT ...............................................................................39
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................39
7.1.1.
Adverse Events.....................................................................................................................39
7.1.2.
Serious Adverse Events........................................................................................................39
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................40
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................40
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................40
7.2.2.
Assessment of Severity.........................................................................................................41
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious Adverse 
Events to Gilead .....................................................................................................................................41
7.4.
Gilead Reporting Requirements .............................................................................................................43
7.5.
Toxicity Management.............................................................................................................................43
7.5.1.
RBV Dose Adjustments (Only Cohort 1).............................................................................43
7.5.2.
Subject Stopping Rules.........................................................................................................45
7.6.
Special Situations Reports......................................................................................................................46
7.6.1.
Definitions of Special Situations ..........................................................................................46
7.6.2.
Instructions for Reporting Special Situations.......................................................................47
8.
STATISTICAL CONSIDERATIONS................................................................................................................49
8.1.
Analysis Objectives and Endpoints........................................................................................................49
8.1.1.
Analysis Objectives..............................................................................................................49
8.1.2.
Primary Endpoint .................................................................................................................49
8.1.3.
Secondary Endpoint..............................................................................................................49
8.1.4.
Other Endpoints of Interest ..................................................................................................50
8.2.
Analysis Conventions.............................................................................................................................50
8.2.1.
Analysis Sets ........................................................................................................................50
8.3.
Data Handling Conventions ...................................................................................................................50
8.4.
Demographic Data and Baseline Characteristics....................................................................................51


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8.5.
Efficacy Analysis ...................................................................................................................................52
8.5.1.
Primary Analysis ..................................................................................................................52
8.5.2.
Secondary Analyses..............................................................................................................52
8.6.
Safety Analysis.......................................................................................................................................52
8.6.1.
Extent of Exposure ...............................................................................................................53
8.6.2.
Adverse Events.....................................................................................................................53
8.6.3.
Laboratory Evaluations ........................................................................................................54
8.6.4.
Other Safety Evaluations......................................................................................................54
8.7.
Sample Size............................................................................................................................................54
9.
RESPONSIBILITIES..........................................................................................................................................55
9.1.
Investigator Responsibilities ..................................................................................................................55
9.1.1.
Good Clinical Practice..........................................................................................................55
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................55
9.1.3.
Informed Consent.................................................................................................................55
9.1.4.
Confidentiality......................................................................................................................56
9.1.5.
Study Files and Retention of Records ..................................................................................56
9.1.6.
Case Report Forms ...............................................................................................................57
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................58
9.1.8.
Inspections............................................................................................................................58
9.1.9.
Protocol Compliance ............................................................................................................58
9.2.
Sponsor Responsibilities ........................................................................................................................58
9.2.1.
Protocol Modifications .........................................................................................................58
9.2.2.
Study Report and Publications .............................................................................................58
9.3.
Joint Investigator/Sponsor Responsibilities............................................................................................59
9.3.1.
Access to Information for Monitoring..................................................................................59
9.3.2.
Access to Information for Auditing or Inspections ..............................................................59
9.3.3.
Study Discontinuation ..........................................................................................................59
10.
REFERENCES....................................................................................................................................................60
11.
APPENDICES ....................................................................................................................................................63
Appendix 1.
Investigator Signature Page....................................................................................................64
Appendix 2.
Study Procedures Table..........................................................................................................65
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............68
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................91
LIST OF IN-TEXT TABLES
Table 5-1.
Dosing and Administration of RBV in Japan .........................................................................30
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for SOF and 
LDV/SOF ...............................................................................................................................32
Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects................................................44
Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects........................................................45


LDV/SOFFDC 
Protocol GS-US-337-1903 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Amendment 1 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
This is a non-IND study 
Not Applicable 
Not Available 
Approximately 40 centers in Japan. 
The primruy objectives of this study ru·e follows: 
• 
To evaluate the antiviral efficacy of therapy with 
ledipasvir/sofosbuvir (LDV /SOF) fixed-dose combination (FDC) as 
measured by sustained virologic response 12 weeks after cessation 
of treatment (SVR12) 
• 
To evaluate the safety and tolerability of each regimen as assessed 
by review of the accumulated safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment 
and after cessation of each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after cessation of treatment 
Explorat01y objectives of this study ru·e: 
IT 
I 
Page 5 
27 Janruuy 2016 


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Study Design:
This is a multicenter, randomized, open-label study in treatment-naïve 
and treatment-experienced adults with chronic genotype 2 HCV 
infection.
Cohort 1: Approximately 200 subjects will be randomized in a 1:1 ratio
to one of the following two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg 
daily as a divided dose) for 12 weeks 
Approximately 10% of subjects may have Child-Pugh-A compensated 
cirrhosis.  Approximately 50% of subjects will be treatment-naïve and 
50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/absence) 
and prior treatment experience (treatment-naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV 
therapy will receive LDV/SOF FDC tablet (90/400 mg) once daily for 
12 weeks. Approximately 10% of subjects may have Child-Pugh-A 
compensated cirrhosis.  
Number of Subjects 
Planned:
Approximately 225 subjects
Target Population:
Treatment naïve and treatment experienced, chronic genotype 2 HCV 
infected adults
Duration of 
Treatment:
Subjects will be treated for 12 weeks.
Diagnosis and Main 
Eligibility Criteria:
Chronic genotype 2 HCV-infected male and non-pregnant/non-lactating 
female subjects, aged 20 years or older, treatment naïve or treatment-
experienced. Approximately 10% in each cohort may have Child-Pugh-
A compensated cirrhosis. In Cohort 2 subjects must be ineligible or 
intolerant of RBV. 


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Study Procedures/
Frequency:
Screening assessments will be completed within 28 days prior to 
the Day 1 visit. The screening window can be extended up to 42 days in 
extenuating circumstances, including the need for a liver biopsy or 
additional HCV genotyping (if initial testing is inconclusive). Study 
visits will occur at Screening, Day 1, and on-treatment at the end of 
Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12. Following the last dose of study 
medication, all subjects will complete 4-Week, 12-Week and 24-Week 
Posttreatment Visits.
Screening assessments will include medical history, physical
examination, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, liver imaging to exclude hepatocellular 
carcinoma (HCC) within 6 months for non-cirrhotics and within 4 months 
for cirrhotics, safety laboratory tests (including hematology, chemistry, 
coagulation, urinalysis), HCV RNA, serum β-hCG (females of child 
bearing potential only), HCV genotype, host IL28B genotype, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c).
On-treatment assessments include physical examination, weight, vital 
signs, 12-lead ECG, AEs, concomitant medications, pregnancy 
prevention counseling, review of study drug adherence and drug 
accountability, study medication dispensing, safety laboratory tests
(including hematology, chemistry, coagulation, urinalysis), HCV RNA, 
viral RNA sequencing/phenotyping sample, urine pregnancy tests 
(females of child bearing potential only).
Posttreatment assessments include physical examination, weight, vital 
signs, AEs and concomitant medications, pregnancy prevention 
counseling, safety laboratory tests (including hematology and
chemistry), HCV RNA, viral RNA sequencing/phenotyping, and urine 
pregnancy tests (females of childbearing potential only). 
For subjects who provide their additional and specific consent, a single 
blood sample will be collected at the Day 1 visit for human genomic 
testing (this sample may be drawn after Day 1, if necessary).
Health Related Quality of Life (HRQoL) Survey will be conducted at 
Day 1, On-treatment Weeks 4, 8, and 12, Early Termination (if 
applicable), and Posttreatment Week 4, 12, and 24. 
Archive plasma samples will be collected at each on-treatment and 
posttreatment study visit for potential future testing.


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Test Product, Dose, and 
Mode of 
Administration:
1. Ledipasvir/sofosbuvir (HARVONI®, LDV/SOF) is manufactured as 
a FDC tablet, consisting of 90 mg LDV and 400 mg SOF, for oral 
administration. Subjects will take 1 tablet daily for 12 weeks.
2. Sofosbuvir (SOVALDI®, SOF) is manufactured as a 400mg tablet 
for oral administration. Subjects will take 1 tablet daily for 12 
weeks.
3. Ribavirin (REBETOL®, RBV) is manufactured as a 200mg capsule. 
Subjects will take weight-based RBV every day (600-1000 mg/day 
in a divided daily dose) in accordance with RBV product labeling. 
The morning dose of RBV will be taken with the SOF tablet and 
with food. The evening dose of RBV will be taken alone with food.
Ribavirin dose reductions and modifications will be performed 
according to the approved RBV labeling.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Safety:
AEs and safety laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using Ampliprep® TaqMan® HCV Test, v2.0. 
Statistical Methods:
The primary efficacy endpoint is SVR12 in all randomized/enrolled and 
treated subjects. 
Cohort 1: The primary analyses will consist of a non-inferiority test of 
treatment LDV/SOF FDC for 12 weeks versus SOF+RBV for 12 weeks 
at the 0.05 significance level.
Non-inferiority will be assessed using the conventional confidence 
interval approach, and a clinically meaningful non-inferiority margin of 
10% will be applied. The two-sided 95% confidence intervals will be 
constructed using stratum-adjusted Mantel-Haenszel (MH) proportions, 
stratified by the randomization stratification factors (ie, cirrhosis status 
and prior treatment experience). 
A sample size of 100 per treatment group will provide over 90% power 
to establish non-inferiority in the SVR12 rates between the two groups. 
It is based on the assumptions that the clinically meaningful non-
inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.
Cohort 2: No statistical hypothesis testing will be performed. A point-
estimate with two-sided 95% exact confidence interval using the 
binomial distribution (Clopper-Pearson method) will be constructed for 
the SVR12 rate.


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The secondary efficacy endpoints include SVR measured at 4 and 
24 weeks after discontinuation of study drug (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; and virologic failure.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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Amendment 1
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
Actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
ANC
Absolute Neutrophil Count 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AV
atrioventricular
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 rate
CLDQ-HCV
Chronic Liver Disease Questionnaire
CM
concomitant medication
cm2
square centimeter
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration 
of drug
Crcl
creatinine clearance
CRO
contract (or clinical) research organization
CSR
Clinical study report
DAA
direct-acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid 
DSPH
Gilead Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
ER
Emergency room
ESLD
End Stage Liver Disease
ET
Early Termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials


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FACIT-F
Fatigue Index
FAS
full analysis set
FCF
yellow # 6 / sunset yellow FCF aluminum lake
FD&C 
Federal Food, Drug and Cosmetic
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
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
genotype
GT-2
genotype 2
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 
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
Interferon
IL28B
Interleukin-28B gene
IMB
Intermenstrual Bleeding
IMP
Investigational Medical Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time


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IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
interactive web response system
JSH
Japanese Society of Hepatology
J-GCP
Ministerial Ordinance on Good Clinical Practice for Drugs
kg
Kilogram
kPA
kilopascal
L
liter
LAM
Lactational amenorrhea method
LAR
legally-authorized representative
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
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
mg
milligram
MGB
minor groove binder
MH
Mantel-Haenszel
MHLW
Japan's Ministry of Health, Labour and Welfare
mL
Milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
mmol
millimole
n
number
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein
PK
Pharmacokinetic
PMDA
Pharmeceuticals and Medical Devices Agency
PPIs
Proton-pump inhibitor
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time
Q1
Quartile 1


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Q3
Quartile 3
QA
Quality assurance
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
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
TND
Target not detected
ULN
Upper limit of normal
US
United States
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
β-hCG
β-human chorionic gonadotropin
μg
microgram
μL
microliter
μmol
micromole


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1.
INTRODUCTION
1.1.
Background
Hepatitis C Virus (HCV) infection is a global health challenge with an estimated 180 million 
individuals infected worldwide {Ghany et al 2009}. Up to 85% of individuals infected with HCV 
fail to clear the virus and progress to chronic infection {Lauer et al 2001}. Consequences of chronic 
infection include cirrhosis and hepatocellular carcinoma {Thein et al 2008}. The annual rate of 
progression to cirrhosis in chronic HCV infected patients with advanced fibrosis is ~10 % {Dienstag 
et al 2011}. Approximately 1 to 4% of patients per year with established cirrhosis will progress to 
hepatocellular carcinoma (HCC) {Degos et al 2000}, {Dienstag et al 2011}, {Nishiguchi et al 
1995}, {Serfaty et al 1998}. Given the asymptomatic nature of early infection, the slow progression 
to chronic liver disease, and the lack of adequate screening in at-risk individuals, it is expected that 
the prevalence of subjects diagnosed with HCV-related complications will peak over the next 
2 decades {Hoofnagle et al 2006}, {World Health Organization (WHO) 2015}, {El-Serag 2004}, 
{Davis et al 2003}.
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 
approximately1.3-2.4 million people chronically infected with HCV. In Japan, it is estimated that 
approximately 20-30% of the 1.3-2.4 million people infected with chronic hepatitis C virus have 
genotype 2 {Sievert et al 2011}, {Chung et al 2010}.  The highest prevalence rates of HCV 
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}. Consequently, the majority of Japanese patients 
with chronic hepatitis C are elderly (average age ~ 70 years) and 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. 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, the current standard of care for chronic genotype 2 HCV infection is the combination of 
sofosbuvir (SOF) 400 mg taken once daily and ribavirin (RBV; 600-1000 mg based on weight, split 
over two daily doses) {The Japan Society of Hepatology 2015}; this regimen is only indicated for 
patients without cirrhosis or for those with compensated cirrhosis. For treatment naïve patients with 
genotype 2 HCV infection, the combination of pegylated interferon (PEG-IFN) plus RBV can also 
be considered; or PEG-IFN monotherapy for treatment naïve patients with low viral load. For 
treatment experienced patients with genotype 2 infection, the protease inhibitor telaprevir, in 
combination with PEG-IFN and RBV, can also be considered. 
The fixed-dose combination of ledipasvir (LDV) 90 mg/SOF 400 mg taken once daily for 12 weeks 
is approved in Japan for the treatment of genotype 1 HCV infection in patients with or without 
compensated cirrhosis.


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1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC
Sofosbuvir (SOF; Sovaldi®) is a nucleotide analog that is a potent and selective inhibitor of 
non-structural protein (NS) 5B-directed HCV replication. 
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC; Harvoni®) combines two HCV
specific direct-acting antiviral (DAA) agents into a single tablet for the treatment of chronic HCV 
infection. Ledipasvir is a HCV NS5A inhibitor and SOF is a nucleotide analog that is a potent and 
selective inhibitor of NS5B-directed HCV replication, irrespective of HCV genotype.
1.2.1.
General Information
Please refer to the current Investigator’s Brochures (IBs) for additional information on SOF and the 
LDV/SOF FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study
1.2.2.1.
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects
This study evaluated SOF (and its metabolites) and LDV PK parameters following single dose 
administration of the SOF or LDV/SOF combination to healthy Japanese and Caucasian subjects. 
SOF and LDV/SOF FDC were well tolerated in this study. PK results support the use of the 400 mg 
SOF dose and the LDV (90 mg)/SOF (400 mg) FDC in both Japanese and non-Japanese subjects.
1.2.2.2.
GS-US-334-0118 SOF+RBV in Treatment Naïve and Treatment Experienced 
Japanese subjects with Chronic Genotype 2 HCV Infection
This Phase 3b study included 140 subjects with genotype 2 HCV who were treated with SOF+RBV 
for 12 weeks. All subjects completed the full 12 weeks of treatment with SOF+RBV. Rates of 
SVR12 in the overall population were 96% (135/140). For treatment-naïve, non-cirrhotic subjects, 
SVR12 was achieved in 97% (73/75) which was superior to the adjusted historical control rate of 
69% (p<0.001). All 5 virologic failures had HCV RNA <LLOQ for the PCR assay at the end of 
treatment and relapsed following discontinuation of treatment.
SOF+RBV was safe and well-tolerated in this study. Most adverse events were mild to moderate in 
severity and were generally not considered related to study drug. The exception being RBV-related 
anemia. The results from this study formed the basis for registration of sofosbuvir (Sovaldi) in Japan 
for the treatment of chronic genotype 2 HCV infection {Omata et al 2014}.


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1.2.2.3.
GS-US-337-0113: LDV/SOF±RBV in Japanese Subjects with Genotype 1 HCV 
With or Without Compensated Cirrhosis
This Phase 3b study included 318 Japanese subjects with genotype 1 HCV treated with 
LDV/SOF±RBV for 12 weeks. In the group receiving LDV/SOF, all subjects (100%; 157/157) 
completed the full 12 weeks of treatment and achieved SVR12, regardless of previous treatment 
history, IL28B genotype, or presence of NS5A RAVs at baseline. In the group receiving 
LDV/SOF+RBV, the SVR12 rate was 98% (158/161), with one subject relapsing. 
LDV/SOF was safe and well-tolerated. Most adverse events were mild to moderate in severity and 
were not considered related to study drug.  This study formed the basis for registration of LDV/SOF 
(Harvoni) in Japan for the treatment of chronic genotype 1 HCV infection {Mizokami et al 2015}.
1.2.2.4.
GS-US-337-1468 (LEPTON) Oral Regimens for the Treatment of Chronic HCV 
Infection
In this multi-cohort study, Cohort 2 Group 1 is comprised of subjects with chronic genotype 2 HCV 
infection who were assigned to receive LDV/SOF for 12 weeks. Of the 26 subjects enrolled, 
twenty-five (96%) completed 12 weeks of treatment with LDV/SOF; 1 subject withdrew consent 
and prematurely discontinued from the study. All 25 subjects who completed treatment achieved 
SVR12 for an overall rate of 96% (25/26). 
Cohort 2 Group 2 is comprised of subjects with chronic genotype 2 HCV infection who were 
assigned to receive LDV/SOF for 8 weeks. Of the 27 subjects enrolled, 74% (20/27) achieved 
SVR12.  Among subjects who did not achieve SVR, one subject experienced on-treatment virologic 
breakthrough and 6 subjects relapsed.
These data demonstrate the clinical activity of LDV/SOF in subjects with chronic genotype 2 HCV 
infection and that 12 weeks of treatment is the optimal treatment length. There were no adverse 
events of anemia, decreased hemoglobin, nor hyperbilirubinemia reported {Gane et al 2015}.
1.3.
Information about Ribavirin
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA and 
DNA viruses{Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV in vivo but can result in normalization 
of serum ALT activity and improvement in liver histology. When combined with IFN or PEG-IFN 
therapy, RBV decreases substantially the relapse rate seen after cessation of IFN therapy {Poynard 
et al 1998}, {McHutchison et al 1998}. Ribavirin 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.


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1.4.
Rationale for This Study
This is a Phase 3b study designed to explore the efficacy of LDV/SOF FDC in subjects with chronic 
genotype 2 HCV infection. The overseas LEPTON study (GS-US-337-1468, Cohort 2 Group 1) has 
demonstrated that for subjects with genotype 2 HCV infection, 12 weeks of therapy with LDV/SOF 
FDC resulted in an SVR rate of 96.2% (25/26) and was safe and well-tolerated. 
The current study will explore the efficacy and safety of LDV/SOF in two different populations of 
Japanese subjects with genotype 2 infection. Cohort 1 will determine if LDV/SOF for 12 weeks is 
non-inferior to SOF+RBV for 12 weeks in Japanese subjects with genotype 2 HCV with or without 
compensated cirrhosis. Cohort 2 addresses an unmet medical need by treating subjects who are 
ineligible for, or intolerant of RBV. Under current Japanese Society of Hepatology (JSH)
guidelines, the only therapy available to patients ineligible for RBV is PEG-IFN monotherapy for up 
to 48 weeks, which has poor tolerability and suboptimal virologic response rates {Lai 2000}. All 
subjects enrolled in Cohort 2 will receive LDV/SOF FDC for 12 weeks. 
1.5.
Risk/Benefit Assessment for the Study
This study will evaluate a RBV-free treatment option for Japanese patients with genotype 2 HCV
infection including those who cannot receive RBV, a population that currently has limited treatment 
options. 
The safety and tolerability of LDV/SOF has been well characterized in overseas studies, Japanese 
studies, and in real world use both in Japan and abroad.  To date, there have been no differences 
seen in safety and tolerability based on genotype {Afdhal et al 2014a}, {Afdhal et al 2014b}, 
{Kowdley et al 2014}, {Mizokami et al 2015}.  If non-inferiority is demonstrated between 
LDV/SOF and SOF+RBV, then Harvoni would represent the first RBV-free, single tablet regimen 
for treatment of genotype 1 and 2 HCV infection.  
The safety profile of SOF is based on approximately 7500 chronic HCV-infected study subjects that 
have been administered SOF in combination with a DAA, PEG-IFN, and/or RBV.  No clinical 
safety issues related to SOF have been identified to date. The safety profile of LDV is based on over 
1200 chronic HCV-infected study subjects receiving LDV/SOF in combination with other DAAs, 
PEG-IFN, and/or RBV. No clinical safety issues related to LDV have been identified to date. 
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities upon 
administration of LDV/SOF together as an FDC. To date, LDV/SOF ± RBV has been administered 
to over 5000 HCV infected study subjects. No clinical safety issues related to LDV/SOF have been 
identified to date.
1.6.
Compliance
This study will be conducted in compliance with this protocol, ICH Good Clinical Practice (GCP), 
and J-GCP (Ministerial Ordinance on Good Clinical Practice for Drugs), and all applicable 
regulatory requirements.


