Clinical trial NCT03036839
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2017-06-27; Completion date: 2019-02-14
Enrollment: 95 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety, efficacy and tolerability of treatment with ledipasvir/sofosbuvir (LDV/SOF) in adults with chronic HCV infection who are on dialysis for ESRD.

Detailed description:

Arms: arm 1: Treatment-naive participants with genotype 1 without cirrhosis will receive LDV/SOF for 8 weeks arm 2: Treatment-experienced participants with genotype 1 and treatment-naive or treatment-experienced participants with genotype 2 (Taiwan only), 4, 5 and 6 without cirrhosis will receive LDV/SOF for 12 weeks arm 3: Participants with compensated cirrhosis will receive LDV/SOF for 24 weeks
Interventions: intervention 1: LDV/SOF
Intervention descriptions: intervention 1: 90/400 mg fixed- dose combination (FDC) tablet administered orally once daily

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Ledipasvir/Sofosbuvir in Subjects with 
Genotype 1, 4, 5 and 6 Chronic HCV Infection Who are on 
Dialysis for End Stage Renal Disease 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
115268 
2016-003489-25 
NCT03036839 
Hepatitis C Vims Infection 
GS-US-337-4063 
Gilead Study Director: 
Name: 
IPIPD 
IPIPD 
IPIPD 
PPU 
Telephone: 
Fax: 
Email address: 
Gilead Medical Monitor: 
Name: 
Telephone: 
Fax: 
Email address: 
Protocol Version/Date: 
Original: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 3.0: 
IPIPD 
IPIPD 
IPIPD 
PPU 
23 September 2016 
29 November 2016 
30 Janmuy2017 
02 March 2017 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 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 Board 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 necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