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OBJECTIVES 
The primruy objectives of this study ru·e as follows: 
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• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine 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 the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study ru·e: 
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3.
STUDY DESIGN
3.1.
Study Design
This is a multi-center, randomized, open-label study in treatment-naïve and treatment-experienced 
adults with chronic genotype 2 HCV infection.
3.2.
Study Treatments
Cohort 1: approximately 200 subjects will be randomized in a 1:1 ratio to one of the following 
two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
Approximately 10% of subjects may have Child-Pugh-A compensated cirrhosis.  Approximately 
50% of subjects will be treatment-naïve and 50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/ absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV therapy will receive LDV/SOF 
FDC tablet (90/400 mg) once daily for 12 weeks.  Approximately 10% of subjects may have 
Child-Pugh-A compensated cirrhosis.
3.3.
Duration of Treatment
Subjects will be treated for 12 weeks.
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 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.
For subjects who have completed an ET visit, the posttreatment Week 4, 12 and 24 visits will be 
completed after last dose of any of the study drug. 
When medically feasible, the medical monitor must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree. Following resolution of intercurrent illness, the subject may
resume study dosing at the discretion of the investigator


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Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Virologic failme (as defmed in Section 3.4.1) 
• 
Pregnancy of female subject (refer to Appendix 4) 
• 
Significant protocol violation that impacts subject safety 
• 
Subject request to discontinue for any reason; it is important to detennine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason 
• 
Subject noncompliance 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 
3.4.1. 
Virologic Response-Based Treatment Stopping Criteria 
The following on-treatment Virologic Response-based Treatment Stopping Criteria will be utilized: 
• 
Confi1med HCV RNA ~ LLOQ after 2 consecutive HCV RNA < LLOQ 
• 
Confi1med > llog10 increase in HCV RNA from nadir 
• 
HCV RNA ~ LLOQ through 8 weeks of treatment 
Confi1mation should be perf01m ed as soon as possible and must occm no later than 2 weeks after an 
initial observation indicating virologic failme dming the on-treatment phase. 
Subjects who te1minate study dmg early due to virologic failme as defmed above will complete the 
Early Te1mination (ET) visit and all posttreatment visits. 
3.5. 
Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 225 subjects will be enrolled in this study with chronic genotype (GT) 2 HCV 
infection who are either treatment-naïve or treatment-experienced. Approximately 10% of subjects 
may have Child-Pugh-A compensated cirrhosis at screening.
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.
Criteria apply to all subjects unless otherwise stipulated:
1) Willing and able to provide written informed consent 
2) Male or female, age 20 years
3) Body weight ≥ 40 kg
4) HCV RNA ≥104 IU/mL at Screening
5) Genotype 2 HCV at Screening as determined by the central laboratory. Any non-definitive HCV 
genotype results will exclude the subject from participation.
6) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.  
7)
HCV treatment status defined as one of the following, and with medical records that include 
sufficient detail to allow for categorization as follows:
a) HCV treatment-naïve: Subject has had no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agents (DAAs).
b) HCV treatment-experienced defined as either of the following: 
i)
Prior virologic failure after treatment with an approved or experimental DAA-containing, 
IFN-containing, or RBV-containing regimen. Subjects must not have discontinued prior 
therapy due to non-compliance.  Note: See Exclusion Criterion #4: if treatment-
experienced, prior exposure to any direct acting antiviral agent targeting the HCV NS5A
or NS5B is prohibited.
ii) Subjects that discontinued HCV treatment due to development or significant worsening 
of a treatment related adverse event


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8) Subjects enrolled in Cohort 2 only must either have contraindications to, or have demonstrated 
intolerance of ribavirin:
a) Examples of contraindications to RBV include:
i)
Unable or unwilling to comply with RBV contraception requirements
ii) Difficult to control cardiac disease (eg, myocardial infarction, cardiac failure, 
arrhythmia, etc.) Note: Per Exclusion Criterion #1g, subjects who have had a significant 
cardiac event in the past year are to be excluded.
iii) Hemoglobin <11 g/dL for female subjects or <12 g/dL for male subjects. Note: Per 
Exclusion Criterion #7a, all subjects require Hb ≥10 g/dL.
iv) Haemoglobinopathy such as thalassaemia or sickle cell anaemia
v) Porphyria
vi) Chronic renal dysfunction with CLCr ≤50 mL/min.  Note: Per Exclusion Criterion #7e, 
all subjects require a CLCr ≥ 30 mL/min.
vii)History of severe psychiatric condition. Note: Per Exclusion Criterion #1i, subjects who 
have had psychiatric hospitalization, suicide attempt, and/or a period of disability as a 
result of their psychiatric illness within the last two years are to be excluded.
viii) Other condition, with approval from the Gilead medical monitor
Note: The ribavirin package insert should be consulted for additional details concerning 
contraindications.
b) Ribavirin intolerance is defined as: The emergence of RBV-related clinical adverse events or 
laboratory abnormalities which could not be adequately managed according to dose 
modification guidance provided in the RBV package insert necessitating permanent 
discontinuation of RBV therapy.
9) Cirrhosis Determination:  
a) Presence of cirrhosis is defined as either of the following:
i)
Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) Fibroscan showing cirrhosis as reflected by a result >12.5 kPa
b) Absence of cirrhosis is defined as either of the following, unless the definition of cirrhosis 
has been met:
i)
Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan within 6 months of Day 1 with a result ≤ 12.5 kPa


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10) Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) performed 
within 4-6 months of Day 1 to exclude hepatocellular carcinoma (HCC) is required:
a) Within 4 months for subjects with cirrhosis
b) Within 6 months for subjects without cirrhosis
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/enrollment.
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) Male subjects must agree and refrain from sperm donation from the date of screening until at 
least 6 months after the last dose of RBV, if applicable, or 90 days after the last dose LDV/SOF 
FDC.
14) Lactating females must agree to discontinue nursing before the study drugs are administered.
15) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the investigator.
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 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 drug
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage, 
Child-Pugh-B or C cirrhosis)
e) Solid organ transplantation
f)
Significant pulmonary disease


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g) Unstable cardiac disease or significant cardiac event within the last one year prior to
Screening
h) Porphyria (Cohort 1 only)
i)
Psychiatric hospitalization, suicide attempt and/or a period of disability as a result of their 
psychiatric illness within the last 2 years of Screening
j)
Malignancy within the 5 years prior to screening with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible
k) Prior or current hepatocellular carcinoma (HCC)
l)
Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
3) Screening ECG with clinically significant abnormalities
4) If treatment-experienced, prior exposure to any direct acting antiviral agent targeting the HCV 
NS5A or NS5B. Exposure to IFN and/or any direct acting antiviral agent (e.g., NS3/4A protease 
inhibitors) within 1 month prior to Screening is prohibited
5) History of clinically significant medical condition associated with other chronic liver disease 
(e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, α-1-antitrypsin deficiency, 
alcoholic liver disease, non-alcoholic steatohepatitis or toxin exposure)
6) Pregnant or nursing female or male with pregnant female partner
7) Subjects with any of the following laboratory parameters at screening:
a) Hemoglobin (Hb)
i)
Cohort 1: Hb < 11 g/dL for female subjects; Hb < 12 g/dL for male subjects
ii) Cohort 2: Hb < 10 g/dL
b) Platelets < 50,000/mm3
c) ALT  >10 x upper limit of normal (ULN)
d) AST > 10 x ULN


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e) Creatinine Clearance (CLCr) as calculated by the Cockcroft-Gault equation {Cockcroft et al 
1976}.
i)
Cohort 1: CLCr < 50 mL/min
ii) Cohort 2: CLCr < 30 mL/min
f)
Albumin < 3g/dL
g) INR > 1.5 x ULN unless the subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
h) Direct bilirubin > 1.5 x ULN
i)
HbA1c ≥ 8.5%
8) Donation or loss of more than 400 mL blood within 2 months prior to Day 1
9) Any other contraindication to LDV/SOF or SOF therapy, or RBV therapy (Cohort 1 only), per 
the approved package inserts
10) Use of any prohibited concomitant medications as described in Section 5.7
11) Known hypersensitivity to sofosbuvir, ledipasvir, or ribavirin (Cohort 1 only) or the metabolites 
or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a randomized, open-label study in adults with chronic genotype 2 HCV infection. This study 
is an open-label study and no blinding will be required.
Cohort 1 (n = approximately 200): 

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
Randomization will be stratified by cirrhosis status (presence/absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2 (n = up to 25):  LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks
5.2.
Description and Handling of LDV/SOF FDC
5.2.1.
Formulation
LDV/SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of LDV 
and 400 mg of SOF.  The tablets are debossed with “GSI” on one side and “7985” on the other side.
In addition to the active ingredients, the LDV/SOF FDC tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene 
glycol and FD&C yellow # 6 /sunset yellow FCF aluminum lake.
5.2.2.
LDV/SOF FDC Packaging and Labeling
LDV/SOF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. Each
bottle contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
LDV/SOF FDC bottles to be distributed to centers in Japan shall be labeled for clinical use to meet 
applicable requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan,
and/or other local regulations as applicable.
5.2.3.
LDV/SOF FDC Storage and Handling
LDV/SOF FDC bottles 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).


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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 LDV/SOF FDC.
5.2.4.
Dosage and Administration of LDV/SOF FDC
LDV/SOF FDC tablet is to be administered once daily either with or without food. Each subject 
must be given instructions to maintain approximately the same daily dosing interval between study 
drug doses.  
If a subject does not take the LDV/SOF 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 medications should not be cut or split.  LDV/SOF FDC tablets will be provided by 
Gilead Sciences for all subjects.  
5.3.
Description and Handling of Sofosbuvir (SOF)
5.3.1.
Formulation
SOF tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg of sofosbuvir.  The 
tablets are debossed with “GSI” on one side and “7977” on the other side. In addition to the active 
ingredient, sofosbuvir tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinylalcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
5.3.2.
SOF Packaging and Labeling
SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 
30 tablets, a silica gel desiccant 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 bottles to be distributed to centers in Japan shall be labeled for clinical use to meet applicable 
requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan, and/or other 
local regulations as applicable.
5.3.3.
SOF Storage and Handling
SOF bottles should be stored at a 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).


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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 sofosbuvir.
5.3.4.
Dosage and Administration of SOF
SOF will be administered as 400 mg once daily by mouth. SOF will be supplied by Gilead Sciences 
for all subjects.
If a subject does not take the SOF 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.
5.4.
Description and Handling of Ribavirin (RBV)
5.4.1.
Formulation
Ribavirin 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 2015}.
5.4.2.
RBV Packaging and Labeling
REBETOLcapsules are packaged in blister packaging of 140 capsules. The ribavirin package shall 
be labeled for clinical use to meet all applicable requirements of the Pharmaceuticals and Medical 
Devices Agency (PMDA) and/or other local regulations as applicable.
5.4.3.
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.


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5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in the 
SOF + RBV Treatment Group)
RBV will be administered in accordance with approved RBV labeling in Japan, see Table 5-1
below.
Table 5-1.
Dosing and Administration of RBV in Japan
Body weight at Day 1
Ribavirin dosage
Daily dosage
After morning meal
After evening meal
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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
RBV dose modification or discontinuation should be performed in accordance with the RBV
package insert.
RBV should be dosed with food and SOF when appropriate.
RBV capsule (200 mg) will be supplied by Gilead Sciences for all applicable subjects.
5.5.
Co-administration of SOF and RBV 
For subjects in Cohort 1 who are randomized to the SOF + RBV treatment group, each subject will 
be given instructions to maintain approximately the same daily dosing interval between study drug 
doses.
For morning doses, subjects will be instructed to take study drugs with food as follows:

One SOF tablet: contains 400 mg SOF

Weight-based RBV (as per Section 5.4.4).
For evening doses, subjects will be instructed to take study drug with food as follows:

Weight-based RBV (as per Section 5.4.4).
If a subject does not take the SOF 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) as per the Rebetol®
product label (Section 5.4.4). If the subject misses a dose of ribavirin 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 ribavirin.  Subjects should be instructed not
to take 2 doses of ribavirin at the same time.


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Study medications should not be cut or split.  No food restrictions apply to SOF; however, SOF
should be taken with the morning dose of RBV which is taken with food.
5.6.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all study medication(s) in the original container at every
study visit after Day 1 through the end of treatment.
Study medication(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 
medication regimen.
5.7.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days after 
the last dose of study drug, need to be recorded in the source documents and electronic case report 
form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 28 days 
prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Investigational agents or devices for any indication

Drugs disallowed per prescribing information of RBV (Cohort 1 only)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies 
(e.g., infliximab).  The Gilead medical monitor will be available to address questions from 
investigators regarding permissible corticosteroid use for this trial.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters, i.e., BCRP and P-gp) with study drug may result in PK interactions resulting in 
increases or decreases in exposure of study drug. 
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment; 
other examples of representative medications which are prohibited or are to be used with caution 
from 21 days prior to Day 1 through the end of treatment are listed below in Table 5-2.


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Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for 
SOF and LDV/SOF
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenytoin, Carbamazepine, 
Phenobarbital, Oxcarbazepine
Antimycobacterialsc
Rifampicin
Rifabutin, Rifapentine,
Cardiac Medications
Amiodarone
Digoxin b
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinacea, Milk thistle (i.e., 
silymarin), Chinese herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
a
LDV plasma concentration may decrease, leading to reduced therapeutic effect of LDV/SOF. In the case of coadministration of 
H2RA, the H2RA dose should not exceed doses comparable to famotidine 40 mg twice daily and should be administered 
simultaneously with or 12 hours apart from LDV/SOF.  PPIs should not be taken before LDV/SOF. In the case of 
coadministration of PPIs, the PPIs at doses comparable to omeprazole 20 mg should be administered simultaneously with 
LDV/SOF under fasted conditions.
b
The plasma concentration of digoxin may be increased. In case of coadministration the plasma concentration monitoring of 
digoxin is recommended.
c
Plasma concentrations of LDV and SOF may be decreased, leading to reduced therapeutic effect of LDV/SOF.
d
The plasma concentration of rosuvastatin may be increased, which is associated with increased risk of myopathy, including 
rhabdomyolysis. 
5.8.
Accountability for Investigational Medicinal Product (IMP)
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
SOF, LDV/SOF FDC, 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 IMP kits

Record the date, subject number, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the person 
recording the information.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor or 
contract research organization (CRO).
6.1.
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 requiring a liver biopsy, additional HCV genotyping (if 
initial testing is inconclusive), or for extenuating circumstances 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 error or due to an 
extenuating circumstance such as intercurrent infection.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for randomization/enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF).  All other untoward 
medical occurrences observed during the screening period, including exacerbation or changes in 
medical history are to be captured on the medical history eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
6.2.
Randomization/Enrollment
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment, 
randomization, and treatment assignment. Randomization stratification factors for Cohort 1 are 
described in Section 5.1.
6.2.1.
Day 1 Assessments
All Day 1 procedures must be performed prior to study drug dosing.  When ready to administer 
drugs to the subject:

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug(s)

Observe the subject taking the first dose of study drug(s).  If the subject is randomized to the 
SOF + RBV treatment group, the patient should take the study drugs with food


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6.3.
Treatment Assessments (3 days)
On-treatment visits will be performed at the end of Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12.
Study medication will be reconciled at every post-Day 1 visit by the investigator in order to monitor 
the subject’s adherence with the medication regimen.  
6.4.
Posttreatment Assessments (5 days)
The posttreatment Week 4, 12, and 24 visits should be timed from the date of last administration of 
any study drug.
6.5.
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 last dose of any of the study drug.  
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
6.6.
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.
6.7.
Procedures and Specifications
6.7.1.
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 and, Reticulocyte count and mean corpuscular 
volume (MCV).
Coagulation: INR, 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 (at screening and 
reflexed from total bilirubin at other visits), Total Bilirubin, Glucose, Lipase, Potassium, Sodium;.
Urinalysis: Blood, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. Reflex to microscopic 
urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. 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.


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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).
Additional Tests: Hemoglobin A1c (HbA1c).
6.7.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
Obtain HCV treatment history in order to categorize the subject as per Inclusion Criteria #7.
Information related to HCV infection will also be collected.
6.7.3.
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.
6.7.4.
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.
6.7.5.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 
as part of routine safety monitoring.


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6.7.6.
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.
6.7.7.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and each visit thereafter 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.
6.7.8.
Pregnancy Testing
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 during the dosing period.  
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test 
at the posttreatment Week 4 visit only.  Females of childbearing potential in the treatment group 
containing 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. Pregnancy test kits 
will be dispensed to female subjects of childbearing potential in the treatment group containing 
RBV after the posttreatment Week 4 visit. 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.
6.7.9.
IL28B Testing
A blood sample will be obtained at screening for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 
6.7.10.
Archive Plasma Sample
The specimens collected for future research 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 drug absorption and disposition. These specimens may be used 
for retesting of the amount of HCV in the blood, clinical laboratory testing to provide additional 
clinical data and to develop non-genetic biomarker or diagnostic assays and establish the 


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perfonnance characteristics of these assays. The collection and analysis of future research 
specimens will facilitate the rational design of new phan naceutical agents and the development of 
diagnostic tests, which may allow for individualized dmg therapy for patients in the future. 
An archive plasma sample (non-genetic) will be collected at each on-treatment and postu·eatment 
study visit. Samples will be collected and archived for future analysis once approved by local 
authorities as applicable according to specific local regulations. 
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 
desu·oyed by intemationally accepted means (e.g. incineration). 
6.7.11. 
Genomic Testing 
PD 
The subject's identity will be protected, and the subject's name will not be attached to the sample. 
The sample may be stored for up to 15 years before being desu·oyed. The sample will be desu·oyed 
by intemationally accepted means (e.g. incineration). 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
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6.7.12.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using
actual body weight (ABW).
Male:
Crcl (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
Crcl (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.8.
End of Study
Subjects are considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment duration or early termination of study drug. 
6.9.
Poststudy 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, 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

Persistent or significant disability/incapacity


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


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The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale for 
Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and 
Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and adverse events related to protocol-
mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study IMP 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 occur after the subject first consents to participate 
in the study (ie, signing the informed consent) and throughout the duration of the study, including 
the protocol-required 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 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.


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SAEs will be reported using a paper serious adverse event reporting form or via electronic SAE 
(eSAE) system. 
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing or 
emailing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of Gilead DSPH or to the designated CRO.
Gilead DSPH (or CRO):
Fax: 1-650-522-5477
Email: Safety_FC@gilead.com
Or
CRO safety Dept. Contact information: TBD
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting form 
and submit within 24 hours to
Gilead DSPH: 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 IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as is 
practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management 
7.5.1.
RBV Dose Adjustments (Only Cohort 1)
Dose reduction or discontinuation of RBV due to toxicity should be performed according to the 
Japanese Rebetol® product label. Information is provided in Table 7-1 and Table 7-2.
In the event a female partner of a male subject becomes pregnant, the male subject must 
permanently discontinue SOF and RBV.


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Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects
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)
< 10 g/dL
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL
Discontinue
Hemoglobin level
(Cardiac disease or history of 
cardiac disease present)
< 10 g/dL, or during administration, 
reduction of 2 g/dL or more relative 
to Day 1 persists for 4 weeks
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL, or after dose reduction, 
less than 12 g/dL even after 4 weeks
Discontinue
Source: Japan Rebetol  Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}


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Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects
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 → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 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 → 400 mg/day
800 mg/day → 400 mg/day
1,000 mg/day → 600 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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
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.
7.5.2.
Subject Stopping Rules
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF FDC or SOF 
unless the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Due to a clinical or laboratory event, administration of all study drug(s) may be discontinued. There 
is no option for LDV/SOF FDC or SOF dose reduction. If LDV/SOF FDC or SOF is stopped due to 
toxicity, it must not be restarted.  If SOF is discontinued then RBV must also be discontinued.  If 
RBV is discontinued permanently, then SOF must also be discontinued. In these cases that study 
drug(s) are discontinued permanently, the subject must complete an ET visit. Posttreatment 4-Week, 
12-Week and 24-Week visits must also be scheduled, 4, 12 and 24 weeks from the last dose of study 
drug.


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Subjects who meet any of the following laboratory criteria must stop all study medication(s):

Elevation of ALT and/or AST above the upper limit of normal and > 5x Day 1 or nadir, 
confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by immediate 
repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed as related to LDV/SOF FDC or 
SOF
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.
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.  


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7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after initiation
of study medication and throughout the study, including the post study drug follow-up period, to the 
CRO Safety Dept. or Gilead DSPH using the pregnancy report form within 24 hours of becoming 
aware of the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism of 
pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH or the CRO Safety Dept.
The subject should receive appropriate monitoring and care until the conclusion of the pregnancy. 
The outcome should be reported to the CRO Safety Dept or 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.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs must 
also be reported and relevant information should be submitted to the CRO Safety Dept or Gilead 
DSPH using the pregnancy and pregnancy outcome forms within 24 hours of the investigator 
becoming aware of the pregnancy. 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.


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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept or Gilead DSPH within 24 hours of the investigator becoming 
aware of the situation. These reports must consist of situations that involve study IMP 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 primmy objective of this study is as follows: 
Final 
Amendment 1 
• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondaiy objectives of this study are as follows: 
• 
To detennine the proportion of subjects who attain SVR4 and SVR24 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study m·e: 
PPO 
I 
8.1.2. 
Primary Endpoint 
The primmy efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of therapy) 
in the Full Analysis Set (F AS) population. 
The primmy safety endpoint is any AE leading to pennanent discontinuation of study dmg(s). 
8.1.3. 
Secondary Endpoint 
The secondaiy 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) 
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
Proportion of subjects who have HCV RNA < LLOQ by visit while on  treatment

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 LDV/SOF FDC, SOF and RBV. Last dose of study drug refers 
to the last dose of any 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. 
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. Treatment-emergent data will be analyzed and defined as data collected from the first 
dose of study drug through the date of last dose of study drug plus 30 days.
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 


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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 drug, the subject will be included in a summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed, then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject is 
missing a pre-dose value, then the subject will be excluded from the calculation of summary 
statistics for the 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.
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).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive methods 
by cohort and treatment group and overall.
Demographic summaries will include age, sex, self-identified race and ethnicity. Baseline
characteristics data will include body mass index, HCV RNA level (log10 IU/mL), IL28B genotype, 
and additional endpoints as necessary. The number (proportion) of subjects in each stratum will be 
summarized for Cohort 1.


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8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
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The primmy efficacy endpoint for this study will be the prop01tion of subjects with SVR12, defined 
as HCV RNA < LLOQ 12 weeks after cessation of treatment. The primmy analysis will be 
perf01med after all randomized subjects have been followed through 12 weeks posttreatment or 
discontinued from study. 
In Coh01t 1, the primmy analyses will consist of a non-inferiority (NI) test of treatment LDV/SOF 
FDC for 12 weeks versus SOF+RBV for 12 weeks at the 0.05 significance level (two-sided). 
Non-inferiority will be assessed using the conventional confidence interval approach, and a 
clinically meaningful non-inferiority mm·gin of 10% will be applied. The two-sided 95% confidence 
intervals will be constmcted using stratum-adjusted Mantel-Haenszel (MH) prop01tions, stratified 
by the randomization su·atification factors (ie, cinhosis status and prior u·eatment experience). 
In the primmy efficacy analysis of Coh01t 2, the SVR12 rate will be calculated along with the 
two-sided 95% exact confidence interval using the binomial disu·ibution (Clopper-Pem·son method). 
No statistical hypothesis testing will be perfonned. 
8.5.2. 
Secondary Analyses 
The prop01tion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) will 
be presented in tabulm· and graphical f01m. 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations including 
HCV RNA values and change from baseline through end of u·eatment, and subjects who experience 
virologic failme. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, and vital 
signs measmements and AEs will be documented at vm·ious time points dming the study. 
All safety data collected, on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized by coh01t and u·eatment group according to the study 
dmg received. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug administration 
page of the eCRF. Exposure data will be summarized by cohort and treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-Level 
Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical 
database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any AE with an onset date on or after the study drug start date and 
no later than 30 days after permanent discontinuation of the study drug; or any AE leading to 
premature discontinuation of the study drug.
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-emergent 
adverse events (by SOC, and PT) will be provided by cohort and 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

All SAEs

All treatment-related SAEs

AEs leading to premature discontinuation of  any study drug

AEs leading to modification or interruption of any study drug
All AEs collected during the course of the study will be presented in data listings.


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8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by cohort and 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 drug plus 30 days will be summarized. 
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 laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and summarized 
by cohort and treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. 
8.7.
Sample Size
For Cohort 1, a sample size of 100 per treatment group will provide over 90% power to establish 
non-inferiority in the SVR12 rates between the two groups. It is based on the assumptions that the 
clinically meaningful non-inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.
Sample size for Cohort 2 is based on practical considerations. With a sample size of 25 subjects in 
Cohort 2, the 2-sided 95% exact CIs for different observed HCV SVR12 rates are presented in the 
table below:
Cohort
Observed HCV SVR12 rate
2-sided 95% exact CI
Cohort 2
80% (20 out of 25)
[59.3%, 93.2%]
92% (23 out of 25)
[74.0%, 99.0%]


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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” (MHLW Ordinance No 87 [30 July 2014])
{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 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 or the subject’s legally authorized 


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representative 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 IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. These documents should be 
classified into at least the following two categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, and 
other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;


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


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correctness, and consistency. The site coordinator is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the trial, 
Gilead will provide the site with a read-only archive copy of the data entered by that site. This 
archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal procedures 
and provide appropriate instruction for destruction of unused IMP supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead QA, 
the site may destroy used (empty or partially empty) and unused IMP supplies in accordance with 
that site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator or designee (ie, pharmacist) must maintain accurate 
records for all IMP destroyed. Records must show the identification and quantity of each unit 
destroyed, the method of destruction, and the person who disposed of the IMP. Upon study 
completion, copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to Gilead’s 
appointed study monitors, to IRB/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.
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.


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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 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 the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir 
for previously treated HCV genotype 1 infection. N Engl J Med 2014a;370 
(16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. 
Intervirology 2010;53 (1):39-43.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic 
hepatitis C in the United States. Liver Transpl 2003;9 (4):331-8.
Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, et al. Hepatitis C virus 
related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 
2000;47 (1):131-6.
Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, et al. A 
prospective study of the rate of progression in compensated, histologically advanced 
chronic hepatitis C. Hepatology 2011;54 (2):396-405.
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 
2004;127 (5 Suppl 1):S27-34.
Gane EJ, Hyland RH, Yang Y, Svarovskaia E, Pang PS, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Single Tablet Regimen Is Effective in Patients With HCV 
Genotype 2 Infection [Presentaton]. International Symposium on Viral Hepatitis and 
Liver Disease (ISVHLD); 2015 26-28 June; Berlin, Germany. 
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis 
C: an update. Hepatology 2009;49 (4):1335-74.
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 
2006;355 (23):2444-51.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Lai MY. Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon 
monotherapy. J Gastroenterol Hepatol 2000;15 Suppl:E130-3.


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Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345 (1):41-52.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-
2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. 
Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 (21):1485-92.
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.
Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, et al. Ledipasvir 
and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in 
treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: 
an open-label, randomised, phase 3 trial. Lancet Infect Dis 2015;15 (6):645-53.
MSD K.K. Kudan-kita Chiyoda-ku. REBETOL® (ribavirin) Capsules 200mg. Japan Prescribing 
Information [English]. Tokyo, Japan. Revised 31 July 2015.
Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of 
effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active 
hepatitis C with cirrhosis. Lancet 1995;346 (8982):1051-5.
Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, et al. Sofosbuvir plus ribavirin in 
Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 
trial. J Viral Hepat 2014;21 (11):762-8.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C 
virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352 
(9138):1426-32.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, et al. 
Determinants of outcome of compensated hepatitis C virus-related cirrhosis. 
Hepatology 1998;27 (5):1435-40.
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.


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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.
The Japan Society of Hepatology. Committee for Hepatitis Management Guidelines, JSH 
Guidelines for the Management of Hepatitis C virus Infection Edition 4.0. 
[Translated from Japanese by Japan Gilead Regulatory Affaris]. September 2015.
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.
World Health Organization (WHO). Hepatitis C Fact sheet N° 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/. Updated July 2015. Accessed: 
03 November 2015.


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


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Amendment I 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects with Chronic Genotype 2 
HCV Infection 
GS-US-337-1903, Amendment 1, 27 January 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents this 
approval. 
PPD 
£+cfhetJ O;eJ,~o s 
Stephen Djedjos, MD 
• 
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. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure that 
they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 64 
27 January 2016 


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Appendix 2.
Study Procedures Table
Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
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
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
Adverse Events and Concomitant Medicationse
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 Lifef
X
X
X
X
X
X
X
X
Imaging for HCCg
X
Review of Study Drug Adherence and Drug 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensingi
X
X
X


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Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Laboratory Assessments
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, aPTT and INR)
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA (Plasma)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing /Phenotyping Sample (Plasma)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testj
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
HCV Genotype, IL28B Genotype
X
HCV Ab, HIV Ab and HBsAg
X
HbA1c
X
Archive plasma sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single Genomic Samplek
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = Early Termination; at all unscheduled visits initiated for the purpose of confirmatory testing, a viral sequence analysis plasma sample must be obtained.
c
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
d
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for clinically signficant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 as part of routine safety monitoring.
e
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drug.
f
Health Related Quality of Life (HRQoL) Surveys (e.g. SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1. 
g
Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all 
subjects. For subjects without cirrhosis, imaging must have been performed within 6 months prior to Day 1. For subjects with cirrhosis, imaging must have been performed 
within 4 months of Day 1.
h
Study medication will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the medication regimen.  Subjects must be 
instructed to bring back all bottles of study medication(s) in the original container at every post- Day 1 visit through the end of treatment.
i
Dispense study drugs as directed by the IWRS 


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j  
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 during the dosing period. 
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test at the posttreatment Week 4 visit only.  Females of childbearing potential 
in the treatment group containing 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.  Pregnancy test kits will be dispensed to female subjects of childbearing potential in the treatment group containing RBV after 
the posttreatment Week 4 visit. 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.
k
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 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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 70
27 January 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 71
27 January 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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 72
27 January 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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 73
27 January 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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 74
27 January 2016
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.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 75
27 January 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 76
27 January 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 77
27 January 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 78
27 January 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 79
27 January 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 80
27 January 2016
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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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


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


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Gilead Sciences, Inc. 
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.


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Final
Gilead Sciences, Inc. 
Amendment 1 
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27 January 2016
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential from 
menarche until becoming postmenopausal, unless permanently sterile or with medically 
documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects 
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Data from clinical pharmacokinetic interaction 
studies of Ribavirin have demonstrated that there is no reduction in the clinical efficacy of 
hormonal contraception or that the effect on hormonal contraception is insignificant. Please refer 
to the latest version of the product insert for additional information
Data from clinical pharmacokinetic interaction studies of SOF, LDV/SOF FDC have 
demonstrated that there is no reduction in the clinical efficacy of hormonal contraception. 
Non-clinical toxicity studies of SOF, LDV/SOF FDC have demonstrated no adverse effect on 
fertility or embryo-fetal development. However, there are no clinical studies of SOF or
LDV/SOF in pregnant women.  Please refer to the latest version of the investigator’s brochure 
for additional information.


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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to randomization/enrollment.  Pregnancy 
tests will be performed every 4 weeks thereafter.  Female subjects must agree to one of the 
following from screening until 6 months after last dose of RBV or 30 days after last dose of 
LDV/SOF FDC:

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below:
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide) (Female condom and male condom 
should not be used together)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone


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Amendment 1
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■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until 6 months after last dose of RBV or 30 days after last dose of LDV/SOF FDC.
3) Contraception Requirements for Male Subjects
Male subjects with female partners of childbearing potential must use condoms during treatment 
and until 6 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC.  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 6 months after the last 
dose of RBV or 90 days after the last dose of LDV/SOF.
Male subjects must agree to refrain from sperm donation for at least 6 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they or their partner (for partners of male 
subjects) become pregnant at any time during the study, or if they become pregnant within 
6 months of last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF 
FDC dose. Subjects who become pregnant or who suspect that they are pregnant must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in
Section 7.6.2.1.

Prot_004.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Gilead Medical 
Monitor: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety ofLedipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-337-1903 
Natne: 
Telephone: 
Fax: 
Email: 
Natne: 
Telephone: 
Fax: 
Email: 
PD 
PPD 
PPD 
PPD 
Protocol Version/Date: 
Original: 
22 December 2015 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pati iculru·ly unpublished data, is the prope1iy or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review 
Boru·d or Independent Ethics Committee. The infonnation is only to be used by you in connection 
with authorized clinical studies of the investigational dmg described in the protocol. You will not 
disclose any of the infonnation to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessaty to obtain inf01med consent from those persons to whom the dmg may 
be administered. 


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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TABLE OF CONTENTS
TABLE OF CONTENTS...............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION...............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.1.1.
HCV Infection in Japan........................................................................................................14
1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC ..........................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study ...............................15
1.3.
Information about Ribavirin...................................................................................................................16
1.4.
Rationale for This Study.........................................................................................................................17
1.5.
Risk/Benefit Assessment for the Study ..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES .....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Study Design ..........................................................................................................................................19
3.2.
Study Treatments....................................................................................................................................19
3.3.
Duration of Treatment............................................................................................................................19
3.4.
Stopping Rules and Discontinuation Criteria .........................................................................................19
3.4.1.
Virologic Response-Based Treatment Stopping Criteria......................................................20
3.5.
Samples for Optional Genomic Research...............................................................................................20
4.
SUBJECT POPULATION..................................................................................................................................22
4.1.
Number of Subjects and Subject Selection.............................................................................................22
4.2.
Inclusion Criteria....................................................................................................................................22
4.3.
Exclusion Criteria...................................................................................................................................24
5.
INVESTIGATIONAL MEDICINAL PRODUCTS............................................................................................27
5.1.
Randomization, Blinding and Treatment Codes.....................................................................................27
5.2.
Description and Handling of LDV/SOF FDC ........................................................................................27
5.2.1.
Formulation ..........................................................................................................................27
5.2.2.
LDV/SOF FDC Packaging and Labeling .............................................................................27
5.2.3.
LDV/SOF FDC Storage and Handling.................................................................................27
5.2.4.
Dosage and Administration of LDV/SOF FDC....................................................................28
5.3.
Description and Handling of Sofosbuvir (SOF) .....................................................................................28
5.3.1.
Formulation ..........................................................................................................................28
5.3.2.
SOF Packaging and Labeling ...............................................................................................28
5.3.3.
SOF Storage and Handling...................................................................................................28
5.3.4.
Dosage and Administration of SOF......................................................................................29
5.4.
Description and Handling of Ribavirin (RBV).......................................................................................29
5.4.1.
Formulation ..........................................................................................................................29
5.4.2.
RBV Packaging and Labeling ..............................................................................................29
5.4.3.
RBV Storage and Handling..................................................................................................29
5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in 
the SOF + RBV Treatment Group) ......................................................................................30
5.5.
Co-administration of SOF and RBV ......................................................................................................30
5.6.
Study Drug Adherence and Drug Accountability...................................................................................31
5.7.
Prior and Concomitant Medications.......................................................................................................31


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5.8.
Accountability for Investigational Medicinal Product (IMP).................................................................32
6.
STUDY PROCEDURES.....................................................................................................................................33
6.1.
Screening Visit .......................................................................................................................................33
6.2.
Randomization/Enrollment ....................................................................................................................33
6.2.1.
Day 1 Assessments...............................................................................................................33
6.3.
Treatment Assessments (3 days)..........................................................................................................34
6.4.
Posttreatment Assessments (5 days).....................................................................................................34
6.5.
Early Termination (ET)..........................................................................................................................34
6.6.
Unscheduled Visit ..................................................................................................................................34
6.7.
Procedures and Specifications................................................................................................................34
6.7.1.
Clinical Laboratory Analytes................................................................................................34
6.7.2.
Medical History....................................................................................................................35
6.7.3.
Complete Physical Examination...........................................................................................35
6.7.4.
Vital Signs............................................................................................................................35
6.7.5.
12-Lead ECGs ......................................................................................................................35
6.7.6.
Health Related Quality of Life (HRQoL).............................................................................36
6.7.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................36
6.7.8.
Pregnancy Testing ................................................................................................................36
6.7.9.
IL28B Testing.......................................................................................................................36
6.7.10.
Archive Plasma Sample........................................................................................................36
6.7.11.
Genomic Testing ..................................................................................................................37
6.7.12.
Creatinine Clearance ............................................................................................................38
6.8.
End of Study...........................................................................................................................................38
6.9.
Poststudy Care........................................................................................................................................38
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT ...............................................................................39
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................39
7.1.1.
Adverse Events.....................................................................................................................39
7.1.2.
Serious Adverse Events........................................................................................................39
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................40
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................40
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................40
7.2.2.
Assessment of Severity.........................................................................................................41
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious Adverse 
Events to Gilead .....................................................................................................................................41
7.4.
Gilead Reporting Requirements .............................................................................................................43
7.5.
Toxicity Management.............................................................................................................................43
7.5.1.
RBV Dose Adjustments (Only Cohort 1).............................................................................43
7.5.2.
Subject Stopping Rules.........................................................................................................45
7.6.
Special Situations Reports......................................................................................................................46
7.6.1.
Definitions of Special Situations ..........................................................................................46
7.6.2.
Instructions for Reporting Special Situations.......................................................................47
8.
STATISTICAL CONSIDERATIONS................................................................................................................49
8.1.
Analysis Objectives and Endpoints........................................................................................................49
8.1.1.
Analysis Objectives..............................................................................................................49
8.1.2.
Primary Endpoint .................................................................................................................49
8.1.3.
Secondary Endpoint..............................................................................................................49
8.1.4.
Other Endpoints of Interest ..................................................................................................50
8.2.
Analysis Conventions.............................................................................................................................50
8.2.1.
Analysis Sets ........................................................................................................................50
8.3.
Data Handling Conventions ...................................................................................................................50
8.4.
Demographic Data and Baseline Characteristics....................................................................................51


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8.5.
Efficacy Analysis ...................................................................................................................................52
8.5.1.
Primary Analysis ..................................................................................................................52
8.5.2.
Secondary Analyses..............................................................................................................52
8.6.
Safety Analysis.......................................................................................................................................52
8.6.1.
Extent of Exposure ...............................................................................................................53
8.6.2.
Adverse Events.....................................................................................................................53
8.6.3.
Laboratory Evaluations ........................................................................................................54
8.6.4.
Other Safety Evaluations......................................................................................................54
8.7.
Sample Size............................................................................................................................................54
9.
RESPONSIBILITIES..........................................................................................................................................55
9.1.
Investigator Responsibilities ..................................................................................................................55
9.1.1.
Good Clinical Practice..........................................................................................................55
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................55
9.1.3.
Informed Consent.................................................................................................................55
9.1.4.
Confidentiality......................................................................................................................56
9.1.5.
Study Files and Retention of Records ..................................................................................56
9.1.6.
Case Report Forms ...............................................................................................................57
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................58
9.1.8.
Inspections............................................................................................................................58
9.1.9.
Protocol Compliance ............................................................................................................58
9.2.
Sponsor Responsibilities ........................................................................................................................58
9.2.1.
Protocol Modifications .........................................................................................................58
9.2.2.
Study Report and Publications .............................................................................................58
9.3.
Joint Investigator/Sponsor Responsibilities............................................................................................59
9.3.1.
Access to Information for Monitoring..................................................................................59
9.3.2.
Access to Information for Auditing or Inspections ..............................................................59
9.3.3.
Study Discontinuation ..........................................................................................................59
10.
REFERENCES....................................................................................................................................................60
11.
APPENDICES ....................................................................................................................................................63
Appendix 1.
Investigator Signature Page....................................................................................................64
Appendix 2.
Study Procedures Table..........................................................................................................65
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............68
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................91
LIST OF IN-TEXT TABLES
Table 5-1.
Dosing and Administration of RBV in Japan .........................................................................30
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for SOF and 
LDV/SOF ...............................................................................................................................32
Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects................................................44
Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects........................................................45


LDV/SOFFDC 
Protocol GS-US-337-1903 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Original 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
This is a non-IND study 
Not Applicable 
Not Available 
Approximately 40 centers in Japan. 
The primruy objectives of this study ru·e follows: 
• 
To evaluate the antiviral efficacy of therapy with 
ledipasvir/sofosbuvir (LDV /SOF) fixed-dose combination (FDC) as 
measured by sustained virologic response 12 weeks after cessation 
of treatment (SVR12) 
• 
To evaluate the safety and tolerability of each regimen as assessed 
by review of the accumulated safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment 
and after cessation of each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after cessation of treatment 
Explorat01y objectives of this study ru·e: 
IT 
I 
Page 5 
22 December 2015 


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Study Design:
This is a multicenter, randomized, open-label study in treatment-naïve 
and treatment-experienced adults with chronic genotype 2 HCV 
infection.
Cohort 1: Approximately 200 subjects will be randomized in a 1:1 ratio
to one of the following two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg 
daily as a divided dose) for 12 weeks 
Approximately 10% of subjects may have Child-Pugh-A compensated 
cirrhosis.  Approximately 50% of subjects will be treatment-naïve and 
50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/absence) 
and prior treatment experience (treatment-naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV 
therapy will receive LDV/SOF FDC tablet (90/400 mg) once daily for 
12 weeks. Approximately 10% of subjects may have Child-Pugh-A 
compensated cirrhosis.  
Number of Subjects 
Planned:
Approximately 225 subjects
Target Population:
Treatment naïve and treatment experienced, chronic genotype 2 HCV 
infected adults
Duration of 
Treatment:
Subjects will be treated for 12 weeks.
Diagnosis and Main 
Eligibility Criteria:
Chronic genotype 2 HCV-infected male and non-pregnant/non-lactating 
female subjects, aged 20 years or older, treatment naïve or treatment-
experienced. Approximately 10% in each treatment group (ie, Cohort 1) 
may have Child-Pugh-A compensated cirrhosis. In Cohort 2 subjects 
must be ineligible or intolerant of RBV. 


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Study Procedures/
Frequency:
Screening assessments will be completed within 28 days prior to 
the Day 1 visit. The screening window can be extended up to 42 days in 
extenuating circumstances, including the need for a liver biopsy or 
additional HCV genotyping (if initial testing is inconclusive). Study 
visits will occur at Screening, Day 1, and on-treatment at the end of 
Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12. Following the last dose of study 
medication, all subjects will complete 4-Week, 12-Week and 24-Week 
Posttreatment Visits.
Screening assessments will include medical history, physical
examination, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, liver imaging to exclude hepatocellular 
carcinoma (HCC) within 6 months for non-cirrhotics and within 4 months 
for cirrhotics, safety laboratory tests (including hematology, chemistry, 
coagulation, urinalysis), HCV RNA, serum β-hCG (females of child 
bearing potential only), HCV genotype, host IL28B genotype, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c).
On-treatment assessments include physical examination, weight, vital 
signs, 12-lead ECG, AEs, concomitant medications, pregnancy 
prevention counseling, review of study drug adherence and drug 
accountability, study medication dispensing, safety laboratory tests
(including hematology, chemistry, coagulation, urinalysis), HCV RNA, 
viral RNA sequencing/phenotyping sample, urine pregnancy tests 
(females of child bearing potential only).
Posttreatment assessments include physical examination, weight, vital 
signs, AEs and concomitant medications, pregnancy prevention 
counseling, safety laboratory tests (including hematology and
chemistry), HCV RNA, viral RNA sequencing/phenotyping, and urine 
pregnancy tests (females of childbearing potential only). 
For subjects who provide their additional and specific consent, a single 
blood sample will be collected at the Day 1 visit for human genomic 
testing (this sample may be drawn after Day 1, if necessary).
Health Related Quality of Life (HRQoL) Survey will be conducted at 
Day 1, On-treatment Weeks 4, 8, and 12, Early Termination (if 
applicable), and Posttreatment Week 4, 12, and 24. 
Archive plasma samples will be collected at each on-treatment and 
posttreatment study visit for potential future testing.


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Test Product, Dose, and 
Mode of 
Administration:
1. Ledipasvir/sofosbuvir (HARVONI®, LDV/SOF) is manufactured as 
a FDC tablet, consisting of 90 mg LDV and 400 mg SOF, for oral 
administration. Subjects will take 1 tablet daily for 12 weeks.
2. Sofosbuvir (SOVALDI®, SOF) is manufactured as a 400mg tablet 
for oral administration. Subjects will take 1 tablet daily for 12 
weeks.
3. Ribavirin (REBETOL®, RBV) is manufactured as a 200mg capsule. 
Subjects will take weight-based RBV every day (600-1000 mg/day 
in a divided daily dose) in accordance with RBV product labeling. 
The morning dose of RBV will be taken with the SOF tablet and 
with food. The evening dose of RBV will be taken alone with food.
Ribavirin dose reductions and modifications will be performed 
according to the approved RBV labeling.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Safety:
AEs and safety laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using Ampliprep® TaqMan® HCV Test, v2.0. Safety 
laboratory tests used for the calculation of these scores will be collected 
throughout the on-treatment and posttreatment periods.
Statistical Methods:
The primary efficacy endpoint is SVR12 in all randomized/enrolled and 
treated subjects. 
Cohort 1: The primary analyses will consist of a non-inferiority test of 
treatment LDV/SOF FDC for 12 weeks versus SOF+RBV for 12 weeks 
at the 0.05 significance level.
Non-inferiority will be assessed using the conventional confidence 
interval approach, and a clinically meaningful non-inferiority margin of 
10% will be applied. The two-sided 95% confidence intervals will be 
constructed using stratum-adjusted Mantel-Haenszel (MH) proportions, 
stratified by the randomization stratification factors (ie, cirrhosis status 
and prior treatment experience). 
A sample size of 100 per treatment group will provide over 90% power 
to establish non-inferiority in the SVR12 rates between the two groups. 
It is based on the assumptions that the clinically meaningful non-
inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.


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Cohort 2: No statistical hypothesis testing will be performed. A point-
estimate with two-sided 95% exact confidence interval using the 
binomial distribution (Clopper-Pearson method) will be constructed for 
the SVR12 rate.
The secondary efficacy endpoints include SVR measured at 4 and 
24 weeks after discontinuation of study drug (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; and virologic failure.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
Actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
ANC
Absolute Neutrophil Count 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AV
atrioventricular
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 rate
CLDQ-HCV
Chronic Liver Disease Questionnaire
CM
concomitant medication
cm2
square centimeter
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration 
of drug
Crcl
creatinine clearance
CRO
contract (or clinical) research organization
CSR
Clinical study report
DAA
direct-acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid 
DSPH
Gilead Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
ER
Emergency room
ESLD
End Stage Liver Disease
ET
Early Termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials


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FACIT-F
Fatigue Index
FAS
full analysis set
FCF
yellow # 6 / sunset yellow FCF aluminum lake
FD&C 
Federal Food, Drug and Cosmetic
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
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
genotype
GT-2
genotype 2
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 
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
Interferon
IL28B
Interleukin-28B gene
IMB
Intermenstrual Bleeding
IMP
Investigational Medical Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time


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IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
interactive web response system
JSH
Japanese Society of Hematology
J-GCP
Ministerial Ordinance on Good Clinical Practice for Drugs
kg
Kilogram
kPA
kilopascal
L
liter
LAM
Lactational amenorrhea method
LAR
legally-authorized representative
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
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
mg
milligram
MGB
minor groove binder
MH
Mantel-Haenszel
MHLW
Japan's Ministry of Health, Labour and Welfare
mL
Milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
mmol
millimole
n
number
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein
PK
Pharmacokinetic
PMDA
Pharmeceuticals and Medical Devices Agency
PPIs
Proton-pump inhibitor
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time
Q1
Quartile 1


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Q3
Quartile 3
QA
Quality assurance
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
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
TND
Target not detected
ULN
Upper limit of normal
US
United States
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
β-hCG
β-human chorionic gonadotropin
μg
microgram
μL
microliter
μmol
micromole


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1.
INTRODUCTION
1.1.
Background
Hepatitis C Virus (HCV) infection is a global health challenge with an estimated 180 million 
individuals infected worldwide {Ghany et al 2009}. Up to 85% of individuals infected with HCV 
fail to clear the virus and progress to chronic infection {Lauer et al 2001}. Consequences of chronic 
infection include cirrhosis and hepatocellular carcinoma {Thein et al 2008}. The annual rate of 
progression to cirrhosis in chronic HCV infected patients with advanced fibrosis is ~10 % {Dienstag 
et al 2011}. Approximately 1 to 4% of patients per year with established cirrhosis will progress to 
hepatocellular carcinoma (HCC) {Degos et al 2000}, {Dienstag et al 2011}, {Nishiguchi et al 
1995}, {Serfaty et al 1998}. Given the asymptomatic nature of early infection, the slow progression 
to chronic liver disease, and the lack of adequate screening in at-risk individuals, it is expected that 
the prevalence of subjects diagnosed with HCV-related complications will peak over the next 
2 decades {Hoofnagle et al 2006}, {World Health Organization (WHO) 2015}, {El-Serag 2004}, 
{Davis et al 2003}.
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 approximately1.3-2.4 
million people chronically infected with HCV. In Japan, it is estimated that approximately 20-30% 
of the 1.3-2.4 million people infected with chronic hepatitis C virus have genotype 2 {Sievert et al 
2011}, {Chung et al 2010}.  The highest prevalence rates of HCV 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}. Consequently, the majority of Japanese patients with chronic hepatitis C are 
elderly (average age ~ 70 years) and 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. 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, the current standard of care for chronic genotype 2 HCV infection is the combination of 
sofosbuvir (SOF) 400 mg taken once daily and ribavirin (RBV; 600-1000 mg based on weight, split 
over two daily doses) {The Japan Society of Hepatology 2015}; this regimen is only indicated for 
patients without cirrhosis or for those with compensated cirrhosis. For treatment naïve patients with 
genotype 2 HCV infection, the combination of pegylated interferon (PEG-IFN) plus RBV can also 
be considered; or PEG-IFN monotherapy for treatment naïve patients with low viral load. For 
treatment experienced patients with genotype 2 infection, the protease inhibitor telaprevir, in 
combination with PEG-IFN and RBV, can also be considered. 
The fixed-dose combination of ledipasvir (LDV) 90 mg/SOF 400 mg taken once daily for 12 weeks 
is approved in Japan for the treatment of genotype 1 HCV infection in patients with or without 
compensated cirrhosis.


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1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC
Sofosbuvir (SOF; Sovaldi®) is a nucleotide analog that is a potent and selective inhibitor of 
non-structural protein (NS) 5B-directed HCV replication. 
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC; Harvoni®) combines two HCV
specific direct-acting antiviral (DAA) agents into a single tablet for the treatment of chronic HCV 
infection. Ledipasvir is a HCV NS5A inhibitor and SOF is a nucleotide analog that is a potent and 
selective inhibitor of NS5B-directed HCV replication, irrespective of HCV genotype.
1.2.1.
General Information
Please refer to the current Investigator’s Brochures (IBs) for additional information on SOF and the 
LDV/SOF FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study
1.2.2.1.
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects
This study evaluated SOF (and its metabolites) and LDV PK parameters following single dose 
administration of the SOF or LDV/SOF combination to healthy Japanese and Caucasian subjects. 
SOF and LDV/SOF FDC were well tolerated in this study. PK results support the use of the 400 mg 
SOF dose and the LDV (90 mg)/SOF (400 mg) FDC in both Japanese and non-Japanese subjects.
1.2.2.2.
GS-US-334-0118 SOF+RBV in Treatment Naïve and Treatment Experienced 
Japanese subjects with Chronic Genotype 2 HCV Infection
This Phase 3b study included 140 subjects with genotype 2 HCV who were treated with SOF+RBV 
for 12 weeks. All subjects completed the full 12 weeks of treatment with SOF+RBV. Rates of 
SVR12 in the overall population were 96% (135/140). For treatment-naïve, non-cirrhotic subjects, 
SVR12 was achieved in 97% (73/75) which was superior to the adjusted historical control rate of 
69% (p<0.001). All 5 virologic failures had HCV RNA <LLOQ for the PCR assay at the end of 
treatment and relapsed following discontinuation of treatment.
SOF+RBV was safe and well-tolerated in this study. Most adverse events were mild to moderate in 
severity and were generally not considered related to study drug. The exception being RBV-related 
anemia. The results from this study formed the basis for registration of sofosbuvir (Sovaldi) in Japan 
for the treatment of chronic genotype 2 HCV infection {Omata et al 2014}.