LDV/SOF 
Protocol GS-US-337-4063 
Gilead Sciences, Inc. 
Final 
Amendment 3.0 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 11 
1. 
INTRODUCTION .............................................................................................................................................. 15 
1.1. 
Background ............................................................................................................................................ 15 
1.2. 
Ledipasvir/Sofosbuvir Fixed Dose Combination ................................................................................... 16 
1.2.1 . 
General Info1mation ............................................................................................................. 16 
1.2.2. 
Additional Clinical Infonnation; Study GS-US-334-0154 ................................................... 16 
1.2.3. 
Additional Non-Clinical Toxicology Infoimation ................................................................ 21 
1.3. 
Rationale for This Study ........................................................................................................................ 21 
1.4. 
Rationale for Dose Selection ofLDV/SOF ............................................................................................ 22 
1.5. 
Risk/BenefitAssess1nent for the Study .................................................................................................. 23 
1.6. 
Compliance ............................................................................................................................................ 24 
2. 
OBJECTIVES ..................................................................................................................................................... 25 
3. 
STUDY DESIGN ................................................................................................................................................ 26 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
Study Design .......................................................................................................................................... 26 
Visit Schedule ........................................................................................................................................ 26 
Dw·ation ofTreatinent ............................................................................................................................ 26 
Stopping Rules and Discontinuation Criteria ......................................................................................... 27 
3 .4.1 . 
Toxicity-Based Stopping Criteria ......................................................................................... 27 
3.4.2. 
Virologic Response Base Stopping Criteria ......................................................................... 28 
HIV Virolo ic Rebound Criteria ............................................................................................................ 28 
. ......................................................................................................... 30 
. ........................................................................................................ 30 
.................................................................................................. 30 
Bio1narker Testing .................................................................................................................................. 30 
3.7.1 . 
Sain les for O tional Future Research ................................................................................. 30 
3.7.2. 
.. ................................................... 31 
4. 
SUBJECT POPULATION .................................................................................................................................. 32 
4.1. 
Inclusion Criteria .................................................................................................................................... 32 
4.2. 
Exclusion Criteria ................................................................................................................................... 33 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 36 
5.1. 
Randomization, Blinding and Treatment Codes .................................................................................... 36 
5.2. 
Description and Handling ofLDV/SOF FDC ........................................................................................ 36 
5.2.1 . 
Fonnulation .......................................................................................................................... 36 
5.2.2. 
Packaging and Labeling ....................................................................................................... 36 
5.2.3. 
Storage and Handling ........................................................................................................... 36 
5.3. 
Dosage and Administration ofLDV/SOF FDC ..................................................................................... 37 
5 .4. 
Prior and Concoinitant Medications ....................................................................................................... 3 7 
5.5. 
Accountability for LDV/SOF FDC ........................................................................................................ 38 
5.5.1 . 
Investigational Medicinal Product Retwn or Disposal ........................................................ 39 
6. 
STUDY PROCEDURES .................................................................................................................................... 40 
CONFIDENTIAL 
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Protocol GS-US-337-4063 
Gilead Sciences, Inc. 
Final 
Amendment 3.0 
6.1. 
Subject Enrollment and Treatment Assignment.. ................................................................................... 40 
6.1.1 . 
Pretreatment Assess1nents .................................................................................................... 40 
6.2. 
Day I Assessments ................................................................................................................................. 42 
6. 3. 
T reatinent Assessments .......................................................................................................................... 43 
6.3.1. 
Week 2 (± 3 days): Group I, 2, and 3 .................................................................................. 43 
6.3.2. 
Week 4 (± 3 days): Group I, 2, and 3 .................................................................................. 44 
6.3.3. 
Week 6 (± 3 days): Group I, 2, and 3 .................................................................................. 45 
6.3.4. 
Week 8 (± 3 days): Group 2 and 3 (For Group I Week 8, see End of 
Treatment Visit) ................................................................................................................... 45 
6.3.5. 
Week 12, 16, and 20 (± 3 days): Group 3 (For Group 2 Week 12, see End 
of Treatment Visit) ............................................................................................................... 46 
6.3.6. 
End of Treatment Visit: Group I Week 8 (± 3 days), Group 2 Week 12 
(± 3 days), Group 3 Week 24 (± 3 days) or Early Te1mination (ET) ................................... 47 
6.4. 
Post-ti·eatment Assessments ................................................................................................................... 48 
6.4.1. 
Postt1·eatment Week 4 Visit (± 5 days): Group I, Group 2, and Group 3 ............................. 48 
6.4.2. 
Postt1·eatment Week 12 Visit (± 5 days): Group I, Group 2 and Group 3 ........................... 49 
6.4.3. 
Postt1·eatment Week 24 Visit (±5 Days): Only for Subjects who Achieved 
SVRl2 .................................................................................................................................. 49 
6.5. 
Early Te1mination (ET) .......................................................................................................................... 50 
6.6. 
Unscheduled Visit .................................................................................................................................. 50 
6.7. 
End ofStudy ........................................................................................................................................... 50 
6.8. 
Post Study Care ...................................................................................................................................... 50 
6.9. 
Procedw·es and Specifications ................................................................................................................ 50 
6.9.1 . 
Clinical Laborato1y Analytes ............................................................................................... 50 
6.9.2. 
Medical Histo1y .................................................................................................................... 51 
6.9.3. 
Complete Physical Examination ........................................................................................... 51 
6.9.4. 
Height & Weight Measw·e1nent. ........................................................................................... 52 
6.9.5. 
Vita.I Signs ............................................................................................................................ 52 
6.9.6. 
Body Mass Index (BMI) ....................................................................................................... 52 
6.9.7. 