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1.2.2.3.
GS-US-337-0113: LDV/SOF±RBV in Japanese Subjects with Genotype 1 HCV 
With or Without Compensated Cirrhosis
This Phase 3b study included 318 Japanese subjects with genotype 1 HCV treated with 
LDV/SOF±RBV for 12 weeks. In the group receiving LDV/SOF, all subjects (100%; 157/157) 
completed the full 12 weeks of treatment and achieved SVR12, regardless of previous treatment 
history, IL28B genotype, or presence of NS5A RAVs at baseline. In the group receiving 
LDV/SOF+RBV, the SVR12 rate was 98% (158/161), with one subject relapsing. 
LDV/SOF was safe and well-tolerated. Most adverse events were mild to moderate in severity and 
were not considered related to study drug.  This study formed the basis for registration of LDV/SOF 
(Harvoni) in Japan for the treatment of chronic genotype 1 HCV infection {Mizokami et al 2015}.
1.2.2.4.
GS-US-337-1468 (LEPTON) Oral Regimens for the Treatment of Chronic HCV 
Infection
In this multi-cohort study, Cohort 2 Group 1 is comprised of subjects with chronic genotype 2 HCV 
infection who were assigned to receive LDV/SOF for 12 weeks. Of the 26 subjects enrolled, 
twenty-five (96%) completed 12 weeks of treatment with LDV/SOF; 1 subject withdrew consent 
and prematurely discontinued from the study. All 25 subjects who completed treatment achieved 
SVR12 for an overall rate of 96% (25/26). 
Cohort 2 Group 2 is comprised of subjects with chronic genotype 2 HCV infection who were 
assigned to receive LDV/SOF for 8 weeks. Of the 27 subjects enrolled, 74% (20/27) achieved 
SVR12.  Among subjects who did not achieve SVR, one subject experienced on-treatment virologic 
breakthrough and 6 subjects relapsed.
These data demonstrate the clinical activity of LDV/SOF in subjects with chronic genotype 2 HCV 
infection and that 12 weeks of treatment is the optimal treatment length. There were no adverse 
events of anemia, decreased hemoglobin, nor hyperbilirubinemia reported {Gane et al 2015}.
1.3.
Information about Ribavirin
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA and 
DNA viruses{Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV in vivo but can result in normalization 
of serum ALT activity and improvement in liver histology. When combined with IFN or PEG-IFN 
therapy, RBV decreases substantially the relapse rate seen after cessation of IFN therapy {Poynard 
et al 1998}, {McHutchison et al 1998}. Ribavirin 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.


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1.4.
Rationale for This Study
This is a Phase 3b study designed to explore the efficacy of LDV/SOF FDC in subjects with chronic 
genotype 2 HCV infection. The overseas LEPTON study (GS-US-337-1468, Cohort 2 Group 1) has 
demonstrated that for subjects with genotype 2 HCV infection, 12 weeks of therapy with LDV/SOF 
FDC resulted in an SVR rate of 96.2% (25/26) and was safe and well-tolerated. 
The current study will explore the efficacy and safety of LDV/SOF in two different populations of 
Japanese subjects with genotype 2 infection. Cohort 1 will determine if LDV/SOF for 12 weeks is 
non-inferior to SOF+RBV for 12 weeks in Japanese subjects with genotype 2 HCV with or without 
compensated cirrhosis. Cohort 2 addresses an unmet medical need by treating subjects who are 
ineligible for, or intolerant of RBV. Under current Japanese Society of Hematology (JSH)
guidelines, the only therapy available to patients ineligible for RBV is PEG-IFN monotherapy for up 
to 48 weeks, which has poor tolerability and suboptimal virologic response rates {Lai 2000}. All 
subjects enrolled in Cohort 2 will receive LDV/SOF FDC for 12 weeks. 
1.5.
Risk/Benefit Assessment for the Study
This study will evaluate a RBV-free treatment option for Japanese patients with genotype 2 HCV
infection including those who cannot receive RBV, a population that currently has limited treatment 
options. 
The safety and tolerability of LDV/SOF has been well characterized in overseas studies, Japanese 
studies, and in real world use both in Japan and abroad.  To date, there have been no differences 
seen in safety and tolerability based on genotype {Afdhal et al 2014a}, {Afdhal et al 2014b}, 
{Kowdley et al 2014}, {Mizokami et al 2015}.  If non-inferiority is demonstrated between 
LDV/SOF and SOF+RBV, then Harvoni would represent the first RBV-free, single tablet regimen 
for treatment of genotype 1 and 2 HCV infection.  
The safety profile of SOF is based on approximately 7500 chronic HCV-infected study subjects that 
have been administered SOF in combination with a DAA, PEG-IFN, and/or RBV.  No clinical 
safety issues related to SOF have been identified to date. The safety profile of LDV is based on over 
1200 chronic HCV-infected study subjects receiving LDV/SOF in combination with other DAAs, 
PEG-IFN, and/or RBV. No clinical safety issues related to LDV have been identified to date. 
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities upon 
administration of LDV/SOF together as an FDC. To date, LDV/SOF ± RBV has been administered 
to over 5000 HCV infected study subjects. No clinical safety issues related to LDV/SOF have been 
identified to date.
1.6.
Compliance
This study will be conducted in compliance with this protocol, ICH Good Clinical Practice (GCP), 
and J-GCP (Ministerial Ordinance on Good Clinical Practice for Drugs), and all applicable 
regulatory requirements.


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OBJECTIVES 
The primruy objectives of this study ru·e as follows: 
• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
Final 
Original 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine 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 the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study ru·e: 
PPO 
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3.
STUDY DESIGN
3.1.
Study Design
This is a multi-center, randomized, open-label study in treatment-naïve and treatment-experienced 
adults with chronic genotype 2 HCV infection.
3.2.
Study Treatments
Cohort 1: approximately 200 subjects will be randomized in a 1:1 ratio to one of the following 
two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
Approximately 10% of subjects may have Child-Pugh-A compensated cirrhosis.  Approximately 
50% of subjects will be treatment-naïve and 50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/ absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV therapy will receive LDV/SOF 
FDC tablet (90/400 mg) once daily for 12 weeks.  Approximately 10% of subjects may have 
Child-Pugh-A compensated cirrhosis.
3.3.
Duration of Treatment
Subjects will be treated for 12 weeks.
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 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.
For subjects who have completed an ET visit, the posttreatment Week 4, 12 and 24 visits will be 
completed after last dose of any of the study drug. 
When medically feasible, the medical monitor must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree. Following resolution of intercurrent illness, the subject may
resume study dosing at the discretion of the investigator


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• 
Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Virologic failme (as defmed in Section 3.4.1) 
• 
Pregnancy of female subject (refer to Appendix 4) 
• 
Significant protocol violation that impacts subject safety 
• 
Subject request to discontinue for any reason; it is important to detennine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason 
• 
Subject noncompliance 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an Institutional 
• 
Review Board (IRB)/Independent Ethics Committee (IEC) 
3.4.1. 
Virologic Response-Based Treatment Stopping Criteria 
The following on-treatment Virologic Response-based Treatment Stopping Criteria will be utilized: 
• 
Confi1med HCV RNA ~ LLOQ after 2 consecutive HCV RNA < LLOQ 
• 
Confi1med > llog10 increase in HCV RNA from nadir 
• 
HCV RNA ~ LLOQ through 8 weeks of treatment 
Confi1mation should be perf01m ed as soon as possible and must occm no later than 2 weeks after an 
initial observation indicating virologic failme dming the on-treatment phase. 
Subjects who te1minate study dmg early due to virologic failme as defmed above will complete the 
Early Te1mination (ET) visit and all posttreatment visits. 
3.5. 
Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 225 subjects will be enrolled in this study with chronic genotype (GT) 2 HCV 
infection who are either treatment-naïve or treatment-experienced. Approximately 10% of subjects 
may have Child-Pugh-A compensated cirrhosis at screening.
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.
Criteria apply to all subjects unless otherwise stipulated:
1) Willing and able to provide written informed consent 
2) Male or female, age 20 years
3) Body weight ≥ 40 kg
4) HCV RNA ≥104 IU/mL at Screening
5) Genotype 2 HCV at Screening as determined by the central laboratory. Any non-definitive HCV 
genotype results will exclude the subject from participation.
6) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.  
7)
HCV treatment status defined as one of the following, and with medical records that include 
sufficient detail to allow for categorization as follows:
a) HCV treatment-naïve: Subject has had no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agents (DAAs).
b) HCV treatment-experienced defined as either of the following: 
i)
Prior virologic failure after treatment with an approved or experimental DAA-containing, 
IFN-containing, or RBV-containing regimen. Subjects must not have discontinued prior 
therapy due to non-compliance.  Note: See Exclusion Criterion #4: if treatment-
experienced, prior exposure to any direct acting antiviral agent targeting the HCV NS5A
or NS5B is prohibited.
ii) Subjects that discontinued HCV treatment due to development or significant worsening 
of a treatment related adverse event


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8) Subjects enrolled in Cohort 2 only must either have contraindications to, or have demonstrated 
intolerance of ribavirin:
a) Examples of contraindications to RBV include:
i)
Unable or unwilling to comply with RBV contraception requirements
ii) Difficult to control cardiac disease (eg, myocardial infarction, cardiac failure, 
arrhythmia, etc.) Note: Per Exclusion Criterion #1g, subjects who have had a significant 
cardiac event in the past year are to be excluded.
iii) Hemoglobin <11 g/dL for female subjects or <12 g/dL for male subjects. Note: Per 
Exclusion Criterion #8a, all subjects require Hg ≥10 g/dL.
iv) Haemoglobinopathy such as thalassaemia or sickle cell anaemia
v) Porphyria
vi) Chronic renal dysfunction with CLCr ≤50 mL/min.  Note: Per Exclusion Criterion #8e, 
all subjects require a CLCr ≥ 30 mL/min.
vii)History of severe psychiatric condition. Note: Per Exclusion Criterion #1i, subjects who 
have had psychiatric hospitalization, suicide attempt, and/or a period of disability as a 
result of their psychiatric illness within the last two years are to be excluded.
viii) Other condition, with approval from the Gilead medical monitor
Note: The ribavirin package insert should be consulted for additional details concerning 
contraindications.
b) Ribavirin intolerance is defined as: The emergence of RBV-related clinical adverse events or 
laboratory abnormalities which could not be adequately managed according to dose 
modification guidance provided in the RBV package insert necessitating permanent 
discontinuation of RBV therapy.
9) Cirrhosis Determination:  
a) Presence of cirrhosis is defined as either of the following:
i)
Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) Fibroscan showing cirrhosis as reflected by a result >12.5 kPa
b) Absence of cirrhosis is defined as either of the following, unless the definition of cirrhosis 
has been met:
i)
Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan within 6 months of Day 1 with a result ≤ 12.5 kPa


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10) Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) performed 
within 4-6 months of Day 1 to exclude hepatocellular carcinoma (HCC) is required:
a) Within 4 months for subjects with cirrhosis
b) Within 6 months for subjects without cirrhosis
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/enrollment.
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) Male subjects must agree and refrain from sperm donation from the date of screening until at 
least 6 months after the last dose of RBV, if applicable, or 90 days after the last dose LDV/SOF 
FDC.
14) Lactating females must agree to discontinue nursing before the study drugs are administered.
15) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the investigator.
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 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 drug
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage, 
Child-Pugh-B or C cirrhosis)
e) Solid organ transplantation
f)
Significant pulmonary disease


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g) Unstable cardiac disease or significant cardiac event within the last one year prior to
Screening
h) Porphyria (Cohort 1 only)
i)
Psychiatric hospitalization, suicide attempt and/or a period of disability as a result of their 
psychiatric illness within the last 2 years of Screening
j)
Malignancy within the 5 years prior to screening with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible
k) Prior or current hepatocellular carcinoma (HCC)
l)
Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
3) Screening ECG with clinically significant abnormalities
4) If treatment-experienced, prior exposure to any direct acting antiviral agent targeting the HCV 
NS5A or NS5B. Exposure to IFN and/or any direct acting antiviral agent (e.g., NS3/4A protease 
inhibitors) within 1 month prior to Screening is prohibited
5) History of clinically significant medical condition associated with other chronic liver disease 
(e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, α-1-antitrypsin deficiency, 
alcoholic liver disease, non-alcoholic steatohepatitis or toxin exposure)
6) Pregnant or nursing female or male partner with pregnant female partner
7) Subjects with any of the following laboratory parameters at screening:
a) Hemoglobin (Hb)
i)
Cohort 1: Hb < 11 g/dL for female subjects; Hb < 12 g/dL for male subjects
ii) Cohort 2: Hb < 10 g/dL
b) Platelets < 50,000/mm3
c) ALT  >10 x upper limit of normal (ULN)
d) AST > 10 x ULN
e) Creatinine Clearance (CLCr) as calculated by the Cockcroft-Gault equation {Cockcroft et al 
1976}.
i)
Cohort 1: CLCr < 50 mL/min


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ii) Cohort 2: CLCr < 30 mL/min
f)
Albumin < 3g/dL
g) INR > 1.5 x ULN unless the subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
h) Direct bilirubin > 1.5 x ULN
i)
HbA1c ≥ 8.5%
8) Donation or loss of more than 400 mL blood within 2 months prior to Day 1
9) Any other contraindication to LDV/SOF or SOF therapy, or RBV therapy (Cohort 1 only), per 
the approved package inserts
10) Use of any prohibited concomitant medications as described in Section 5.7
11) Known hypersensitivity to sofosbuvir, ledipasvir, or ribavirin (Cohort 1 only) or the metabolites 
or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a randomized, open-label study in adults with chronic genotype 2 HCV infection. This study 
is an open-label study and no blinding will be required.
Cohort 1 (n = approximately 200): 

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
Randomization will be stratified by cirrhosis status (presence/absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2 (n = up to 25):  LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks
5.2.
Description and Handling of LDV/SOF FDC
5.2.1.
Formulation
LDV/SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of LDV 
and 400 mg of SOF.  The tablets are debossed with “GSI” on one side and “7985” on the other side.
In addition to the active ingredients, the LDV/SOF FDC tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene 
glycol and FD&C yellow # 6 /sunset yellow FCF aluminium lake.
5.2.2.
LDV/SOF FDC Packaging and Labeling
LDV/SOF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. Each
bottle contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
LDV/SOF FDC bottles to be distributed to centers in Japan shall be labeled for clinical use to meet 
applicable requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan,
and/or other local regulations as applicable.
5.2.3.
LDV/SOF FDC Storage and Handling
LDV/SOF FDC bottles 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).


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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 LDV/SOF FDC.
5.2.4.
Dosage and Administration of LDV/SOF FDC
LDV/SOF FDC tablet is to be administered once daily either with or without food. Each subject 
must be given instructions to maintain approximately the same daily dosing interval between study 
drug doses.  
If a subject does not take the LDV/SOF 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 medications should not be cut or split.  LDV/SOF FDC tablets will be provided by 
Gilead Sciences for all subjects.  
5.3.
Description and Handling of Sofosbuvir (SOF)
5.3.1.
Formulation
SOF tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg of sofosbuvir.  The 
tablets are debossed with “GSI” on one side and “7977” on the other side. In addition to the active 
ingredient, sofosbuvir tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinylalcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
5.3.2.
SOF Packaging and Labeling
SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 
30 tablets, a silica gel desiccant 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 bottles to be distributed to centers in Japan shall be labeled for clinical use to meet applicable 
requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan, and/or other 
local regulations as applicable.
5.3.3.
SOF Storage and Handling
SOF bottles should be stored at a 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).


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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 sofosbuvir.
5.3.4.
Dosage and Administration of SOF
SOF will be administered as 400 mg once daily by mouth. SOF will be supplied by Gilead Sciences 
for all subjects.
If a subject does not take the SOF 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.
5.4.
Description and Handling of Ribavirin (RBV)
5.4.1.
Formulation
Ribavirin 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 2015}.
5.4.2.
RBV Packaging and Labeling
REBETOLcapsules are packaged in blister packaging of 140 capsules. The ribavirin package shall 
be labeled for clinical use to meet all applicable requirements of the Pharmaceuticals and Medical 
Devices Agency (PMDA) and/or other local regulations as applicable.
5.4.3.
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.


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5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in the 
SOF + RBV Treatment Group)
RBV will be administered in accordance with approved RBV labeling in Japan, see Table 5-1
below.
Table 5-1.
Dosing and Administration of RBV in Japan
Body weight at Day 1
Ribavirin dosage
Daily dosage
After morning meal
After evening meal
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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
RBV dose modification or discontinuation should be performed in accordance with the RBV
package insert.
RBV should be dosed with food and SOF when appropriate.
RBV capsule (200 mg) will be supplied by Gilead Sciences for all applicable subjects.
5.5.
Co-administration of SOF and RBV 
For subjects in Cohort 1 who are randomized to the SOF + RBV treatment group, each subject will 
be given instructions to maintain approximately the same daily dosing interval between study drug 
doses.
For morning doses, subjects will be instructed to take study drugs with food as follows:

One SOF tablet: contains 400 mg SOF

Weight-based RBV (as per Section 5.4.4).
For evening doses, subjects will be instructed to take study drug with food as follows:

Weight-based RBV (as per Section 5.4.4).
If a subject does not take the SOF 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) as per the Rebetol®
product label (Section 5.4.4). If the subject misses a dose of ribavirin 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 ribavirin.  Subjects should be instructed not
to take 2 doses of ribavirin at the same time.


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Study medications should not be cut or split.  No food restrictions apply to SOF; however, SOF
should be taken with the morning dose of RBV which is taken with food.
5.6.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all study medication(s) in the original container at every
study visit after Day 1 through the end of treatment.
Study medication(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 
medication regimen.
5.7.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days after 
the last dose of study drug, need to be recorded in the source documents and electronic case report 
form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 28 days 
prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Investigational agents or devices for any indication

Drugs disallowed per prescribing information of RBV (Cohort 1 only)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies 
(e.g., infliximab).  The Gilead medical monitor will be available to address questions from 
investigators regarding permissible corticosteroid use for this trial.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters, i.e., BCRP and P-gp) with study drug may result in PK interactions resulting in 
increases or decreases in exposure of study drug. 
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment; 
other examples of representative medications which are prohibited or are to be used with caution 
from 21 days prior to Day 1 through the end of treatment are listed below in Table 5-2.


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Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for 
SOF and LDV/SOF
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenytoin, Carbamazepine, 
Phenobarbital, Oxcarbazepine
Antimycobacterialsc
Rifampicin
Rifabutin, Rifapentine,
Cardiac Medications
Amiodarone
Digoxin b
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinacea, Milk thistle (i.e., 
silymarin), Chinese herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
a
LDV plasma concentration may decrease, leading to reduced therapeutic effect of LDV/SOF. In the case of coadministration of 
H2RA, the H2RA dose should not exceed doses comparable to famotidine 40 mg twice daily and should be administered 
simultaneously with or 12 hours apart from LDV/SOF.  PPIs should not be taken before LDV/SOF. In the case of 
coadministration of PPIs, the PPIs at doses comparable to omeprazole 20 mg should be administered simultaneously with 
LDV/SOF under fasted conditions.
b
The plasma concentration of digoxin may be increased. In case of coadministration the plasma concentration monitoring of 
digoxin is recommended.
c
Plasma concentrations of LDV and SOF may be decreased, leading to reduced therapeutic effect of LDV/SOF.
d
The plasma concentration of rosuvastatin may be increased, which is associated with increased risk of myopathy, including 
rhabdomyolysis. 
5.8.
Accountability for Investigational Medicinal Product (IMP)
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
SOF, LDV/SOF FDC, 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 IMP kits

Record the date, subject number, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the person 
recording the information.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor or 
contract research organization (CRO).
6.1.
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 requiring a liver biopsy, additional HCV genotyping (if 
initial testing is inconclusive), or for extenuating circumstances 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 error or due to an 
extenuating circumstance such as intercurrent infection.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for randomization/enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF).  All other untoward 
medical occurrences observed during the screening period, including exacerbation or changes in 
medical history are to be captured on the medical history eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
6.2.
Randomization/Enrollment
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment, 
randomization, and treatment assignment. Randomization stratification factors for Cohort 1 are 
described in Section 5.1.
6.2.1.
Day 1 Assessments
All Day 1 procedures must be performed prior to study drug dosing.  When ready to administer 
drugs to the subject:

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug(s)

Observe the subject taking the first dose of study drug(s).  If the subject is randomized to the 
SOF + RBV treatment group, the patient should take the study drugs with food


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6.3.
Treatment Assessments (3 days)
On-treatment visits will be performed at the end of Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12.
Study medication will be reconciled at every post-Day 1 visit by the investigator in order to monitor 
the subject’s adherence with the medication regimen.  
6.4.
Posttreatment Assessments (5 days)
The posttreatment Week 4, 12, and 24 visits should be timed from the date of last administration of 
any study drug.
6.5.
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 last dose of any of the study drug.  
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
6.6.
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.
6.7.
Procedures and Specifications
6.7.1.
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 and, Reticulocyte count and mean corpuscular 
volume (MCV).
Coagulation: INR, 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 (at screening and 
reflexed from total bilirubin at other visits), Total Bilirubin, Glucose, Lipase, Potassium, Sodium;.
Urinalysis: Blood, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. Reflex to microscopic 
urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. 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 Abbott RealTime HCV genotype II 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.


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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).
Additional Tests: Hemoglobin A1c (HbA1c).
6.7.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
Obtain HCV treatment history in order to categorize the subject as per Inclusion Criteria #7.
Information related to HCV infection will also be collected.
6.7.3.
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.
6.7.4.
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.
6.7.5.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 
as part of routine safety monitoring.


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6.7.6.
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.
6.7.7.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and each visit thereafter 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.
6.7.8.
Pregnancy Testing
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 during the dosing period.  
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test 
at the posttreatment Week 4 visit only.  Females of childbearing potential in the treatment group 
containing 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. Pregnancy test kits 
will be dispensed to female subjects of childbearing potential in the treatment group containing 
RBV after the posttreatment Week 4 visit. 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.
6.7.9.
IL28B Testing
A blood sample will be obtained at screening for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 
6.7.10.
Archive Plasma Sample
The specimens collected for future research 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 drug absorption and disposition. These specimens may be used 
for retesting of the amount of HCV in the blood, clinical laboratory testing to provide additional 
clinical data and to develop non-genetic biomarker or diagnostic assays and establish the 


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perfonnance characteristics of these assays. The collection and analysis of future research 
specimens will facilitate the rational design of new phan naceutical agents and the development of 
diagnostic tests, which may allow for individualized dmg therapy for patients in the future. 
An archive plasma sample (non-genetic) will be collected at each on-treatment and postu·eatment 
study visit. Samples will be collected and archived for future analysis once approved by local 
authorities as applicable according to specific local regulations. 
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 
desu·oyed by intemationally accepted means (e.g. incineration). 
6.7.11. 
Genomic Testing 
PD 
PPD 
I 
~ 
[ 
I 
I 
The subject's identity will be protected, and the subject's name will not be attached to the sample. 
The sample may be stored for up to 15 years before being desu·oyed. The sample will be desu·oyed 
by intemationally accepted means (e.g. incineration). 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
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6.7.12.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using
actual body weight (ABW).
Male:
Crcl (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
Crcl (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.8.
End of Study
Subjects are considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment duration or early termination of study drug. 
6.9.
Poststudy 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, 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

Persistent or significant disability/incapacity


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


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
No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale for 
Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and 
Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and adverse events related to protocol-
mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study IMP 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 occur after the subject first consents to participate 
in the study (ie, signing the informed consent) and throughout the duration of the study, including 
the protocol-required 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 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
SAEs will be reported using a paper serious adverse event reporting form or via electronic SAE 
(eSAE) system. 


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Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing or 
emailing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of Gilead DSPH or to the designated CRO.
Gilead DSPH (or CRO):
Fax: 1-650-522-5477
Email: Safety_FC@gilead.com
Or
CRO safety Dept. Contact information: TBD
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting form 
and submit within 24 hours to
Gilead DSPH: 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 IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as is 
practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management 
7.5.1.
RBV Dose Adjustments (Only Cohort 1)
Dose reduction or discontinuation of RBV due to toxicity should be performed according to the 
Japanese Rebetol® product label. Information is provided in Table 7-1 and Table 7-2.
In the event a female partner of a male subject becomes pregnant, the male subject must 
permanently discontinue RBV.


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Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects
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)
< 10 g/dL
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL
Discontinue
Hemoglobin level
(Cardiac disease or history of 
cardiac disease present)
< 10 g/dL, or during administration, 
reduction of 2 g/dL or more relative 
to Day 1 persists for 4 weeks
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL, or after dose reduction, 
less than 12 g/dL even after 4 weeks
Discontinue
Source: Japan Rebetol  Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}


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Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects
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 → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 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 → 400 mg/day
800 mg/day → 400 mg/day
1,000 mg/day → 600 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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
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.
7.5.2.
Subject Stopping Rules
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF FDC or SOF 
unless the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Due to a clinical or laboratory event, administration of all study drug(s) may be discontinued. There 
is no option for LDV/SOF FDC or SOF dose reduction. If LDV/SOF FDC or SOF is stopped due to 
toxicity, it must not be restarted.  If SOF is discontinued then RBV must also be discontinued.  If 
RBV is discontinued permanently, then SOF must also be discontinued. In these cases that study 
drug(s) are discontinued permanently, the subject must complete an ET visit. Posttreatment 4-Week, 
12-Week and 24-Week visits must also be scheduled, 4, 12 and 24 weeks from the last dose of study 
drug.


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Subjects who meet any of the following laboratory criteria must stop all study medication(s):

Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate repeat 
testing

Abnormal elevation of ALT > 3 x Baseline/Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed as related to LDV/SOF FDC or 
SOF
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.
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.  


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7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after initiation
of study medication and throughout the study, including the post study drug follow-up period, to the 
CRO Safety Dept. or Gilead DSPH using the pregnancy report form within 24 hours of becoming 
aware of the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism of 
pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH or the CRO Safety Dept.
The subject should receive appropriate monitoring and care until the conclusion of the pregnancy. 
The outcome should be reported to the CRO Safety Dept or 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.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs must 
also be reported and relevant information should be submitted to the CRO Safety Dept or Gilead 
DSPH using the pregnancy and pregnancy outcome forms within 24 hours of the investigator 
becoming aware of the pregnancy. 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.


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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept or Gilead DSPH within 24 hours of the investigator becoming 
aware of the situation. These reports must consist of situations that involve study IMP 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 primmy objective of this study is as follows: 
• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
Final 
Original 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondaiy objectives of this study are as follows: 
• 
To detennine the proportion of subjects who attain SVR4 and SVR24 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study m·e: 
PPO 
I 
8.1.2. 
Primary Endpoint 
The primmy efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of therapy) 
in the Full Analysis Set (F AS) population. 
The primmy safety endpoint is any AE leading to pennanent discontinuation of study dmg(s). 
8.1.3. 
Secondary Endpoint 
The secondaiy 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) 
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
Proportion of subjects who have HCV RNA < LLOQ by visit while on  treatment

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 LDV/SOF FDC, SOF and RBV. Last dose of study drug refers 
to the last dose of any 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. 
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. Treatment-emergent data will be analyzed and defined as data collected from the first 
dose of study drug through the date of last dose of study drug plus 30 days.
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 


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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 drug, the subject will be included in a summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed, then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject is 
missing a pre-dose value, then the subject will be excluded from the calculation of summary 
statistics for the 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.
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).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive methods 
by cohort and treatment group and overall.
Demographic summaries will include age, sex, self-identified race and ethnicity. Baseline
characteristics data will include body mass index, HCV RNA level (log10 IU/mL), IL28B genotype, 
and additional endpoints as necessary. The number (proportion) of subjects in each stratum will be 
summarized for Cohort 1.


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8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
Final 
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The primmy efficacy endpoint for this study will be the prop01iion of subjects with SVR12, defmed 
as HCV RNA < LLOQ 12 weeks after cessation of treatment. The primmy analysis will be 
perf01m ed after all randomized subjects have been followed through 12 weeks posttreatment or 
discontinued from study. 
In Coh01i 1, the primmy analyses will consist of a non-inferiority (NI) test of treatment LDV/SOF 
FDC for 12 weeks versus SOF+RBV for 12 weeks at the 0.05 significance level (two-sided). 
Non-inferiority will be assessed using the conventional confidence interval approach, and a 
clinically meaningful non-inferiority mm·gin of 10% will be applied. The two-sided 95% confidence 
intervals will be constmcted using stratum-adjusted Mantel-Haenszel (MH) prop01iions, stratified 
by the randomization su·atification factors (ie, cinhosis status and prior u·eatment experience). 
In the primmy efficacy analysis of Coh01i 2, the SVR12 rate will be calculated along with the 
two-sided 95% exact confidence interval using the binomial disu·ibution (Clopper-Pem·son method). 
No statistical hypothesis testing will be perfonned. 
8.5.2. 
Secondary Analyses 
The prop01iion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) will 
be presented in tabulm· and graphical f01m . 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations including 
HCV RNA values and change from baseline through end of u·eatment, and subjects who experience 
virologic failme. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, and vital 
signs measmements and AEs will be documented at vm·ious time points dming the study. 
All safety data collected, on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized by coh01i and u·eatment group according to the study 
dmg received. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug administration 
page of the eCRF. Exposure data will be summarized by cohort and treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-Level 
Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical 
database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any AE with an onset date on or after the study drug start date and 
no later than 30 days after permanent discontinuation of the study drug; or any AE leading to 
premature discontinuation of the study drug.
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-emergent 
adverse events (by SOC, and PT) will be provided by cohort and 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

All SAEs

All treatment-related SAEs

AEs leading to premature discontinuation of  any study drug

AEs leading to modification or interruption of any study drug
All AEs collected during the course of the study will be presented in data listings.


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8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by cohort and 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 drug plus 30 days will be summarized. 
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 laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and summarized 
by cohort and treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. 
8.7.
Sample Size
For Cohort 1, a sample size of 100 per treatment group will provide over 90% power to establish 
non-inferiority in the SVR12 rates between the two groups. It is based on the assumptions that the 
clinically meaningful non-inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.
Sample size for Cohort 2 is based on practical considerations. With a sample size of 25 subjects in 
Cohort 2, the 2-sided 95% exact CIs for different observed HCV SVR12 rates are presented in the 
table below:
Cohort
Observed HCV SVR12 rate
2-sided 95% exact CI
Cohort 2
80% (20 out of 25)
[59.3%, 93.2%]
92% (23 out of 25)
[74.0%, 99.0%]


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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” (MHLW Ordinance No 87 [30 July 2014])
{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 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 or the subject’s legally authorized 


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representative 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 IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. These documents should be 
classified into at least the following two categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, and 
other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;


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


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correctness, and consistency. The site coordinator is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the trial, 
Gilead will provide the site with a read-only archive copy of the data entered by that site. This 
archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal procedures 
and provide appropriate instruction for destruction of unused IMP supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead QA, 
the site may destroy used (empty or partially empty) and unused IMP supplies in accordance with 
that site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator or designee (ie, pharmacist) must maintain accurate 
records for all IMP destroyed. Records must show the identification and quantity of each unit 
destroyed, the method of destruction, and the person who disposed of the IMP. Upon study 
completion, copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to Gilead’s 
appointed study monitors, to IRB/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.
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.


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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 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 the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir 
for previously treated HCV genotype 1 infection. N Engl J Med 2014a;370 
(16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. 
Intervirology 2010;53 (1):39-43.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic 
hepatitis C in the United States. Liver Transpl 2003;9 (4):331-8.
Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, et al. Hepatitis C virus 
related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 
2000;47 (1):131-6.
Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, et al. A 
prospective study of the rate of progression in compensated, histologically advanced 
chronic hepatitis C. Hepatology 2011;54 (2):396-405.
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 
2004;127 (5 Suppl 1):S27-34.
Gane EJ, Hyland RH, Yang Y, Svarovskaia E, Pang PS, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Single Tablet Regimen Is Effective in Patients With HCV 
Genotype 2 Infection [Presentaton]. International Symposium on Viral Hepatitis and 
Liver Disease (ISVHLD); 2015 26-28 June; Berlin, Germany. 
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis 
C: an update. Hepatology 2009;49 (4):1335-74.
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 
2006;355 (23):2444-51.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Lai MY. Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon 
monotherapy. J Gastroenterol Hepatol 2000;15 Suppl:E130-3.


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Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345 (1):41-52.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-
2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. 
Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 (21):1485-92.
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.
Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, et al. Ledipasvir 
and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in 
treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: 
an open-label, randomised, phase 3 trial. Lancet Infect Dis 2015;15 (6):645-53.
MSD K.K. Kudan-kita Chiyoda-ku. REBETOL® (ribavirin) Capsules 200mg. Japan Prescribing 
Information [English]. Tokyo, Japan. Revised 31 July 2015.
Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of 
effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active 
hepatitis C with cirrhosis. Lancet 1995;346 (8982):1051-5.
Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, et al. Sofosbuvir plus ribavirin in 
Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 
trial. J Viral Hepat 2014;21 (11):762-8.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C 
virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352 
(9138):1426-32.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, et al. 
Determinants of outcome of compensated hepatitis C virus-related cirrhosis. 
Hepatology 1998;27 (5):1435-40.
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.


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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.
The Japan Society of Hepatology. Committee for Hepatitis Management Guidelines, JSH 
Guidelines for the Management of Hepatitis C virus Infection Edition 4.0. 
[Translated from Japanese by Japan Gilead Regulatory Affaris]. September 2015.
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.
World Health Organization (WHO). Hepatitis C Fact sheet N° 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/. Updated July 2015. Accessed: 
03 November 2015.


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


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects with Chronic Genotype 2 
HCV Infection 
GS-US-337-1903, Original, 22 December 2015 
This protocol bas been approved by Gilead Sciences, Inc. The following signature documents this 
approval. 
PPD 
Stephen Djedjos, MD 
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. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure that 
they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 64 
22 December 2015 


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Appendix 2.
Study Procedures Table
Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
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
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
Adverse Events and Concomitant Medicationse
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 Lifef
X
X
X
X
X
X
X
X
Imaging for HCCg
X
Review of Study Drug Adherence and Drug 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensingi
X
X
X


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Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Laboratory Assessments
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, aPTT and INR)
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA (Serum)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing /Phenotyping Sample (Plasma)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testj
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
HCV Genotype, IL28B Genotype
X
HCV Ab, HIV Ab and HBsAg
X
HbA1c
X
Archive plasma sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single Genomic Samplek
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = Early Termination; at all unscheduled visits initiated for the purpose of confirmatory testing, a viral sequence analysis plasma sample must be obtained.
c
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
d
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for clinically signficant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 as part of routine safety monitoring.
e
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drug.
f
Health Related Quality of Life (HRQoL) Surveys (e.g. SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1. 
g
Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all 
subjects. For subjects without cirrhosis, imaging must have been performed within 6 months prior to Day 1. For subjects with cirrhosis, imaging must have been performed 
within 4 months of Day 1.
h
Study medication will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the medication regimen.  Subjects must be 
instructed to bring back all bottles of study medication(s) in the original container at every post- Day 1 visit through the end of treatment.
i
Dispense study drugs as directed by the IWRS 


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j  
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 during the dosing period. 
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test at the posttreatment Week 4 visit only.  Females of childbearing potential 
in the treatment group containing 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.  Pregnancy test kits will be dispensed to female subjects of childbearing potential in the treatment group containing RBV after 
the posttreatment Week 4 visit. 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.
k
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 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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 70
22 December 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 71
22 December 2015
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 72
22 December 2015
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 73
22 December 2015
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 74
22 December 2015
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.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 76
22 December 2015
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.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
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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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
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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)


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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


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Original
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22 December 2015
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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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Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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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Protocol GS-US-337-1903
Final
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Original
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22 December 2015
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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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Page 86
22 December 2015
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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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Page 87
22 December 2015
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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Original
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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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Protocol GS-US-337-1903
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Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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22 December 2015
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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
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.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Original
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22 December 2015
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential from 
menarche until becoming postmenopausal, unless permanently sterile or with medically 
documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects 
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Data from clinical pharmacokinetic interaction 
studies of Ribavirin have demonstrated that there is no reduction in the clinical efficacy of 
hormonal contraception or that the effect on hormonal contraception is insignificant. Please refer 
to the latest version of the product insert for additional information
Data from clinical pharmacokinetic interaction studies of SOF, LDV/SOF FDC have 
demonstrated that there is no reduction in the clinical efficacy of hormonal contraception. 
Non-clinical toxicity studies of SOF, LDV/SOF FDC have demonstrated no adverse effect on 
fertility or embryo-fetal development. However, there are no clinical studies of SOF or
LDV/SOF in pregnant women.  Please refer to the latest version of the investigator’s brochure 
for additional information.


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Protocol GS-US-337-1903
Final
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Original
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22 December 2015
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to randomization/enrollment.  Pregnancy 
tests will be performed every 4 weeks thereafter.  Female subjects must agree to one of the 
following from screening until 6 months after last dose of RBV or 30 days after last dose of 
LDV/SOF FDC:

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below:
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide) (Female condom and male condom 
should not be used together)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone


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■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until 6 months after last dose of RBV or 30 days after last dose of LDV/SOF FDC.
3) Contraception Requirements for Male Subjects
Male subjects with female partners of childbearing potential must use condoms during treatment 
and until 6 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC.  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 6 months after the last 
dose of RBV or 90 days after the last dose of LDV/SOF.
Male subjects must agree to refrain from sperm donation for at least 6 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they or their partner (for partners of male 
subjects) become pregnant at any time during the study, or if they become pregnant within 6 
months of last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF 
FDC dose. Subjects who become pregnant or who suspect that they are pregnant must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in
Section 7.6.2.1.

SAP_007.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 3b, Multicenter, Randomized, Open-Label Study to 
Investigate the Efficacy and Safety of Ledipasvir/Sofosbuvir 
Fixed-Dose Combination for 12 Weeks in Subjects with Chronic 
Genotype 2 Hepatitis C Virus (HCV) Infection 
 
 
Name of Test Drug: 
Ledipasvir/Sofosbuvir (HARVONI®, LDV/SOF) Fixed-Dose 
Combination (FDC) 
 
 
Study Number: 
GS-US-337-1903 
 
 
Protocol Version (Date): 
Amendment 2: 23 February 2016 
 
 
Analysis Type: 
SVR12 and Final Analysis 
 
 
Analysis Plan Version: 
Version 1.0 
 
 
Analysis Plan Date: 
21 February 2017 
 
 
Analysis Plan Author: 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
PPD


LDV/SOF FDC  
GS-US-337-1903 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 2 
 
21 February 2017 
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 ............................................................................................................................................ 6 
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 Enrolled/Randomized Analysis Set .................................................................................. 9 
3.1.2. 
Full Analysis Set .................................................................................................................... 9 
3.1.3. 
Safety Analysis Set ................................................................................................................. 9 
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 .................................................................................................................................. 17 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 17 
4.2. 
Extent of Exposure ................................................................................................................................. 18 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 18 
4.2.2. 
Adherence to Study Drug ..................................................................................................... 19 
4.3. 
Protocol Deviations ................................................................................................................................ 20 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 21 
5.1. 
Demographics ........................................................................................................................................ 21 
5.2. 
Other Baseline Characteristics ............................................................................................................... 21 
5.3. 
Medical History ...................................................................................................................................... 22 
6. 
EFFICACY ANALYSES ................................................................................................................................... 23 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 23 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 23 


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6.1.2. 
Statistical Hypothesis for the Primary Efficacy Endpoint .................................................... 23 
6.1.3. 
Primary Analysis of the Primary Efficacy Endpoint ............................................................ 23 
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 ............................................................................................................. 27 
6.3.1. 
Definition of Exploratory Efficacy Endpoints ...................................................................... 27 
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints ........................................................ 27 
6.4. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 28 
7. 
SAFETY ANALYSES ........................................................................................................................................ 29 
7.1. 
Adverse Events and Deaths .................................................................................................................... 29 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 29 
7.1.2. 
Adverse Event Severity ........................................................................................................ 29 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 29 
7.1.4. 
Serious Adverse Events ........................................................................................................ 29 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 29 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 30 
7.2. 
Laboratory Evaluations .......................................................................................................................... 32 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 32 
7.2.2. 
Graded Laboratory Values ................................................................................................... 33 
7.3. 
Body Weight, Height, and Vital Signs ................................................................................................... 34 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 34 
7.5. 
Electrocardiogram Results ..................................................................................................................... 35 
7.6. 
Other Safety Measures ........................................................................................................................... 35 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 35 
8. 
REFERENCES ................................................................................................................................................... 36 
9. 
SOFTWARE ....................................................................................................................................................... 37 
10. APPENDICES .................................................................................................................................................... 38 
 
Appendix 1. 
Study Procedures Table .......................................................................................................... 39 
Appendix 2. 
QOL Score Calculation Algorithm ......................................................................................... 42 
 
 
LIST OF IN-TEXT TABLES 
 
Table 3-1. 
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................ 15 
Table 3-2. 
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................ 15 
Table 3-3. 
Analysis Windows for On-treatment ECG Data ..................................................................... 15 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CSR 
clinical study report 
DAA 
direct acting antiviral 
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 
LDV 
Ledipasvir 
LLT 
lower level term 
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
Peg-IFN 
pegylated interferon 
PT 
preferred term 
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 


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SOC 
system organ class 
SOF 
sofosbuvir (Sovaldi®) 
SVR 
sustained virologic response 
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 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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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-337-1903. This SAP is based on the study protocol amendment 2 dated 
23 Febmary 2016 and the electronic case rep01t 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 primary objective of this study is as follows: 
• 
To evaluate the antiviral efficacy of therapy with ledipasvir/sofosbuvir (LDV/SOF) 
fixed-dose combination (FDC) as measured by sustained virologic response (SVR) 12 weeks 
after cessation of treatment (SVR12) 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the 
accumulated safety data 
The secondary objectives of this study are as follows: 
• 
To detennine the prop01tion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01t ion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are as follows: 
PPO 
I 
1.2. 
Study Design 
This is a multicenter, randomized, open-label Phase 3 study to evaluate the safety, tolerability 
and antiviral efficacy of LDV/SOF for 12 weeks compared with SOF + Ribavirin (RBV) for 
12 weeks in subjects with treatment-naive and treatment-experienced adults with chronic 
genotype 2 HCV infection. 
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Cohort 1: approximately 200 subjects will be randomized in a 1:1 ratio to one of the following 
two treatment groups: 
1) LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks 
2) SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 
12 weeks 
At least 20 subjects will have Child-Pugh-A compensated cirrhosis. Approximately 50% of 
subjects will be treatment-naïve and 50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/absence) and prior treatment 
experience (treatment-naive/treatment-experienced).  
Cohort 2: up to 25 subjects who are ineligible or intolerant for RBV therapy will receive 
LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks. Approximately 2 subjects will have 
Child-Pugh-A compensated cirrhosis.  
The total time to complete all study visits is up to approximately 42 weeks, including the 
following periods: 
• 42-day (6-week) screening period 
• 12-week treatment period 
• Up to 24-week posttreatment period 
1.3. 
Sample Size and Power 
For Cohort 1, a sample size of 100 per treatment group will provide over 90% power to establish 
non-inferiority in the SVR12 rates between the two groups. It is based on the assumptions that 
the clinically meaningful non-inferiority margin is 10%, both groups have a SVR12 rate of 96%, 
and the significance level is 0.025 one-sided. 
Sample size for Cohort 2 is based on practical considerations. With a sample size of 25 subjects 
in Cohort 2, the 2-sided 95% exact confidence intervals (CIs) for different observed HCV 
SVR12 rates are presented in the table below: 
Cohort 
Observed HCV SVR12 rate 
2-sided 95% exact CI 
Cohort 2 
80% (20 out of 25) 
[59.3%, 93.2%] 
92% (23 out of 25) 
[74.0%, 99.0%] 
 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Data Monitoring Committee 
This study does not have a data monitoring committee (DMC). 
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 (SVR12 will not be 
evaluated at this time). 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 
The final analysis will be conducted when all subjects have completed the 24 week posttreatment 
visit or prematurely discontinue from study. The data will be finalized after all data queries are 
resolved for study visits through completion of the 24-week posttreatment visit. At the 
conclusion of data finalization, the study statistician and statistical programmers will run the 
final version of tables, figures and listings (TFLs). 


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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.  
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 for each cohort.  
3.1.1. 
All Enrolled/Randomized Analysis Set 
All Enrolled/Randomized Analysis Set includes all subjects enrolled (Cohort 2) or randomized 
(Cohort 1) in the study after screening. All analyses based on the All Enrolled/Randomized 
Analysis Set will be performed according to the treatment subjects enrolled/randomized within 
each cohort. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were either randomized or enrolled into 
the study, and received at least 1 dose of study drug. The study drugs in this study are LDV/SOF 
and SOF+RBV for Cohort 1 and LDV/SOF for Cohort 2. For Cohort 1, 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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3.2. 
Subject Grouping 
For analyses based on the All Enrolled/Randomized Analysis Set or FAS, subjects in Cohort 1 
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 for Cohort 1 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 
For Cohort 1, 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:  
• Cirrhosis status (presence versus absence) 
• Prior treatment experience (treatment-naive versus treatment-experienced) 
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.  
Subjects with missing cirrhosis status in the clinical database will be analyzed as cirrhosis 
absence in the Cochran-Mantel-Haenszel (CMH) test or stratum-adjusted Mantel-Haenszel (MH) 
proportions. 
For Cohort 2, this study does not use a stratified randomization schedule for enrolling subjects. 
3.4. 
Examination of Subject Subsets 
Subsetting of subjects based on randomization stratification factors will be explored for subgroup 
analyses. 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.  
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)  
• HCV genotype subtype (if applicable) 
• cirrhosis (cirrhosis, absence of cirrhosis, missing) 


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• IL28B (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 alanine aminotransferase (ALT) (≤ 1.5 × upper limit of normal [ULN], 
> 1.5 × ULN) 
• prior HCV treatment experience (treatment naive, treatment-experienced) 
• most recent prior HCV treatment response (non-responder, relapse/breakthrough, early 
treatment discontinuation, met a virologic stopping rule, not otherwise listed, unknown) for 
treatment-experienced subjects 
• completed study treatment, discontinued study treatment 
• adherence to study regimen (<80%, ≥ 80%) 
The primary efficacy endpoint for Cohort 2 will be examined using the applicable subsets above.  
3.5. 
Multiple Comparisons 
No multiplicity adjustment will be made for testing. 
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 
dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit 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 then the on-treatment value at that visit will remain 
missing.  
If an HCV RNA data point is missing and is preceded and followed in time by values that are 
“< 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 


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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 at on-treatment visits and posttreatment follow-up Week 4 (FU-4) visit, and 
posttreatment follow-up Week 12 (FU-12) visit will not be imputed. Last observation carried 
forward will be used for imputation of missing data at posttreatment follow-up Week 24 (FU-24) 
visit. 
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 at all, then the date the informed consent was signed 
will be used instead of first dose date of study drug. For some countries, only birth year is 
collected on the case report form (CRF). In those cases, “01 January” will be used for the 
unknown birth day and month for the purpose of age calculation, unless age is captured on the 
CRF.  


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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 one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “< x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 49 
and 4.9, respectively, will be used for calculation of summary statistics. An exception for this 
rule is any value reported < 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 one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the 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, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical 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 discontinued” 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, 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, vital signs and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in 
Table 3-1. 


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Table 3-1. 
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data 
Nominal Visit 
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 
49 
Week 8 
56 
50 
63 
Week 10 
70 
64 
77 
Week 12 
84 
78 
≥ 85 
 
HCV RNA, vital sign, 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 3-2.  
Table 3-2. 
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data 
Nominal 
FUa Visit 
HCV RNA 
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 FU-4 visit (up to 30 days after last dose). 
ECG data collected up to the last dose date + 3 days are considered to be on-treatment data. 
Qualitative assessments of whether the ECG is normal or abnormal will be assessed for on-
treatment data based on the visit windows as shown in Table 3-3. 
Table 3-3. 
Analysis Windows for On-treatment ECG Data 
Nominal Visit 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
1 
(none) 
1 
Week 1 
7 
2 
45 
Week 12 
84 
46 
(none) 
Note: ECGs are to be collected at screening, baseline, Week 1, and Week 12 or End of Treatment. For purposes of analysis, 
baseline value will be the last available value prior to the first dose of study drug and end of treatment value will be the last 
available value on or prior to the last dose date + 3 days. 