12-LeadECG ....................................................................................................................... 52 
6.9.8. 
Health Related Quality of Life (HRQoL) ............................................................................. 52 
6.9.9. 
Viral Sequencing/Phenotyping (Archive) ............................................................................ 53 
6.9.10. 
S arsePKSam le ................................................................................................................ 53 
6.9.11. 
.. ....................................................................................................... 53 
6.9.12. 
.. ................................................................................................ 53 
6.9.13. 
P a1macogeno1rucs Testmg .................................................................................................. 54 
6.9.14. 
Archive sainple ..................................................................................................................... 54 
6.9.15. 
Pregnancy Testing ................................................................................................................ 54 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 55 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 55 
7.1.1 . 
AdverseEvents ..................................................................................................................... 55 
7.1.2. 
Serious Adverse Events ........................................................................................................ 55 
7.1.3. 
Clinical Laborato1y Abno1malities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 56 
7 .1.4. 
Assessment of Causality for Study Thugs and Procedures ................................................... 56 
7.1.5. 
Assessment of Severity ........................................................................................................ 57 
7 .2. 
Investigator Requirements and Instiuctions for Repo1ting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 57 
7 .2.1. 
Requirements for collection prior to study dmg initiation: .................................................. 57 
7.2.2. 
Adverse Events ..................................................................................................................... 57 
7.2.3. 
Serious Adverse Events ........................................................................................................ 57 
7.2.4. 
Electi·onic Serious Adverse Event (eSAE) Repo1ting Process ............................................. 58 
7 .3. 
Gilead Repo1ting Re.quirements ............................................................................................................. 58 
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Toxicity Management ............................................................................................................................59
7.4.
7.4.1.
Subject Stopping Rules ........................................................................................................59
Special Situations Reports......................................................................................................................59
7.5.
7.5.1.
Definitions of Special Situations..........................................................................................59
7.5.2.
Instructions for Reporting Special Situations.......................................................................60
8.
STATISTICAL CONSIDERATIONS................................................................................................................62
Analysis Objectives and Endpoints........................................................................................................62
8.1.
8.1.1.
Analysis Objectives..............................................................................................................62
8.1.2.
Primary Endpoint .................................................................................................................62
8.1.3.
Secondary Endpoint .............................................................................................................63
8.1.4.
Other Endpoints of Interest ..................................................................................................63
Analysis Conventions.............................................................................................................................63
8.2.
8.2.1.
Analysis Sets ........................................................................................................................63
Data Handling Conventions ...................................................................................................................64
8.3.
Demographic Data and Baseline Characteristics ...................................................................................66
8.4.
Efficacy Analysis ...................................................................................................................................66
8.5.
8.5.1.
Primary Analysis..................................................................................................................66
8.5.2.
Secondary Analyses .............................................................................................................66
Safety Analysis.......................................................................................................................................66
8.6.
8.6.1.
Extent of Exposure...............................................................................................................66
8.6.2.
Adverse Events.....................................................................................................................67
8.6.3.
Laboratory Evaluations ........................................................................................................67
Other Safety Evaluations........................................................................................................................68
8.7.
Pharmacokinetic Analysis......................................................................................................................68
8.8.
Sample Size............................................................................................................................................68
8.9.
Data Monitoring Committee ..................................................................................................................68
8.10.
9.
RESPONSIBILITIES..........................................................................................................................................69
Investigator Responsibilities ..................................................................................................................69
9.1.
9.1.1.
Good Clinical Practice..........................................................................................................69
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IECReview and Approval...................................................................................................69
9.1.3.
Informed Consent.................................................................................................................69
9.1.4.
Confidentiality......................................................................................................................70
9.1.5.
Study Files and Retention of Records..................................................................................70
9.1.6.
Case Report Forms...............................................................................................................71
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................72
9.1.8.
Inspections............................................................................................................................72
9.1.9.
Protocol Compliance............................................................................................................72
Sponsor Responsibilities........................................................................................................................73
9.2.
9.2.1.
Protocol Modifications.........................................................................................................73
9.2.2.
Study Report and Publications .............................................................................................73
Joint Investigator/Sponsor Responsibilities ...........................................................................................73
9.3.
9.3.1.
Payment Reporting...............................................................................................................73
9.3.2.
Access to Information for Monitoring..................................................................................74
9.3.3.
Access to Information for Auditing or Inspections ..............................................................74
9.3.4.
Study Discontinuation..........................................................................................................74
10.
REFERENCES ...................................................................................................................................................75
11.
APPENDICES ....................................................................................................................................................77
Appendix 1.
Investigator Signature Page....................................................................................................78


LDV/SOF
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Gilead Sciences, Inc. 
Amendment 3.0
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Appendix 2.
Study Procedures Table..........................................................................................................79
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............85
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................107
Appendix 5.
Opportunistic Infections .......................................................................................................110
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
HIV Virologic Rebound Schema............................................................................................29


LDV/SOF
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Gilead Sciences, Inc. 
Amendment 3.0
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy 
and Safety of Ledipasvir/Sofosbuvir in Subjects with 
Genotype 1, 4, 5 and 6 Chronic HCV Infection Who are on Dialysis 
for End Stage Renal Disease
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
115268
2016-003489-25
NCT03036839
Study Centers Planned:
Approximately 35 centers in, North America, Europe, and Asia 
Pacific
Objectives:
The primary objectives of this study are as follows:

To evaluate the antiviral efficacy of treatment with 
ledipasvir/sofosbuvir (LDV/SOF) for 8, 12, or 24 weeks in 
subjects with chronic hepatitis C virus (HCV) infection who are 
on dialysis for End Stage Renal Disease (ESRD), as measured by 
the proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of each treatment regimen
The secondary objectives of this study are as follows: 

To determine the proportion of subjects who attain SVR at 4 and 
24 weeks after cessation of each study treatment regimen (SVR4 
and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment

To evaluate the emergence of viral resistance to LDV and SOF
during treatment and after cessation of treatment

To evaluate the steady-state pharmacokinetics of LDV and SOF 
and its metabolites in subjects who are on dialysis for (ESRD)