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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. 
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 within each cohort 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.  
For Cohort 1, a similar enrollment table will be provided by randomization stratum for each 
treatment group and overall. The denominator for the percentage of subjects in the stratum will 
be the total number of subjects in the Safety Analysis Set in Cohort 1 within that stratum for each 
treatment group and overall. If there are discrepancies in the value used for stratification 
assignment between the IWRS and the clinical database including CRF and laboratory data, the 
value collected in the clinical database will be used for the summary. A listing of subjects with 
the IWRS randomization strata that differ from stratification factor data entered in the clinical 
database at the time of data finalization will be provided.  
The randomization schedule used for the study will be provided as an appendix to the CSR. 
A summary of subject disposition will be provided by treatment group and overall for each 
cohort. This summary will present the number of subjects screened, the number of subjects 
randomized/enrolled, the number of subjects randomized/enrolled but never treated, and the 
number and percentage of subjects in each of the categories listed below. For the “Treated” 
category, the denominator for the percentage calculation will be the total number of subjects 
enrolled for each column. For all other categories, the denominator for the percentage calculation 
will be the total number of subjects in the Safety Analysis Set for each column.  
• Treated (Safety Analysis Set)  
• In FAS 
• Continuing study treatment if applicable 
• 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 


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Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for: 
• Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and 
thereafter) 
• 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) 
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 complete 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 using 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 8 (Day 56), Week 10 (Day 70), and Week 12 (Day 84). A 
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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 within each cohort for the Safety Analysis Set.  
4.2.2. 
Adherence to Study Drug 
The total number of tablets administered  will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum).  
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: 
(
) (
)
∑
∑
−
=
ed
administer
not 
 
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: 
Total Amount of Study Drug Administered  
Level of Adherence (%) 
100
Total Amount of Study Drug Prescribed at baseline  


=
×




 
Note: If calculated adherence is greater than 100%, the result will be set to 100%. 
In Cohort 1, for Group 1, the total amount of LDV/SOF (90 mg/400 mg) prescribed for 12 weeks 
would require 84 tablets; for Group 2, the total amount of SOF (400 mg) prescribed for 12 weeks 
would require 84 tablets and weight-based RBV (200 mg) prescribed for 12 weeks would require 
252  (3 tablets/day for baseline weight ≤ 60 kg) or 336 (4 tablets/day for baseline weight > 60 kg 
to ≤ 80 kg) tablets or 420 (5 tables/day for baseline weight > 80 kg) tablets. 
In Cohort 2, the total amount of LDV/SOF (90 mg/400 mg) prescribed for 12 weeks would 
require 84 tablets. 
Subjects who prematurely discontinue 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 are 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 is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero. 
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 
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Set for both cohorts. Categorical displays will be provided for the number of subjects who are at 
least 80% adherent to their drug regimen for both cohorts and all drugs (ie, adherence is ≥ 80% 
for each of the study drugs).  
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). 
4.3. 
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 for both cohorts and total 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:  
• body mass index (BMI; in kg/m2) as a continuous variable and as categories (< 25 kg/m2, 
≥ 25 kg/m2)  
• HCV genotype subtype (if applicable) 
• cirrhosis (cirrhosis, absence of cirrhosis, missing) 
• IL28B (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 x ULN, > 1.5 x ULN) 
• prior HCV treatment experience (treatment-naive, treatment-experienced) 
• most recent prior HCV treatment response (non-responder, relapse/breakthrough, early 
treatment discontinuation, met a virologic stopping rule, not otherwise listed, unknown) for 
treatment-experienced subjects 
• estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation 
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. 


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These baseline characteristics will be summarized for both cohorts by treatment group and total 
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 
General medical history data will not be coded, but will be listed only. 
A by-subject listing of disease-specific medical history will be provided by subject ID number in 
ascending 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/enrolled 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 Cohort 1, the primary analyses will consist of a non-inferiority (NI) test of treatment 
LDV/SOF FDC for 12 weeks versus SOF+RBV for 12 weeks at the 0.05 significance level 
(two-sided). A clinically meaningful non-inferiority margin of 10% will be applied. 
If we denote SVR12 rate for treatment group 1 (LDV/SOF for 12 weeks) as P1, and SVR12 rate 
for treatment group 2 (SOF+RBV for 12 weeks) as P2, the null and alternative hypotheses for 
non-inferiority for Cohort 1 are as follows: 
H0: P1 – P2 <= -10%  
H1: P1 – P2 > -10%  
In the primary efficacy analysis of Cohort 2, no statistical hypothesis testing will be performed. 
6.1.3. 
Primary Analysis of the Primary Efficacy Endpoint 
In Cohort 1, the primary analyses will consist of a non-inferiority (delta=10%) of LDV/SOF for 
12 weeks to SOF+RBV for 12 weeks at the 0.05 significance level (two-sided). Non-inferiority 
will be demonstrated (ie, non-inferiority null hypothesis will be rejected) if the lower bound of 
the two-sided 95% CI for the difference (P1 – P2) in SVR12 is greater than -10%.  
The two-sided 95% CI on the difference in SVR12 rates between the 2 treatment groups will be 
constructed based on stratum-adjusted MH proportions for the assessment of non-inferiority as 
follows {Koch 1989}:  
P1 – P2 ± Z(1-α/2 )* SE(P1 – P2), 


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Z:wd 
(P1- P2) = L h h , is the stratum-adjusted MH propmiion difference, where d h = p1h - p2h 
wh 
• 
is the difference in the proportion ofSVR12 ofTreatment Groups 1 and Treatment Group 2 
in stratum h (h=1 and 2). 
wh 
n1hn2h 
, is the weight based on the hatmonic mean of sample size per treatment group 
n ih+ n 2h 
for each stratum where n1h and n2h are the satnple sizes of Treatment Groups 1 and 2 in 
stratum h. 
• 
a= 0.05 for this study 
• 
Z(l-a12) = Z0.975 = 1.96 is the 97 .5th percentile of the nmmal distribution 
If the computed lower confidence bound is less than - 1, the lower bmmd is defined as - 1. If the 
computed upper confidence bmmd is greater than 1, then the upper bound is defmed as 1. 
The two-sided 95% exact CI based on binomial distribution (Clopper-Peru·son method) will be 
provided for the SVR12 rate for each treatment group in Cohmt 1 {Clopper 1934}. 
In the primru·y efficacy analysis ofCohmi 2, the SVR12 rate will be calculated along with 
two-sided 95% exact CI using Clopper-Peru·son method. 
6.1.4. 
Subgroup Analysis of the Primary Efficacy Endpoint 
Point estimates and 95% exact Cis of the SVR12 rates for each treatment group in each cohmt, 
and of the difference (Group 1- Group 2) in SVR12 rates will be displayed for each subgroup 
outlined in Section3.4 for cohmi 1. 
The two-sided 95% exact CI based on Clopper-Peru·son method will be provided for the SVR12 
rate within each treatment group and subgroup. Cis on the difference of SVR12 rates within each 
subgroup will be constmcted based on the standru·dized statistic and invetiing two 1-sided tests 
{Chan 1999}. 
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A Forest Plot will graphically present point estimates and the two-sided 95% exact CIs on the 
treatment differences (Group 1 – Group 2) in SVR12 rates for each of the subgroups for 
Cohort 1. 
6.2. 
Secondary Efficacy Endpoints 
6.2.1. 
Definition of Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• The percentage of subjects with HCV RNA < LLOQ 4 and 24 weeks after discontinuation of 
treatment (SVR 4 and SVR 24) 
• The percentage of subjects with HCV RNA < LLOQ while on treatment by study visit 
• HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT)  
• The percentage 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 LDV/SOF and SOF+RBV 


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6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints 
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 two-sided 95% exact confidence interval based 
on Clopper-Pearson method will be provided 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. 
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) 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. 
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. 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. 
A concordance table between SVR12 and SVR24 will be provided for each treatment group in 
each cohort. Subjects with both observed SVR12 and observed SVR24 data will be included for 
this analysis. 
Drug resistant substitutions will be analyzed as part of the Virology Study Report. 


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6.3. 
Exploratory Efficacy Endpoints 
6.3.1. 
Definition of Exploratory Efficacy Endpoints 
PPD 
I 
I 
I 
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints 
PPD 
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Changes From Protocol-Specified Efficacy Analyses 
There are no planned changes fi:om 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 in each cohort 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 that led to premature discontinuation of any study drug, any AE that led to 
premature discontinuation of LDV/SOF, any AE that led to premature discontinuation of SOF, 
any AE that led to premature discontinuation of RBV, any AE that led to modification or 
interruption of any study drug, any AE that led to interruption of LDV/SOF, any AE that led to 
interruption of SOF, and any AE that led to modification or interruption of RBV. 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 AEs by age group (ie, <65 years, ≥65 years) and by cirrhotic status will also 
be explored. 
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, by age group, treatment group and overall based on the Safety Analysis Set for 
both cohorts as follows: 
• 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 


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• 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 LDV/SOF 
• AEs leading to modification or interruption of any study drug 
• AEs leading to interruption of LDV/SOF 
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed for each cohort 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.  
For each cohort, in addition to the above summary tables, TEAEs will be summarized by PT 
only, in order of descending incidence within the treatment group (Cohort 2) or pooled 
(Cohort 1) 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 LDV/SOF 
• AEs leading to modification or interruption of any study drug 
• AEs leading to interruption of LDV/SOF 
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 


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• SAEs 
• Deaths 
• AEs leading to premature discontinuation 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 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate. 
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, and INR as follows: 
• Baseline values  
• Values at each postbaseline visit 
• Change  from baseline at each postbaseline visit 


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A baseline laboratory value will be defined as the 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, neutrophils, lymphocytes, platelets, and albumin will be 
plotted using a line plot by treatment group and visit.  
For hemoglobin, the descriptive statistics and Median (Q1, Q3) plot will also be provided by age 
group within each cohort and treatment. 
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 visits (up 
to 30 days after the last dose of any study drug) will be summarized by treatment group and age 
group for each cohort. 
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.  
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 


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For all summaries of 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 for each cohort. 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. 
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’s treatment period (including study drug’s 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. 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. 


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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. 
7.5. 
Electrocardiogram Results 
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. No inferential statistics will be provided. 
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. 
7.6. 
Other Safety Measures 
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. 
REFERENCES 
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics 1999;55 (4):1202-9. 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13. 
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21.  
 
 


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9. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland. 


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10. 
APPENDICES 
Appendix 1. 
Study Procedures Table 
Appendix 2. 
QOL Score Calculation Algorithm 
 


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Appendix 1. 
Study Procedures Table 
 
Screening 
Day1a 
Treatment Week 
(±3 days) 
ETb 
Posttreatment Week 
(±5 days) 
1 
2 
3 
4 
5 
6 
8 
10 
12/EOT 
4 
12 
24 
Clinical Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
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 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Adverse Events and Concomitant Medicationse 
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 Lifef 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Imaging for HCCg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Study Drug Adherence and 
Drug Accountabilityh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Dispensingi 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 


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Screening 
Day1a 
Treatment Week 
(±3 days) 
ETb 
Posttreatment Week 
(±5 days) 
1 
2 
3 
4 
5 
6 
8 
10 
12/EOT 
4 
12 
24 
Laboratory Assessments 
Hematology & Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation (PT, aPTT and INR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
HCV RNA (Plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral RNA Sequencing /Phenotyping Sample (Plasma)b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Testj 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
HCV Genotype, IL28B Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab, HIV Ab and HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibrotest® with APRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archive plasma sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Single Genomic Samplek 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Day 1 assessments must be performed prior to dosing. 
b 
ET = Early Termination; at all unscheduled visits initiated for the purpose of confirmatory testing, a viral sequence analysis plasma sample must be obtained. 
c 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
d 
Subjects will be required to rest in a supine position for  ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for clinically signficant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 as part of routine safety monitoring. 
e 
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drug. 
f 
Health Related Quality of Life (HRQoL) Surveys (e.g. SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1.  
g 
Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all 
subjects. For subjects without cirrhosis, imaging must have been performed within 6 months prior to Day 1. For subjects with cirrhosis, imaging must have been performed 
within 4 months of Day 1. 
h 
Study medication will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the medication regimen.  Subjects must be 
instructed to bring back all bottles of study medication(s) in the original container at every post- Day 1 visit through the end of treatment. 
i 
Dispense study drugs as directed by the IWRS  


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j 
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 during the dosing period. 
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test at the posttreatment Week 4 visit only.  Females of childbearing potential 
in the treatment group containing 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.  Pregnancy test kits will be dispensed to female subjects of childbearing potential in the treatment group containing RBV after 
the posttreatment Week 4 visit. 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. 
k 
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. 

Prot_006.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety ofLedipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-337-1903 
Gilead Study Director: 
Natne: 
PD 
PPD 
PPD 
PPD 
Telephone: 
Fax: 
Email: 
Gilead Medical 
Natne: 
Monitor: 
Telephone: 
Fax: 
Email: 
Protocol Version/Date: 
Original: 
22 December 2015 
Amendment 1: 27 Januruy2016 
Amendment 2: 23 Febmaty 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, patiiculru·ly unpublished data, is the prope1iy or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review 
Boru·d or Independent Ethics Committee. The infonnation is only to be used by you in connection 
with authorized clinical studies of the investigational dmg described in the protocol. You will not 
disclose any of the infonnation to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessaty to obtain inf01med consent from those persons to whom the dmg may 
be administered. 


LDV/SOF FDC
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Amendment 2
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS...............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION...............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.1.1.
HCV Infection in Japan........................................................................................................14
1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC ..........................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study ...............................15
1.3.
Information about Ribavirin...................................................................................................................16
1.4.
Rationale for This Study.........................................................................................................................17
1.5.
Risk/Benefit Assessment for the Study ..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES .....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Study Design ..........................................................................................................................................19
3.2.
Study Treatments....................................................................................................................................19
3.3.
Duration of Treatment............................................................................................................................19
3.4.
Stopping Rules and Discontinuation Criteria .........................................................................................19
3.4.1.
Virologic Response-Based Treatment Stopping Criteria......................................................20
3.5.
Samples for Optional Genomic Research...............................................................................................20
4.
SUBJECT POPULATION..................................................................................................................................22
4.1.
Number of Subjects and Subject Selection.............................................................................................22
4.2.
Inclusion Criteria....................................................................................................................................22
4.3.
Exclusion Criteria...................................................................................................................................24
5.
INVESTIGATIONAL MEDICINAL PRODUCTS............................................................................................27
5.1.
Randomization, Blinding and Treatment Codes.....................................................................................27
5.2.
Description and Handling of LDV/SOF FDC ........................................................................................27
5.2.1.
Formulation ..........................................................................................................................27
5.2.2.
LDV/SOF FDC Packaging and Labeling .............................................................................27
5.2.3.
LDV/SOF FDC Storage and Handling.................................................................................27
5.2.4.
Dosage and Administration of LDV/SOF FDC....................................................................28
5.3.
Description and Handling of Sofosbuvir (SOF) .....................................................................................28
5.3.1.
Formulation ..........................................................................................................................28
5.3.2.
SOF Packaging and Labeling ...............................................................................................28
5.3.3.
SOF Storage and Handling...................................................................................................28
5.3.4.
Dosage and Administration of SOF......................................................................................29
5.4.
Description and Handling of Ribavirin (RBV).......................................................................................29
5.4.1.
Formulation ..........................................................................................................................29
5.4.2.
RBV Packaging and Labeling ..............................................................................................29
5.4.3.
RBV Storage and Handling..................................................................................................29
5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in 
the SOF + RBV Treatment Group) ......................................................................................30
5.5.
Co-administration of SOF and RBV ......................................................................................................30
5.6.
Study Drug Adherence and Drug Accountability...................................................................................31
5.7.
Prior and Concomitant Medications.......................................................................................................31


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5.8.
Accountability for Investigational Medicinal Product (IMP).................................................................32
6.
STUDY PROCEDURES.....................................................................................................................................33
6.1.
Screening Visit .......................................................................................................................................33
6.2.
Randomization/Enrollment ....................................................................................................................33
6.2.1.
Day 1 Assessments...............................................................................................................33
6.3.
Treatment Assessments (3 days)..........................................................................................................34
6.4.
Posttreatment Assessments (5 days).....................................................................................................34
6.5.
Early Termination (ET)..........................................................................................................................34
6.6.
Unscheduled Visit ..................................................................................................................................34
6.7.
Procedures and Specifications................................................................................................................34
6.7.1.
Clinical Laboratory Analytes................................................................................................34
6.7.2.
Medical History....................................................................................................................35
6.7.3.
Complete Physical Examination...........................................................................................35
6.7.4.
Vital Signs............................................................................................................................35
6.7.5.
12-Lead ECGs ......................................................................................................................36
6.7.6.
Health Related Quality of Life (HRQoL).............................................................................36
6.7.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................36
6.7.8.
Pregnancy Testing ................................................................................................................36
6.7.9.
IL28B Testing.......................................................................................................................36
6.7.10.
Archive Plasma Sample........................................................................................................37
6.7.11.
Genomic Testing ..................................................................................................................37
6.7.12.
Creatinine Clearance ............................................................................................................38
6.8.
End of Study...........................................................................................................................................38
6.9.
Poststudy Care........................................................................................................................................38
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT ...............................................................................39
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................39
7.1.1.
Adverse Events.....................................................................................................................39
7.1.2.
Serious Adverse Events........................................................................................................39
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................40
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................40
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................40
7.2.2.
Assessment of Severity.........................................................................................................41
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious Adverse 
Events to Gilead .....................................................................................................................................41
7.4.
Gilead Reporting Requirements .............................................................................................................42
7.5.
Toxicity Management.............................................................................................................................43
7.5.1.
RBV Dose Adjustments (Only Cohort 1).............................................................................43
7.5.2.
Subject Stopping Rules.........................................................................................................44
7.6.
Special Situations Reports......................................................................................................................45
7.6.1.
Definitions of Special Situations ..........................................................................................45
7.6.2.
Instructions for Reporting Special Situations.......................................................................46
8.
STATISTICAL CONSIDERATIONS................................................................................................................48
8.1.
Analysis Objectives and Endpoints........................................................................................................48
8.1.1.
Analysis Objectives..............................................................................................................48
8.1.2.
Primary Endpoint .................................................................................................................48
8.1.3.
Secondary Endpoint..............................................................................................................49
8.1.4.
Other Endpoints of Interest ..................................................................................................49
8.2.
Analysis Conventions.............................................................................................................................49
8.2.1.
Analysis Sets ........................................................................................................................49
8.3.
Data Handling Conventions ...................................................................................................................49
8.4.
Demographic Data and Baseline Characteristics....................................................................................50


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8.5.
Efficacy Analysis ...................................................................................................................................51
8.5.1.
Primary Analysis ..................................................................................................................51
8.5.2.
Secondary Analyses..............................................................................................................51
8.6.
Safety Analysis.......................................................................................................................................51
8.6.1.
Extent of Exposure ...............................................................................................................52
8.6.2.
Adverse Events.....................................................................................................................52
8.6.3.
Laboratory Evaluations ........................................................................................................53
8.6.4.
Other Safety Evaluations......................................................................................................53
8.7.
Sample Size............................................................................................................................................53
9.
RESPONSIBILITIES..........................................................................................................................................54
9.1.
Investigator Responsibilities ..................................................................................................................54
9.1.1.
Good Clinical Practice..........................................................................................................54
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................54
9.1.3.
Informed Consent.................................................................................................................54
9.1.4.
Confidentiality......................................................................................................................55
9.1.5.
Study Files and Retention of Records ..................................................................................55
9.1.6.
Case Report Forms ...............................................................................................................56
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................57
9.1.8.
Inspections............................................................................................................................57
9.1.9.
Protocol Compliance ............................................................................................................57
9.2.
Sponsor Responsibilities ........................................................................................................................57
9.2.1.
Protocol Modifications .........................................................................................................57
9.2.2.
Study Report and Publications .............................................................................................57
9.3.
Joint Investigator/Sponsor Responsibilities............................................................................................58
9.3.1.
Access to Information for Monitoring..................................................................................58
9.3.2.
Access to Information for Auditing or Inspections ..............................................................58
9.3.3.
Study Discontinuation ..........................................................................................................58
10.
REFERENCES....................................................................................................................................................59
11.
APPENDICES ....................................................................................................................................................62
Appendix 1.
Investigator Signature Page....................................................................................................63
Appendix 2.
Study Procedures Table..........................................................................................................64
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............67
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................90
LIST OF IN-TEXT TABLES
Table 5-1.
Dosing and Administration of RBV in Japan .........................................................................30
Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for SOF and 
LDV/SOF ...............................................................................................................................32
Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects................................................43
Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects........................................................44


LDV/SOFFDC 
Protocol GS-US-337-1903 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Amendment2 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate 
the Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic Genotype 2 HCV 
Infection 
This is a non-IND study 
Not Applicable 
Not Available 
Approximately 40 centers in Japan. 
The primruy objectives of this study ru·e follows: 
• 
To evaluate the antiviral efficacy of therapy with 
ledipasvir/sofosbuvir (LDV /SOF) fixed-dose combination (FDC) as 
measured by sustained virologic response 12 weeks after cessation 
of treatment (SVR12) 
• 
To evaluate the safety and tolerability of each regimen as assessed 
by review of the accumulated safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment 
and after cessation of each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after cessation of treatment 
Explorat01y objectives of this study ru·e: 
IT 
I 
Page 5 
23 FebiUaiy 2016 


LDV/SOF FDC
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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 6
23 February 2016
Study Design:
This is a multicenter, randomized, open-label study in treatment-naïve 
and treatment-experienced adults with chronic genotype 2 HCV 
infection.
Cohort 1: Approximately 200 subjects will be randomized in a 1:1 ratio
to one of the following two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg 
daily as a divided dose) for 12 weeks 
At least 20 subjects will have Child-Pugh-A compensated cirrhosis.  
Approximately 50% of subjects will be treatment-naïve and 50% will be 
treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/absence) 
and prior treatment experience (treatment-naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV 
therapy will receive LDV/SOF FDC tablet (90/400 mg) once daily for 
12 weeks. Approximately 2 subjects will have Child-Pugh-A 
compensated cirrhosis.  
Number of Subjects 
Planned:
Approximately 225 subjects
Target Population:
Treatment naïve and treatment experienced, chronic genotype 2 HCV 
infected adults
Duration of 
Treatment:
Subjects will be treated for 12 weeks.
Diagnosis and Main 
Eligibility Criteria:
Chronic genotype 2 HCV-infected male and non-pregnant/non-lactating 
female subjects, aged 20 years or older, treatment naïve or treatment-
experienced. At least 20 subjects in Cohort 1, and approximately 2 
subjects in Cohort 2 will have Child-Pugh-A compensated cirrhosis. In 
Cohort 2 subjects must be ineligible or intolerant of RBV. 


LDV/SOF FDC
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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Study Procedures/
Frequency:
Screening assessments will be completed within 28 days prior to 
the Day 1 visit. The screening window can be extended up to 42 days in 
extenuating circumstances, including the need for a liver biopsy or 
additional HCV genotyping (if initial testing is inconclusive). Study 
visits will occur at Screening, Day 1, and on-treatment at the end of 
Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12. Following the last dose of study 
medication, all subjects will complete 4-Week, 12-Week and 24-Week 
Posttreatment Visits.
Screening assessments will include medical history, physical
examination, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, liver imaging to exclude hepatocellular 
carcinoma (HCC) within 6 months for non-cirrhotics and within 4 months 
for cirrhotics, safety laboratory tests (including hematology, chemistry, 
coagulation, urinalysis), HCV RNA, serum β-hCG (females of child 
bearing potential only), HCV genotype, host IL28B genotype, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c), and assessment of the 
presence or absence of cirrhosis (including FibroTest®).
On-treatment assessments include physical examination, weight, vital 
signs, 12-lead ECG, AEs, concomitant medications, pregnancy 
prevention counseling, review of study drug adherence and drug 
accountability, study medication dispensing, safety laboratory tests
(including hematology, chemistry, coagulation, urinalysis), HCV RNA, 
viral RNA sequencing/phenotyping sample, urine pregnancy tests 
(females of child bearing potential only).
Posttreatment assessments include physical examination, weight, vital 
signs, AEs and concomitant medications, pregnancy prevention 
counseling, safety laboratory tests (including hematology and
chemistry), HCV RNA, viral RNA sequencing/phenotyping, and urine 
pregnancy tests (females of childbearing potential only). 
For subjects who provide their additional and specific consent, a single 
blood sample will be collected at the Day 1 visit for human genomic 
testing (this sample may be drawn after Day 1, if necessary).
Health Related Quality of Life (HRQoL) Survey will be conducted at 
Day 1, On-treatment Weeks 4, 8, and 12, Early Termination (if 
applicable), and Posttreatment Week 4, 12, and 24. 
Archive plasma samples will be collected at each on-treatment and 
posttreatment study visit for potential future testing.