LDV/SOF 
Protocol GS-US-337-4063 
Gilead Sciences, Inc. 
Study Design: 
Substudies 
CONFIDENTIAL 
The explorato1y objectives of this study are: 
Final 
Amendment 3.0 
Approximately 100 subjects with genotype 1, 4, 5, or 6 HCV 
infection will be emolled to 1 of 3 groups and will receive treatment 
with LDV/SOF for 8, 12, or 24 weeks. The treatment group to which 
subjects are assigned will be detennined by genotype, the absence or 
presence of ciIThosis and whether the subject is treatment na'ive or 
treatment experienced. 
Group 1: Treatment na'ive genotype 1 subjects without cinhosis 
will be treated with LDV/SOF for 8 weeks 
Group 2: Treatment experienced genotype 1 subjects and treatment 
na'ive or treatment experienced genotype 4, 5, and 6 
subjects without ciIThosis will be treated with LDV /SOF 
for 12 weeks 
Group 3: Subjects with compensated cinhosis will be treated with 
LDV /SOF for 24 weeks 
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LDV/SOF 
Protocol GS-US-337-4063 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of 
Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Approximately 100 subjects 
Final 
Amendment 3.0 
Adults with chronic hepatitis C vims (HCV) infection who are on 
dialysis for ESRD 
Subjects will be treated for 8, 12, or 24 weeks. 
Chronic HCV infected genotype 1, 4, 5, or 6 male and non-pregnant/ 
non-lactating female subjects aged 18 years or older who are on 
dialysis for ESRD, including subjects with HIV co-infection if they 
are suppressed on a stable, protocol-approved antiretroviral (ARV) 
regimens for ~8 weeks prior to Screening. 
For a list of assessments at each visit, refer to the Study Procedures 
Tables in Appendix 2: for subjects in Group 1 can be found in 
Appendix Table 1, for Group 2 in Appendix Table 2 and for Group 3 
in Appendix Table 3. Subjects who achieve SVR12 will also 
complete the posttreatment week 24 visit. 
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended up to 
42 days in extenuating circumstances, with the approval of the 
medical monitor. 
Screening assessments will include physical examination, medical 
history, height, weight, vital signs, 12-lead electrncardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, safety laborato1y tests (including 
hematology, chemistry, and coagulation), HCV RNA, serology 
(HIV, HCV, HBV) hemoglobin Ale (HbAlc), assessment of the 
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LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
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presence or absence of cirrhosis, screening for hepatocellular 
carcinoma (HCC) for subjects with cirrhosis, serum β-hCG (females 
of child bearing potential only), HCV genotyping, IL28B 
genotyping, and serum drug screen. HIV/HCV co-infected subjects 
will have additional testing for CD4 T-cell count and HIV-1 RNA.
Study visits will occur at Day 1 and at the end of Weeks 2, 4, 6, and 
8 for subjects in Group 1.
Study visits will occur at Day 1 and at the end of Weeks 2, 4, 6, 8, 
and 12 for subjects in Group 2.
Study visits will occur at Day 1 and at the end of Weeks 2, 4, 6, 8, 
12, 16, 20, and 24 for subjects in Group 3.
On-treatment assessments include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, weight, vital signs, safety laboratory tests, HCV RNA, 
HBV DNA (for HBcAb+ subjects only), sparse PK sampling, and 
serum β-hCG (females of child bearing potential only). HIV/HCV 
co-infected subjects will have additional assessments, including CD4 
T-cell count and HIV-1 RNA assessments.
Single 12-lead ECGs will be collected at Screening, Day 1 (prior to 
study drug administration), and at the on-treatment Week 8 
(Group 1), Week 12 (Group 2) and Week 24 (Group 3) visits, or 
Early Termination (ET) visit (if applicable). At the time of 
collection, ECGs will be reviewed by qualified study staff (as 
determined by the investigator) for clinically significant
abnormalities. End of treatment or ET results will be compared to 
the subject’s Day 1 ECG as part of routine safety monitoring.
All subjects will complete posttreatment visits at Weeks 4 and 12 
after completion of treatment. Subjects who achieve SVR12 will 
also complete the posttreatment Week 24 visit.
Post-treatment assessments include AEs, concomitant medications, 
vital signs, physical examination, safety laboratory tests, HCV RNA, 
HBV DNA (for HBcAb+ subjects only), and serum β-hCG (females 
of child bearing potential only). HIV/HCV co-infected subjects will 
have additional assessments including CD4 T-cell count and HIV-1 
RNA assessments.
HRQoL surveys (SF-36, CLDQ-HCV, FACIT-F, and WPAI) will be 
conducted at Day 1, on-treatment Weeks 8 (Group 1), Week 12 
(Group 2), Week 24 (Group 3), or (ET) (if applicable), and 
posttreatment Week 12.
Samples for HCV or HIV viral sequencing / phenotyping will be 
collected at Baseline/Day 1 and every visit thereafter. 


LDV/SOF 
Protocol GS-US-337-4063 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
Phaimacokinetics: 
Statistical Methods: 
Final 
Amendment 3.0 
LDV/SOF fixed dose combination (FDC) is manufactured as a 
90mg/400mg tablet for oral administrntion. Sub'ects will take 
1 tablet dail with or without food. 
None. 
AEs and laborato1y tests will be collected throughout the study. 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA perfo1med using CO BAS® AmpliPrep®/COBAS® TaqMan® 
HCV Quantitative Test, v2.0. 
The PK of LDV and SOF (and metabolites) may be assessed. 
The prima1y efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. 
In the primaiy efficacy analysis, the point estimate and the 2-sided 
95% exact confidence interval of SVR12 rate will be provided for 
each treatment group and overall. 
With a sample size of 100 subjects, a 2-sided 95% exact confidence 
interval will extend at the most 20% in length. 
Seconda1y efficacy endpoints include SVR4, SVR24, and the 
propo1iion of subjects with virologic failure. Steady state PK plasma 
parameters will be listed by subject and sUllllllai·ized by treatment 
group and overall using descriptive statistics for each analyte 
(SOF [and its metabolites] and LDV, as appropriate). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
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Gilead Sciences, Inc. 
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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
ARV
antiretroviral
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
CRO
contract (or clinical) research organization
CSR
Clinical study report
CT
Computerized Tomography
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
ESRD
End Stage Renal Disease
ET
Early Termination
EU
European Union


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Amendment 3.0
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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
h
hour
H2
Histamine
Hb
Hemoglobin 
HbA1c
Hemoglobin A1c 
HBsAg
Hepatitis B surface antigen
HBcAb
Hepatitis B core antibody
HBcAb+
Hepatitis B core antibody-positive
HBsAb
Hepatitis B surface antibody
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


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Gilead Sciences, Inc. 
Amendment 3.0
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IMB
Intermenstrual Bleeding
IMP
Investigational Medical Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time
IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
kPa
kilopascal
L
liter
LAM
Lactational amenorrhea method
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
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
Pharmaceuticals and Medical Devices Agency
PPIs
Proton-pump inhibitor
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time
Q1
Quartile 1
Q3
Quartile 3


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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
Background
1.1.
Hepatitis C virus infection is a global health challenge with the estimated number of persons 
infected ranging from 80 to 150 million worldwide {Gower 2014, World Health Organization 
(WHO) 2014}. Hepatitis C virus has significant genetic (RNA sequence) variability and is 
classified on this basis into at least 6 genotypes. There is significant geographical variation in the 
distribution of HCV genotypes. In North America and Europe, genotype 1 HCV infection 
predominates. In Asia, genotype 1 and 3 HCV infections are the most prevalent. Genotype 4, 5,
and 6 are highly prevalent in northern Africa, southern Africa, and southeast Asia, respectively.
The disease burden of HCV infection is due to progression of chronic liver disease, which can 
lead to cirrhosis, liver failure, HCC, and death. Globally, 27% of all subjects with cirrhosis and 
25% of those who develop HCC are attributable to HCV infection {Perz 2006}. In addition to 
having a higher incidence of HCC, subjects with chronic HCV infection have a higher incidence 
and mortality of many types of non-liver cancers including pancreatic, rectal, kidney, 
non-Hodgkin’s lymphoma, and lung cancers, compared with the general population 
{Allison 2015}. Curing HCV infection is associated with numerous health benefits including 
more than 70% reduction in the risk of HCC and a 90% reduction in the risk of liver-related 
mortality and liver transplantation {Morgan 2013, Poynard 2002, van der Meer 2012, 
Veldt 2007}.
Recently, there has been a transformation in the treatment of HCV infection with the 
development of direct-acting antiviral agents (DAAs) targeting viral proteins essential to viral 
replication. DAA based treatment regimens are generally well tolerated and result in high 
sustained virologic response (SVR) at 12 weeks following completion of all treatment (SVR12) 
rates across most patient populations {AbbVie Inc 2016, Bristol-Myers Squibb 2016, 
Gilead Sciences Inc 2015a, Gilead Sciences Inc 2015b, Gilead Sciences Inc 2016, 
Merck & Co Inc 2016}. SOF based regimens (Sovaldi® and Harvoni®) are the most widely 
prescribed treatments for HCV infection due to the efficacy, tolerability, and simplicity of the 
dosing regimens. In addition, SOF-based regimens offer the advantages of having relatively few
drug-drug interactions, strong concordance between clinical trial and “real world” data, and 
absence of a requirement for baseline NS5A polymorphism testing {Arias 2016, 
Gilead Sciences Inc 2015a, Gilead Sciences Inc 2015b, Ioannou 2016}.
Despite the progress made in the development of effective treatments for HCV infection, many
challenges remain. These include the evaluation of DAA based regimens in patient populations 
not evaluated in registration clinical studies, including subjects with advanced hepatic disease, or 
advanced renal disease and in pediatric populations. In addition, the treatment of populations 
with high HCV prevalence such as the incarcerated, or injection drug users will require the 
development of treatment models tailored to these specific populations. Finally, as the highest 
prevalence of HCV infection occurs in low and middle income countries, the development of 
treatment algorithms that can be implemented in resource limited settings will be necessary to 
decrease the global prevalence and burden of HCV infection.