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Amendment 2
CONFIDENTIAL
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Test Product, Dose, and 
Mode of 
Administration:
1. Ledipasvir/sofosbuvir (HARVONI®, LDV/SOF) is manufactured as 
a FDC tablet, consisting of 90 mg LDV and 400 mg SOF, for oral 
administration. Subjects will take 1 tablet daily for 12 weeks.
2. Sofosbuvir (SOVALDI®, SOF) is manufactured as a 400mg tablet 
for oral administration. Subjects will take 1 tablet daily for 12 
weeks.
3. Ribavirin (REBETOL®, RBV) is manufactured as a 200mg capsule. 
Subjects will take weight-based RBV every day (600-1000 mg/day 
in a divided daily dose) in accordance with RBV product labeling. 
The morning dose of RBV will be taken with the SOF tablet and 
with food. The evening dose of RBV will be taken alone with food.
Ribavirin dose reductions and modifications will be performed 
according to the approved RBV labeling.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Safety:
AEs and safety laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using Ampliprep® TaqMan® HCV Test, v2.0. 
Statistical Methods:
The primary efficacy endpoint is SVR12 in all randomized/enrolled and 
treated subjects. 
Cohort 1: The primary analyses will consist of a non-inferiority test of 
treatment LDV/SOF FDC for 12 weeks versus SOF+RBV for 12 weeks 
at the 0.05 significance level.
Non-inferiority will be assessed using the conventional confidence 
interval approach, and a clinically meaningful non-inferiority margin of 
10% will be applied. The two-sided 95% confidence intervals will be 
constructed using stratum-adjusted Mantel-Haenszel (MH) proportions, 
stratified by the randomization stratification factors (ie, cirrhosis status 
and prior treatment experience). 
A sample size of 100 per treatment group will provide over 90% power 
to establish non-inferiority in the SVR12 rates between the two groups. 
It is based on the assumptions that the clinically meaningful non-
inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.
Cohort 2: No statistical hypothesis testing will be performed. A point-
estimate with two-sided 95% exact confidence interval using the 
binomial distribution (Clopper-Pearson method) will be constructed for 
the SVR12 rate.


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Gilead Sciences, Inc. 
Amendment 2
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The secondary efficacy endpoints include SVR measured at 4 and 
24 weeks after discontinuation of study drug (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; and virologic failure.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


LDV/SOF FDC
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Final
Gilead Sciences, Inc. 
Amendment 2
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
Actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
ANC
Absolute Neutrophil Count 
APRI
AST: platelet ratio index
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AV
atrioventricular
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 rate
CLDQ-HCV
Chronic Liver Disease Questionnaire
CM
concomitant medication
cm2
square centimeter
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Crcl
creatinine clearance
CRO
contract (or clinical) research organization
CSR
Clinical study report
DAA
direct-acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid 
DSPH
Gilead Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
ER
Emergency room
ESLD
End Stage Liver Disease
ET
Early Termination
EU
European Union


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Amendment 2
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EudraCT
European Union Drug Regulating Authorities Clinical Trials
FACIT-F
Fatigue Index
FAS
full analysis set
FCF
yellow # 6 / sunset yellow FCF aluminum lake
FD&C 
Federal Food, Drug and Cosmetic
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
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
genotype
GT-2
genotype 2
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 
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
Interferon
IL28B
Interleukin-28B gene
IMB
Intermenstrual Bleeding
IMP
Investigational Medical Product
IND
Investigational New Drug (Application)


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Amendment 2
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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
JSH
Japanese Society of Hepatology
J-GCP
Ministerial Ordinance on Good Clinical Practice for Drugs
kg
Kilogram
kPA
kilopascal
L
liter
LAM
Lactational amenorrhea method
LAR
legally-authorized representative
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
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
mg
milligram
MGB
minor groove binder
MH
Mantel-Haenszel
MHLW
Japan's Ministry of Health, Labour and Welfare
mL
Milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
mmol
millimole
n
number
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein
PK
Pharmacokinetic
PMDA
Pharmeceuticals and Medical Devices Agency
PPIs
Proton-pump inhibitor
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time


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Q1
Quartile 1
Q3
Quartile 3
QA
Quality assurance
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
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
TND
Target not detected
ULN
Upper limit of normal
US
United States
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
β-hCG
β-human chorionic gonadotropin
μg
microgram
μL
microliter
μmol
micromole


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1.
INTRODUCTION
1.1.
Background
Hepatitis C Virus (HCV) infection is a global health challenge with an estimated 180 million 
individuals infected worldwide {Ghany et al 2009}. Up to 85% of individuals infected with HCV 
fail to clear the virus and progress to chronic infection {Lauer et al 2001}. Consequences of chronic 
infection include cirrhosis and hepatocellular carcinoma {Thein et al 2008}. The annual rate of 
progression to cirrhosis in chronic HCV infected patients with advanced fibrosis is ~10 % {Dienstag 
et al 2011}. Approximately 1 to 4% of patients per year with established cirrhosis will progress to 
hepatocellular carcinoma (HCC) {Degos et al 2000}, {Dienstag et al 2011}, {Nishiguchi et al 
1995}, {Serfaty et al 1998}. Given the asymptomatic nature of early infection, the slow progression 
to chronic liver disease, and the lack of adequate screening in at-risk individuals, it is expected that 
the prevalence of subjects diagnosed with HCV-related complications will peak over the next 
2 decades {Hoofnagle et al 2006}, {World Health Organization (WHO) 2015}, {El-Serag 2004}, 
{Davis et al 2003}.
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 
approximately1.3-2.4 million people chronically infected with HCV. In Japan, it is estimated that 
approximately 20-30% of the 1.3-2.4 million people infected with chronic hepatitis C virus have 
genotype 2 {Sievert et al 2011}, {Chung et al 2010}.  The highest prevalence rates of HCV 
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}. Consequently, the majority of Japanese patients 
with chronic hepatitis C are elderly (average age ~ 70 years) and 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. 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, the current standard of care for chronic genotype 2 HCV infection is the combination of 
sofosbuvir (SOF) 400 mg taken once daily and ribavirin (RBV; 600-1000 mg based on weight, split 
over two daily doses) {The Japan Society of Hepatology 2015}; this regimen is only indicated for 
patients without cirrhosis or for those with compensated cirrhosis. For treatment naïve patients with 
genotype 2 HCV infection, the combination of pegylated interferon (PEG-IFN) plus RBV can also 
be considered; or PEG-IFN monotherapy for treatment naïve patients with low viral load. For 
treatment experienced patients with genotype 2 infection, the protease inhibitor telaprevir, in 
combination with PEG-IFN and RBV, can also be considered. 
The fixed-dose combination of ledipasvir (LDV) 90 mg/SOF 400 mg taken once daily for 12 weeks 
is approved in Japan for the treatment of genotype 1 HCV infection in patients with or without 
compensated cirrhosis.


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Amendment 2
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1.2.
Sofosbuvir and Ledipasvir/Sofosbuvir FDC
Sofosbuvir (SOF; Sovaldi®) is a nucleotide analog that is a potent and selective inhibitor of 
non-structural protein (NS) 5B-directed HCV replication. 
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC; Harvoni®) combines two HCV
specific direct-acting antiviral (DAA) agents into a single tablet for the treatment of chronic HCV 
infection. Ledipasvir is a HCV NS5A inhibitor and SOF is a nucleotide analog that is a potent and 
selective inhibitor of NS5B-directed HCV replication, irrespective of HCV genotype.
1.2.1.
General Information
Please refer to the current Investigator’s Brochures (IBs) for additional information on SOF and the 
LDV/SOF FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Clinical Trials of SOF and LDV/SOF Relevant to the Proposed Study
1.2.2.1.
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects
This study evaluated SOF (and its metabolites) and LDV PK parameters following single dose 
administration of the SOF or LDV/SOF combination to healthy Japanese and Caucasian subjects.
SOF and LDV/SOF FDC were well tolerated in this study. PK results support the use of the 400 mg 
SOF dose and the LDV (90 mg)/SOF (400 mg) FDC in both Japanese and non-Japanese subjects.
1.2.2.2.
GS-US-334-0118 SOF+RBV in Treatment Naïve and Treatment Experienced 
Japanese subjects with Chronic Genotype 2 HCV Infection
This Phase 3b study included 140 subjects with genotype 2 HCV who were treated with SOF+RBV 
for 12 weeks. All subjects completed the full 12 weeks of treatment with SOF+RBV. Rates of 
SVR12 in the overall population were 96% (135/140). For treatment-naïve, non-cirrhotic subjects, 
SVR12 was achieved in 97% (73/75) which was superior to the adjusted historical control rate of 
69% (p<0.001). All 5 virologic failures had HCV RNA <LLOQ for the PCR assay at the end of 
treatment and relapsed following discontinuation of treatment.
SOF+RBV was safe and well-tolerated in this study. Most adverse events were mild to moderate in 
severity and were generally not considered related to study drug. The exception being RBV-related 
anemia. The results from this study formed the basis for registration of sofosbuvir (Sovaldi) in Japan 
for the treatment of chronic genotype 2 HCV infection {Omata et al 2014}.


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1.2.2.3.
GS-US-337-0113: LDV/SOF±RBV in Japanese Subjects with Genotype 1 HCV 
With or Without Compensated Cirrhosis
This Phase 3b study included 318 Japanese subjects with genotype 1 HCV treated with 
LDV/SOF±RBV for 12 weeks. In the group receiving LDV/SOF, all subjects (100%; 157/157) 
completed the full 12 weeks of treatment and achieved SVR12, regardless of previous treatment 
history, IL28B genotype, or presence of NS5A RAVs at baseline. In the group receiving 
LDV/SOF+RBV, the SVR12 rate was 98% (158/161), with one subject relapsing. 
LDV/SOF was safe and well-tolerated. Most adverse events were mild to moderate in severity and 
were not considered related to study drug.  This study formed the basis for registration of LDV/SOF 
(Harvoni) in Japan for the treatment of chronic genotype 1 HCV infection {Mizokami et al 2015}.
1.2.2.4.
GS-US-337-1468 (LEPTON) Oral Regimens for the Treatment of Chronic HCV 
Infection
In this multi-cohort study, Cohort 2 Group 1 is comprised of subjects with chronic genotype 2 HCV 
infection who were assigned to receive LDV/SOF for 12 weeks. Of the 26 subjects enrolled, 
twenty-five (96%) completed 12 weeks of treatment with LDV/SOF; 1 subject withdrew consent 
and prematurely discontinued from the study. All 25 subjects who completed treatment achieved 
SVR12 for an overall rate of 96% (25/26). 
Cohort 2 Group 2 is comprised of subjects with chronic genotype 2 HCV infection who were 
assigned to receive LDV/SOF for 8 weeks. Of the 27 subjects enrolled, 74% (20/27) achieved 
SVR12.  Among subjects who did not achieve SVR, one subject experienced on-treatment virologic 
breakthrough and 6 subjects relapsed.
These data demonstrate the clinical activity of LDV/SOF in subjects with chronic genotype 2 HCV 
infection and that 12 weeks of treatment is the optimal treatment length. There were no adverse 
events of anemia, decreased hemoglobin, nor hyperbilirubinemia reported {Gane et al 2015}.
1.3.
Information about Ribavirin
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA and 
DNA viruses{Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV in vivo but can result in normalization 
of serum ALT activity and improvement in liver histology. When combined with IFN or PEG-IFN 
therapy, RBV decreases substantially the relapse rate seen after cessation of IFN therapy {Poynard 
et al 1998}, {McHutchison et al 1998}. Ribavirin 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.


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Amendment 2
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1.4.
Rationale for This Study
This is a Phase 3b study designed to explore the efficacy of LDV/SOF FDC in subjects with chronic 
genotype 2 HCV infection. The overseas LEPTON study (GS-US-337-1468, Cohort 2 Group 1) has 
demonstrated that for subjects with genotype 2 HCV infection, 12 weeks of therapy with LDV/SOF 
FDC resulted in an SVR rate of 96.2% (25/26) and was safe and well-tolerated. 
The current study will explore the efficacy and safety of LDV/SOF in two different populations of 
Japanese subjects with genotype 2 infection. Cohort 1 will determine if LDV/SOF for 12 weeks is 
non-inferior to SOF+RBV for 12 weeks in Japanese subjects with genotype 2 HCV with or without 
compensated cirrhosis. Cohort 2 addresses an unmet medical need by treating subjects who are 
ineligible for, or intolerant of RBV. Under current Japanese Society of Hepatology (JSH)
guidelines, the only therapy available to patients ineligible for RBV is PEG-IFN monotherapy for up 
to 48 weeks, which has poor tolerability and suboptimal virologic response rates {Lai 2000}. All 
subjects enrolled in Cohort 2 will receive LDV/SOF FDC for 12 weeks. 
1.5.
Risk/Benefit Assessment for the Study
This study will evaluate a RBV-free treatment option for Japanese patients with genotype 2 HCV
infection including those who cannot receive RBV, a population that currently has limited treatment 
options. 
The safety and tolerability of LDV/SOF has been well characterized in overseas studies, Japanese 
studies, and in real world use both in Japan and abroad.  To date, there have been no differences 
seen in safety and tolerability based on genotype {Afdhal et al 2014a}, {Afdhal et al 2014b}, 
{Kowdley et al 2014}, {Mizokami et al 2015}.  If non-inferiority is demonstrated between 
LDV/SOF and SOF+RBV, then Harvoni would represent the first RBV-free, single tablet regimen 
for treatment of genotype 1 and 2 HCV infection.  
The safety profile of SOF is based on approximately 7500 chronic HCV-infected study subjects that 
have been administered SOF in combination with a DAA, PEG-IFN, and/or RBV.  No clinical 
safety issues related to SOF have been identified to date. The safety profile of LDV is based on over 
1200 chronic HCV-infected study subjects receiving LDV/SOF in combination with other DAAs, 
PEG-IFN, and/or RBV. No clinical safety issues related to LDV have been identified to date. 
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities upon 
administration of LDV/SOF together as an FDC. To date, LDV/SOF ± RBV has been administered 
to over 5000 HCV infected study subjects. No clinical safety issues related to LDV/SOF have been 
identified to date.
1.6.
Compliance
This study will be conducted in compliance with this protocol, ICH Good Clinical Practice (GCP), 
and J-GCP (Ministerial Ordinance on Good Clinical Practice for Drugs), and all applicable 
regulatory requirements.


LDV/SOFFDC 
Protocol GS-US-337-1903 
Gilead Sciences, Inc. 
2-
OBJECTIVES 
The primruy objectives of this study ru·e as follows: 
Final 
Amendment 2 
• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondruy objectives of this study ru·e as follows: 
• 
To detennine 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 the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study ru·e: 
PPO 
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3.
STUDY DESIGN
3.1.
Study Design
This is a multi-center, randomized, open-label study in treatment-naïve and treatment-experienced 
adults with chronic genotype 2 HCV infection.
3.2.
Study Treatments
Cohort 1: approximately 200 subjects will be randomized in a 1:1 ratio to one of the following 
two treatment groups:

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
At least 20 subjects will have Child-Pugh-A compensated cirrhosis.  Approximately 50% of subjects 
will be treatment-naïve and 50% will be treatment-experienced. 
Randomization will be stratified by cirrhosis status (presence/ absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2: Up to 25 subjects who are ineligible or intolerant for RBV therapy will receive LDV/SOF 
FDC tablet (90/400 mg) once daily for 12 weeks.  Approximately 2 subjects will have Child-Pugh-
A compensated cirrhosis.
3.3.
Duration of Treatment
Subjects will be treated for 12 weeks.
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 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.
For subjects who have completed an ET visit, the posttreatment Week 4, 12 and 24 visits will be 
completed after last dose of any of the study drug. 
When medically feasible, the medical monitor must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree. Following resolution of intercurrent illness, the subject may
resume study dosing at the discretion of the investigator


LDV/SOFFDC 
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Amendment2 
• 
Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Virologic failme (as defmed in Section 3.4.1) 
• 
Pregnancy of female subject (refer to Appendix 4) 
• 
Significant protocol violation that impacts subject safety 
• 
Subject request to discontinue for any reason; it is important to detennine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason 
• 
Subject noncompliance 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 
3.4.1. 
Virologic Response-Based Treatment Stopping Criteria 
The following on-treatment Virologic Response-based Treatment Stopping Criteria will be utilized: 
• 
Confi1med HCV RNA ~ LLOQ after 2 consecutive HCV RNA < LLOQ 
• 
Confi1med > llog10 increase in HCV RNA from nadir 
• 
HCV RNA ~ LLOQ through 8 weeks of treatment 
Confi1mation should be perf01m ed as soon as possible and must occm no later than 2 weeks after an 
initial observation indicating virologic failme dming the on-treatment phase. 
Subjects who te1minate study dmg early due to virologic failme as defmed above will complete the 
Early Te1mination (ET) visit and all posttreatment visits. 
3.5. 
Samples for Optional Genomic Research 
PPD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 225 subjects will be enrolled in this study with chronic genotype (GT) 2 HCV 
infection who are either treatment-naïve or treatment-experienced. At least 20 subjects in Cohort 1 
and approximately 2 subjects in Cohort 2 will have Child-Pugh-A compensated cirrhosis at 
screening.
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.
Criteria apply to all subjects unless otherwise stipulated:
1) Willing and able to provide written informed consent 
2) Male or female, age 20 years
3) Body weight ≥ 40 kg
4) HCV RNA ≥104 IU/mL at Screening
5) Genotype 2 HCV at Screening as determined by the central laboratory. Any non-definitive HCV 
genotype results will exclude the subject from participation.
6) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.  
7)
HCV treatment status defined as one of the following, and with medical records that include 
sufficient detail to allow for categorization as follows:
a) HCV treatment-naïve: Subject has had no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agents (DAAs).
b) HCV treatment-experienced defined as either of the following: 
i)
Prior virologic failure after treatment with an approved or experimental DAA-containing, 
IFN-containing, or RBV-containing regimen. Subjects must not have discontinued prior 
therapy due to non-compliance.  Note: See Exclusion Criterion #4: if treatment-
experienced, prior exposure to any direct acting antiviral agent targeting the HCV NS5A
or NS5B is prohibited.
ii) Subjects that discontinued HCV treatment due to development or significant worsening 
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8) Subjects enrolled in Cohort 2 only must either have contraindications to, or have demonstrated 
intolerance of ribavirin:
a) Examples of contraindications to RBV include:
i)
Unable or unwilling to comply with RBV contraception requirements
ii) Difficult to control cardiac disease (eg, myocardial infarction, cardiac failure, 
arrhythmia, etc.) Note: Per Exclusion Criterion #1g, subjects who have had a significant 
cardiac event in the past year are to be excluded.
iii) Hemoglobin <11 g/dL for female subjects or <12 g/dL for male subjects. Note: Per 
Exclusion Criterion #7a, all subjects require Hb ≥10 g/dL.
iv) Haemoglobinopathy such as thalassaemia or sickle cell anaemia
v) Porphyria
vi) Chronic renal dysfunction with CLCr ≤50 mL/min.  Note: Per Exclusion Criterion #7e, 
all subjects require a CLCr ≥ 30 mL/min.
vii)History of severe psychiatric condition. Note: Per Exclusion Criterion #1i, subjects who 
have had psychiatric hospitalization, suicide attempt, and/or a period of disability as a 
result of their psychiatric illness within the last two years are to be excluded.
viii) Other condition, with approval from the Gilead medical monitor
Note: The ribavirin package insert should be consulted for additional details concerning 
contraindications.
b) Ribavirin intolerance is defined as: The emergence of RBV-related clinical adverse events or 
laboratory abnormalities which could not be adequately managed according to dose 
modification guidance provided in the RBV package insert necessitating permanent 
discontinuation of RBV therapy.
9) Cirrhosis Determination:  
a) Presence of cirrhosis is defined as any one of the following:
i)
FibroTest® score > 0.75 and AST:platelet ratio index (APRI) > 2 during Screening
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
iii) Fibroscan showing cirrhosis as reflected by a result >12.5 kPa
b) Absence of cirrhosis is defined as any one of the following, unless the definition of cirrhosis 
has been met:
i)
FibroTest® score ≤0.48 and APRI ≤1 performed during Screening


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ii) Liver biopsy within 2 years of Screening showing absence of cirrhosis
iii) Fibroscan within 6 months of Day 1 with a result ≤ 12.5 kPa
10) Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) performed 
within 4-6 months of Day 1 to exclude hepatocellular carcinoma (HCC) is required:
a) Within 4 months for subjects with cirrhosis
b) Within 6 months for subjects without cirrhosis
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/enrollment.
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) Male subjects must agree and refrain from sperm donation from the date of screening until at 
least 6 months after the last dose of RBV, if applicable, or 90 days after the last dose LDV/SOF 
FDC.
14) Lactating females must agree to discontinue nursing before the study drugs are administered.
15) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the investigator.
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 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 drug
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage, 
Child-Pugh-B or C cirrhosis)


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e) Solid organ transplantation
f)
Significant pulmonary disease
g) Unstable cardiac disease or significant cardiac event within the last one year prior to
Screening
h) Porphyria (Cohort 1 only)
i)
Psychiatric hospitalization, suicide attempt and/or a period of disability as a result of their 
psychiatric illness within the last 2 years of Screening
j)
Malignancy within the 5 years prior to screening with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible
k) Prior or current hepatocellular carcinoma (HCC)
l)
Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
3) Screening ECG with clinically significant abnormalities
4) If treatment-experienced, prior exposure to any direct acting antiviral agent targeting the HCV 
NS5A or NS5B. Exposure to IFN and/or any direct acting antiviral agent (e.g., NS3/4A protease 
inhibitors) within 1 month prior to Screening is prohibited
5) History of clinically significant medical condition associated with other chronic liver disease 
(e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, α-1-antitrypsin deficiency, 
alcoholic liver disease, non-alcoholic steatohepatitis or toxin exposure)
6) Pregnant or nursing female or male with pregnant female partner
7) Subjects with any of the following laboratory parameters at screening:
a) Hemoglobin (Hb)
i)
Cohort 1: Hb < 11 g/dL for female subjects; Hb < 12 g/dL for male subjects
ii) Cohort 2: Hb < 10 g/dL
b) Platelets < 50,000/mm3
c) ALT  >10 x upper limit of normal (ULN)
d) AST > 10 x ULN


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e) Creatinine Clearance (CLCr) as calculated by the Cockcroft-Gault equation {Cockcroft et al 
1976}.
i)
Cohort 1: CLCr < 50 mL/min
ii) Cohort 2: CLCr < 30 mL/min
f)
Albumin < 3g/dL
g) INR > 1.5 x ULN unless the subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
h) Direct bilirubin > 1.5 x ULN
i)
HbA1c ≥ 8.5%
8) Donation or loss of more than 400 mL blood within 2 months prior to Day 1
9) Any other contraindication to LDV/SOF or SOF therapy, or RBV therapy (Cohort 1 only), per 
the approved package inserts
10) Use of any prohibited concomitant medications as described in Section 5.7
11) Known hypersensitivity to sofosbuvir, ledipasvir, or ribavirin (Cohort 1 only) or the metabolites 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a randomized, open-label study in adults with chronic genotype 2 HCV infection. This study 
is an open-label study and no blinding will be required.
Cohort 1 (n = approximately 200): 

LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks

SOF tablet (400 mg) once daily and RBV (600-1000 mg daily as a divided dose) for 12 weeks 
Randomization will be stratified by cirrhosis status (presence/absence) and prior treatment 
experience (treatment naïve/treatment-experienced).
Cohort 2 (n = up to 25):  LDV/SOF FDC tablet (90/400 mg) once daily for 12 weeks
5.2.
Description and Handling of LDV/SOF FDC
5.2.1.
Formulation
LDV/SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of LDV 
and 400 mg of SOF.  The tablets are debossed with “GSI” on one side and “7985” on the other side.
In addition to the active ingredients, the LDV/SOF FDC tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene 
glycol and FD&C yellow # 6 /sunset yellow FCF aluminum lake.
5.2.2.
LDV/SOF FDC Packaging and Labeling
LDV/SOF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. Each
bottle contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
LDV/SOF FDC bottles to be distributed to centers in Japan shall be labeled for clinical use to meet 
applicable requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan,
and/or other local regulations as applicable.
5.2.3.
LDV/SOF FDC Storage and Handling
LDV/SOF FDC bottles 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).


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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 LDV/SOF FDC.
5.2.4.
Dosage and Administration of LDV/SOF FDC
LDV/SOF FDC tablet is to be administered once daily either with or without food. Each subject 
must be given instructions to maintain approximately the same daily dosing interval between study 
drug doses.  
If a subject does not take the LDV/SOF 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 medications should not be cut or split.  LDV/SOF FDC tablets will be provided by 
Gilead Sciences for all subjects.  
5.3.
Description and Handling of Sofosbuvir (SOF)
5.3.1.
Formulation
SOF tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg of sofosbuvir.  The 
tablets are debossed with “GSI” on one side and “7977” on the other side. In addition to the active 
ingredient, sofosbuvir tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinylalcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
5.3.2.
SOF Packaging and Labeling
SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 
30 tablets, a silica gel desiccant 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 bottles to be distributed to centers in Japan shall be labeled for clinical use to meet applicable 
requirements of the Pharmaceuticals and Medical Devices Agency (PMDA), Japan, and/or other 
local regulations as applicable.
5.3.3.
SOF Storage and Handling
SOF bottles should be stored at a 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).


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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 sofosbuvir.
5.3.4.
Dosage and Administration of SOF
SOF will be administered as 400 mg once daily by mouth. SOF will be supplied by Gilead Sciences 
for all subjects.
If a subject does not take the SOF 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.
5.4.
Description and Handling of Ribavirin (RBV)
5.4.1.
Formulation
Ribavirin 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 2015}.
5.4.2.
RBV Packaging and Labeling
REBETOLcapsules are packaged in blister packaging of 140 capsules. The ribavirin package shall 
be labeled for clinical use to meet all applicable requirements of the Pharmaceuticals and Medical 
Devices Agency (PMDA) and/or other local regulations as applicable.
5.4.3.
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.


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5.4.4.
Dosage and Administration of Ribavirin (RBV) (Only Cohort 1 Subjects in the 
SOF + RBV Treatment Group)
RBV will be administered in accordance with approved RBV labeling in Japan, see Table 5-1
below.
Table 5-1.
Dosing and Administration of RBV in Japan
Body weight at Day 1
Ribavirin dosage
Daily dosage
After morning meal
After evening meal
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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
RBV dose modification or discontinuation should be performed in accordance with the RBV
package insert.
RBV should be dosed with food and SOF when appropriate.
RBV capsule (200 mg) will be supplied by Gilead Sciences for all applicable subjects.
5.5.
Co-administration of SOF and RBV 
For subjects in Cohort 1 who are randomized to the SOF + RBV treatment group, each subject will 
be given instructions to maintain approximately the same daily dosing interval between study drug 
doses.
For morning doses, subjects will be instructed to take study drugs with food as follows:

One SOF tablet: contains 400 mg SOF

Weight-based RBV (as per Section 5.4.4).
For evening doses, subjects will be instructed to take study drug with food as follows:

Weight-based RBV (as per Section 5.4.4).
If a subject does not take the SOF 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) as per the Rebetol®
product label (Section 5.4.4). If the subject misses a dose of ribavirin 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 ribavirin.  Subjects should be instructed not
to take 2 doses of ribavirin at the same time.


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Study medications should not be cut or split.  No food restrictions apply to SOF; however, SOF
should be taken with the morning dose of RBV which is taken with food.
5.6.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all study medication(s) in the original container at every
study visit after Day 1 through the end of treatment.
Study medication(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 
medication regimen.
5.7.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days after 
the last dose of study drug, need to be recorded in the source documents and electronic case report 
form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 28 days 
prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Investigational agents or devices for any indication

Drugs disallowed per prescribing information of RBV (Cohort 1 only)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies 
(e.g., infliximab).  The Gilead medical monitor will be available to address questions from 
investigators regarding permissible corticosteroid use for this trial.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters, i.e., BCRP and P-gp) with study drug may result in PK interactions resulting in 
increases or decreases in exposure of study drug. 
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment; 
other examples of representative medications which are prohibited or are to be used with caution 
from 21 days prior to Day 1 through the end of treatment are listed below in Table 5-2.


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Table 5-2.
Disallowed and Concomitant Medications to be Used with Caution for 
SOF and LDV/SOF
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenytoin, Carbamazepine, 
Phenobarbital, Oxcarbazepine
Antimycobacterialsc
Rifampicin
Rifabutin, Rifapentine,
Cardiac Medications
Amiodarone
Digoxin b
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinacea, Milk thistle (i.e., 
silymarin), Chinese herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
a
LDV plasma concentration may decrease, leading to reduced therapeutic effect of LDV/SOF. In the case of coadministration of 
H2RA, the H2RA dose should not exceed doses comparable to famotidine 40 mg twice daily and should be administered 
simultaneously with or 12 hours apart from LDV/SOF.  PPIs should not be taken before LDV/SOF. In the case of 
coadministration of PPIs, the PPIs at doses comparable to omeprazole 20 mg should be administered simultaneously with 
LDV/SOF under fasted conditions.
b
The plasma concentration of digoxin may be increased. In case of coadministration the plasma concentration monitoring of 
digoxin is recommended.
c
Plasma concentrations of LDV and SOF may be decreased, leading to reduced therapeutic effect of LDV/SOF.
d
The plasma concentration of rosuvastatin may be increased, which is associated with increased risk of myopathy, including 
rhabdomyolysis. 
5.8.
Accountability for Investigational Medicinal Product (IMP)
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
SOF, LDV/SOF FDC, 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 IMP kits

Record the date, subject number, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the person 
recording the information.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor or 
contract research organization (CRO).
6.1.
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 requiring a liver biopsy, additional HCV genotyping (if 
initial testing is inconclusive), or for extenuating circumstances 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 error or due to an 
extenuating circumstance such as intercurrent infection.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for randomization/enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF).  All other untoward 
medical occurrences observed during the screening period, including exacerbation or changes in 
medical history are to be captured on the medical history eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
6.2.
Randomization/Enrollment
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment, 
randomization, and treatment assignment. Randomization stratification factors for Cohort 1 are 
described in Section 5.1.
6.2.1.
Day 1 Assessments
All Day 1 procedures must be performed prior to study drug dosing.  When ready to administer 
drugs to the subject:

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug(s)

Observe the subject taking the first dose of study drug(s).  If the subject is randomized to the 
SOF + RBV treatment group, the patient should take the study drugs with food


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6.3.
Treatment Assessments (3 days)
On-treatment visits will be performed at the end of Weeks 1, 2, 3, 4, 5, 6, 8, 10, and 12.
Study medication will be reconciled at every post-Day 1 visit by the investigator in order to monitor 
the subject’s adherence with the medication regimen.  
6.4.
Posttreatment Assessments (5 days)
The posttreatment Week 4, 12, and 24 visits should be timed from the date of last administration of 
any study drug.
6.5.
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 last dose of any of the study drug.  
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
6.6.
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.
6.7.
Procedures and Specifications
6.7.1.
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 and, Reticulocyte count and mean corpuscular 
volume (MCV).
Coagulation: INR, 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 (at screening and 
reflexed from total bilirubin at other visits), Total Bilirubin, Glucose, Lipase, Potassium, Sodium,
FibroTest®/APRI calculation 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. 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 


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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).
Additional Tests: Hemoglobin A1c (HbA1c).
6.7.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
Obtain HCV treatment history in order to categorize the subject as per Inclusion Criteria #7.
Information related to HCV infection will also be collected.
6.7.3.
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.
6.7.4.
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.


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6.7.5.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 
as part of routine safety monitoring.
6.7.6.
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.
6.7.7.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and each visit thereafter 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.
6.7.8.
Pregnancy Testing
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 during the dosing period.  
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test 
at the posttreatment Week 4 visit only.  Females of childbearing potential in the treatment group 
containing 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. Pregnancy test kits 
will be dispensed to female subjects of childbearing potential in the treatment group containing 
RBV after the posttreatment Week 4 visit. 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.
6.7.9.
IL28B Testing
A blood sample will be obtained at screening for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 


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Final 
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The specimens collected for future research will be used to increase our knowledge and 
understanding of the biology pathogenesis, progression and/or u·eatment outcomes, including 
efficacy, AEs, and the processes of dmg absorption and disposition. These specimens may be used 
for retesting of the ammmt of HCV in the blood, clinicallaborat01y testing to provide additional 
clinical data and to develop non-genetic biomarker or diagnostic assays and establish the 
perfonnance characteristics of these assays. The collection and analysis of future research 
specimens will facilitate the rational design of new phannaceutical agents and the development of 
diagnostic tests, which may allow for individualized dmg therapy for patients in the future. 
An archive plasma sample (non-genetic) will be collected at each on-u·eatment and postu·eatment 
study visit. Samples will be collected and archived for future analysis once approved by local 
authorities as applicable according to specific local regulations. 
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 
desu·oyed by intemationally accepted means (e.g. incineration). 
6.7.11. 
Genomic Testing 
PPD 
The subject's identity will be protected, and the subject's name will not be attached to the sample. 
The sample may be stored for up to 15 years before being desu·oyed. The sample will be desu·oyed 
by intemationally accepted means (e.g. incineration). 
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Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.7.12.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using
actual body weight (ABW).
Male:
Crcl (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
Crcl (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.8.
End of Study
Subjects are considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment duration or early termination of study drug. 
6.9.
Poststudy 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, 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

Persistent or significant disability/incapacity


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


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The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale for 
Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and 
Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and adverse events related to protocol-
mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study IMP 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 occur after the subject first consents to participate 
in the study (ie, signing the informed consent) and throughout the duration of the study, including 
the protocol-required 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 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.


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Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting form 
and submit within 24 hours to
Gilead DSPH: 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.
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. 


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All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as is 
practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management 
7.5.1.
RBV Dose Adjustments (Only Cohort 1)
Dose reduction or discontinuation of RBV due to toxicity should be performed according to the 
Japanese Rebetol® product label. Information is provided in Table 7-1 and Table 7-2.
In the event a female partner of a male subject becomes pregnant, the male subject must 
permanently discontinue SOF and RBV.
Table 7-1.
RBV Dose Reduction Guidelines for Non-Cirrhotic Subjects
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)
< 10 g/dL
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL
Discontinue
Hemoglobin level
(Cardiac disease or history of 
cardiac disease present)
< 10 g/dL, or during administration, 
reduction of 2 g/dL or more relative 
to Day 1 persists for 4 weeks
Reduce dose
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 mg/day
< 8.5 g/dL, or after dose reduction, 
less than 12 g/dL even after 4 weeks
Discontinue
Source: Japan Rebetol  Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}


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Table 7-2.
RBV Dose Reduction Guidelines for Cirrhotic Subjects
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 → 400 mg/day
800 mg/day → 600 mg/day
1,000 mg/day → 600 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 → 400 mg/day
800 mg/day → 400 mg/day
1,000 mg/day → 600 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
Source: Japan Rebetol®Product Label {MSD K.K. Kudan-kita Chiyoda-ku 2015}
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.
7.5.2.
Subject Stopping Rules
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF FDC or SOF 
unless the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Due to a clinical or laboratory event, administration of all study drug(s) may be discontinued. There 
is no option for LDV/SOF FDC or SOF dose reduction. If LDV/SOF FDC or SOF is stopped due to 
toxicity, it must not be restarted.  If SOF is discontinued then RBV must also be discontinued.  If 
RBV is discontinued permanently, then SOF must also be discontinued. In these cases that study 
drug(s) are discontinued permanently, the subject must complete an ET visit. Posttreatment 4-Week, 
12-Week and 24-Week visits must also be scheduled, 4, 12 and 24 weeks from the last dose of study 
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Subjects who meet any of the following laboratory criteria must stop all study medication(s):

Elevation of ALT and/or AST above the upper limit of normal and > 5x Day 1 or nadir, 
confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by immediate 
repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed as related to LDV/SOF FDC or 
SOF
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.
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.  


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7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after initiation
of study medication and throughout the study, including the post study drug 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.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs must
also be reported and relevant information should be submitted to Gilead DSPH using the pregnancy 
and pregnancy outcome forms within 24 hours of the investigator becoming aware of the pregnancy. 
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.


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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. 
These reports must consist of situations that involve study IMP 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 primmy objective of this study is as follows: 
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• 
To evaluate the antiviral efficacy of therapy with LDV/SOF FDC as measured by SVR12 
• 
To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated 
safety data 
The secondaiy objectives of this study are as follows: 
• 
To detennine the proportion of subjects who attain SVR4 and SVR24 
• 
To evaluate the prop01iion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of each 
treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
cessation of treatment 
Explorat01y objectives of this study m·e: 
PPO 
I 
8.1.2. 
Primary Endpoint 
The primmy efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of therapy) 
in the Full Analysis Set (F AS) population. 
The primmy safety endpoint is any AE leading to pennanent discontinuation of study dmg(s). 
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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

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 LDV/SOF FDC, SOF and RBV. Last dose of study drug refers 
to the last dose of any 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. 
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. Treatment-emergent data will be analyzed and defined as data collected from the first 
dose of study drug through the date of last dose of study drug plus 30 days.
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.


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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 drug, the subject will be included in a summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed, then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject is 
missing a pre-dose value, then the subject will be excluded from the calculation of summary 
statistics for the 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.
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).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive methods 
by cohort and treatment group and overall.
Demographic summaries will include age, sex, self-identified race and ethnicity. Baseline
characteristics data will include body mass index, HCV RNA level (log10 IU/mL), IL28B genotype, 
and additional endpoints as necessary. The number (proportion) of subjects in each stratum will be 
summarized for Cohort 1.


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8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
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The primmy efficacy endpoint for this study will be the prop01tion of subjects with SVR12, defined 
as HCV RNA < LLOQ 12 weeks after cessation of treatment. The primmy analysis will be 
perf01m ed after all randomized subjects have been followed through 12 weeks posttreatment or 
discontinued from study. 
In Coh01t 1, the primmy analyses will consist of a non-inferiority (NI) test of treatment LDV/SOF 
FDC for 12 weeks versus SOF+RBV for 12 weeks at the 0.05 significance level (two-sided). 
Non-inferiority will be assessed using the conventional confidence interval approach, and a 
clinically meaningful non-inferiority mm·gin of 10% will be applied. The two-sided 95% confidence 
intervals will be constmcted using stratum-adjusted Mantel-Haenszel (MH) prop01tions, stratified 
by the randomization su·atification factors (ie, cinhosis status and prior u·eatment experience). 
In the primmy efficacy analysis of Coh01t 2, the SVR12 rate will be calculated along with the 
two-sided 95% exact confidence interval using the binomial disu·ibution (Clopper-Pem·son method). 
No statistical hypothesis testing will be perfonned. 
8.5.2. 
Secondary Analyses 
The prop01tion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) will 
be presented in tabulm· and graphical f01m. 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations including 
HCV RNA values and change from baseline through end of u·eatment, and subjects who experience 
virologic failme. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, and vital 
signs measmements and AEs will be documented at vm·ious time points dming the study. 
All safety data collected, on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized by coh01t and u·eatment group according to the study 
dmg received. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug administration
page of the eCRF. Exposure data will be summarized by cohort and treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-Level 
Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical 
database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any AE with an onset date on or after the study drug start date and 
no later than 30 days after permanent discontinuation of the study drug; or any AE leading to 
premature discontinuation of the study drug.
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-emergent 
adverse events (by SOC, and PT) will be provided by cohort and 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

All SAEs

All treatment-related SAEs

AEs leading to premature discontinuation of  any study drug

AEs leading to modification or interruption of any study drug
All AEs collected during the course of the study will be presented in data listings.


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8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by cohort and 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 drug plus 30 days will be summarized. 
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 laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and summarized 
by cohort and treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. 
8.7.
Sample Size
For Cohort 1, a sample size of 100 per treatment group will provide over 90% power to establish 
non-inferiority in the SVR12 rates between the two groups. It is based on the assumptions that the 
clinically meaningful non-inferiority margin is 10%, both groups have a SVR12 rate of 96%, and 
the significance level is 0.025 one-sided.
Sample size for Cohort 2 is based on practical considerations. With a sample size of 25 subjects in 
Cohort 2, the 2-sided 95% exact CIs for different observed HCV SVR12 rates are presented in the 
table below:
Cohort
Observed HCV SVR12 rate
2-sided 95% exact CI
Cohort 2
80% (20 out of 25)
[59.3%, 93.2%]
92% (23 out of 25)
[74.0%, 99.0%]


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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” (MHLW Ordinance No 87 [30 July 2014])
{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 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 or the subject’s legally authorized 


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representative 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 IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. These documents should be 
classified into at least the following two categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, and 
other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;


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


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correctness, and consistency. The site coordinator is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the trial, 
Gilead will provide the site with a read-only archive copy of the data entered by that site. This 
archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal procedures 
and provide appropriate instruction for destruction of unused IMP supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead, the 
site may destroy used (empty or partially empty) and unused IMP supplies in accordance with that
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator or designee (ie, pharmacist) must maintain accurate 
records for all IMP destroyed. Records must show the identification and quantity of each unit 
destroyed, the method of destruction, and the person who disposed of the IMP. Upon study 
completion, copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to Gilead’s 
appointed study monitors, to IRB/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.
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.


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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 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 the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir 
for previously treated HCV genotype 1 infection. N Engl J Med 2014a;370 
(16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. 
Intervirology 2010;53 (1):39-43.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic 
hepatitis C in the United States. Liver Transpl 2003;9 (4):331-8.
Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, et al. Hepatitis C virus 
related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 
2000;47 (1):131-6.
Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, et al. A 
prospective study of the rate of progression in compensated, histologically advanced 
chronic hepatitis C. Hepatology 2011;54 (2):396-405.
El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 
2004;127 (5 Suppl 1):S27-34.
Gane EJ, Hyland RH, Yang Y, Svarovskaia E, Pang PS, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Single Tablet Regimen Is Effective in Patients With HCV 
Genotype 2 Infection [Presentaton]. International Symposium on Viral Hepatitis and 
Liver Disease (ISVHLD); 2015 26-28 June; Berlin, Germany. 
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis 
C: an update. Hepatology 2009;49 (4):1335-74.
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 
2006;355 (23):2444-51.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Lai MY. Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon 
monotherapy. J Gastroenterol Hepatol 2000;15 Suppl:E130-3.


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Amendment 2
CONFIDENTIAL
Page 60
23 February 2016
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345 (1):41-52.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-
2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. 
Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 (21):1485-92.
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.
Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, et al. Ledipasvir 
and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in 
treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: 
an open-label, randomised, phase 3 trial. Lancet Infect Dis 2015;15 (6):645-53.
MSD K.K. Kudan-kita Chiyoda-ku. REBETOL® (ribavirin) Capsules 200mg. Japan Prescribing 
Information [English]. Tokyo, Japan. Revised 31 July 2015.
Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of 
effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active 
hepatitis C with cirrhosis. Lancet 1995;346 (8982):1051-5.
Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, et al. Sofosbuvir plus ribavirin in 
Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 
trial. J Viral Hepat 2014;21 (11):762-8.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C 
virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352 
(9138):1426-32.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, et al. 
Determinants of outcome of compensated hepatitis C virus-related cirrhosis. 
Hepatology 1998;27 (5):1435-40.
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.


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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.
The Japan Society of Hepatology. Committee for Hepatitis Management Guidelines, JSH 
Guidelines for the Management of Hepatitis C virus Infection Edition 4.0. 
[Translated from Japanese by Japan Gilead Regulatory Affaris]. September 2015.
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.
World Health Organization (WHO). Hepatitis C Fact sheet N° 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/. Updated July 2015. Accessed: 
03 November 2015.


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Amendment 2
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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


LDV/SOFFDC 
Protocol GS-US-337-1903 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects with Chronic Genotype 2 
HCV Infection 
GS-US-337-1903, Amendment 2, 23 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents this 
approval. 
~l{k11 Dt·J:o) 
Stephen Djedjos, M 
v 
> 
PPD 
....._._0~-~---------" 
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. r 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 
Page63 
23 February 2016 


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Appendix 2.
Study Procedures Table
Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
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
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
Adverse Events and Concomitant Medicationse
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 Lifef
X
X
X
X
X
X
X
X
Imaging for HCCg
X
Review of Study Drug Adherence and Drug 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensingi
X
X
X


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Amendment 2
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Screening
Day1a
Treatment Week
(3 days)
ETb
Posttreatment 
Week (5 days)
1
2
3
4
5
6
8
10
12/EOT
4
12
24
Laboratory Assessments
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, aPTT and INR)
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA (Plasma)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral RNA Sequencing /Phenotyping Sample (Plasma)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testj
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
HCV Genotype, IL28B Genotype
X
HCV Ab, HIV Ab and HBsAg
X
HbA1c
X
FibroTest® with APRI
X
Archive plasma sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single Genomic Samplek
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = Early Termination; at all unscheduled visits initiated for the purpose of confirmatory testing, a viral sequence analysis plasma sample must be obtained.
c
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
d
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for clinically signficant abnormalities. On treatment ECGs should be compared to the subject’s Day 1 as part of routine safety monitoring.
e
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drug.
f
Health Related Quality of Life (HRQoL) Surveys (e.g. SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1. 
g
Liver imaging (e.g., ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all 
subjects. For subjects without cirrhosis, imaging must have been performed within 6 months prior to Day 1. For subjects with cirrhosis, imaging must have been performed 
within 4 months of Day 1.


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h
Study medication will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the medication regimen.  Subjects must be 
instructed to bring back all bottles of study medication(s) in the original container at every post- Day 1 visit through the end of treatment.
i
Dispense study drugs as directed by the IWRS 
j  
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 during the dosing period. 
Females of childbearing potential in treatment groups without RBV will have a urine pregnancy test at the posttreatment Week 4 visit only.  Females of childbearing potential 
in the treatment group containing 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.  Pregnancy test kits will be dispensed to female subjects of childbearing potential in the treatment group containing RBV after 
the posttreatment Week 4 visit. 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.
k
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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Amendment 2
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L


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Amendment 2
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN


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Amendment 2
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.  


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Amendment 2
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 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


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Amendment 2
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 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


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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 72
23 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
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 2
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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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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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-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 75
23 February 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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


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


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Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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23 February 2016
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


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Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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23 February 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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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Amendment 2
CONFIDENTIAL
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23 February 2016
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 2
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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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Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 84
23 February 2016
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 85
23 February 2016
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 86
23 February 2016
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]


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 87
23 February 2016
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 88
23 February 2016
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


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 89
23 February 2016
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.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2 
CONFIDENTIAL
Page 90
23 February 2016
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential from 
menarche until becoming postmenopausal, unless permanently sterile or with medically 
documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects 
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Data from clinical pharmacokinetic interaction 
studies of Ribavirin have demonstrated that there is no reduction in the clinical efficacy of 
hormonal contraception or that the effect on hormonal contraception is insignificant. Please refer 
to the latest version of the product insert for additional information
Data from clinical pharmacokinetic interaction studies of SOF, LDV/SOF FDC have 
demonstrated that there is no reduction in the clinical efficacy of hormonal contraception. 
Non-clinical toxicity studies of SOF, LDV/SOF FDC have demonstrated no adverse effect on 
fertility or embryo-fetal development. However, there are no clinical studies of SOF or
LDV/SOF in pregnant women.  Please refer to the latest version of the investigator’s brochure 
for additional information.


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 91
23 February 2016
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to randomization/enrollment.  Pregnancy 
tests will be performed every 4 weeks thereafter.  Female subjects must agree to one of the 
following from screening until 6 months after last dose of RBV or 30 days after last dose of 
LDV/SOF FDC:

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below:
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide) (Female condom and male condom 
should not be used together)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone


LDV/SOF FDC
Protocol GS-US-337-1903
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 92
23 February 2016
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until 6 months after last dose of RBV or 30 days after last dose of LDV/SOF FDC.
3) Contraception Requirements for Male Subjects
Male subjects with female partners of childbearing potential must use condoms during treatment 
and until 6 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC.  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 6 months after the last 
dose of RBV or 90 days after the last dose of LDV/SOF.
Male subjects must agree to refrain from sperm donation for at least 6 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they or their partner (for partners of male 
subjects) become pregnant at any time during the study, or if they become pregnant within 
6 months of last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF 
FDC dose. Subjects who become pregnant or who suspect that they are pregnant must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in
Section 7.6.2.1.