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Ledipasvir/Sofosbuvir Fixed Dose Combination
1.2.
Ledipasvir is a HCV NS5A inhibitor with potent activity against genotype 1, 4, 5, and 6 HCV. 
Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor. LDV/SOF (Harvoni®) is a 
co-formulation of LDV 90 mg and SOF 400 mg that is approved in the US, EU, and other 
regions for the treatment of HCV infection in adults.
1.2.1.
General Information
Please refer to the Investigator’s Brochure (IB) for additional information on LDV/SOF, 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.
Additional Clinical Information; Study GS-US-334-0154
1.2.2.1.
Study Design
Study GS-US-334-0154 is an ongoing Phase 2b, open-label study of SOF-based regimens in 
subjects with severe renal impairment. In Part A, subjects with genotype 1 or 3 HCV infection 
and severe renal impairment were randomized to SOF 200 mg + RBV 200 mg for 24 weeks 
(Cohort 1) or SOF 400 mg + RBV 200 mg (Cohort 2) for 24 Weeks. Based on data from 
Cohort 1 and 2, Cohort 3 was opened for enrollment and subjects with genotype 1 or 4 HCV 
infection and severe renal impairment were treated with LDV/SOF (90/400 mg) for 12 weeks.
Final data is available for Cohort 1 and Cohort 2 and is presented below. Enrollment in Cohort 3 
is ongoing and preliminary data is summarized in Section 1.2.2.8.
1.2.2.2.
Disposition (Cohort 1 and 2)
A total of 20 subjects were enrolled and received at least 1 dose of study drug; 10 subjects in
Cohort 1 [SOF 200 mg + RBV 200 mg] and 10 subjects in Cohort 2 [SOF 400 mg + RBV 
200 mg]. The majority of subjects (80.0%) completed study treatment (8 subjects in each 
cohort). Four of the 20 enrolled and treated subjects, prematurely discontinued study treatment
(20.0%, 2 subjects in each cohort). The reasons for premature discontinuation of study treatment 
were AEs (2 subjects from Cohort 2), noncompliance with study drug (1 subject from Cohort 1), 
and withdrawn consent (1 subject in Cohort 1).


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1.2.2.3.
Demographics and Baseline Characteristics (Cohorts 1 and 2)
Demographics and baseline characteristics were similar in both treatment groups. The majority 
of subjects were male (70.0%), 45.0% of subjects were black and 35.0% of subjects were white, 
the majority of subjects were non-Hispanic/Latino (85.0%), and the mean age was 60 years 
(range: 45−75). The mean (SD) baseline body mass index (BMI) for subjects was 
27.3 (3.71) kg/m2 and 70.0% of subjects had BMI < 30 kg/m2.
The majority of subjects had genotype 1a HCV infection (65.0%, 13 subjects), 20.0% 
(4 subjects) had genotype 1b, and 15.0% (3 subjects) had genotype 3a. In Cohort 1, the majority 
of subjects had non-CC (CT or TT) IL28B alleles (80.0%); while 50.0% of subjects in Cohort 2 
had non-CC (CT or TT) IL28B alleles. Overall, the majority of subjects had HCV RNA 
≥6 log10 IU/mL (65.0%, 13 subjects), with a mean (SD) HCV RNA value of 
6.4 (0.47) log10 IU/mL. A total of 4 subjects (20.0%, all in Cohort 2) had cirrhosis at screening. 
In Cohort 1, no subjects reported a known history of cirrhosis; however, 20.0% (2 subjects) had 
FibroTest scores corresponding to stage of F3-F4 (severe fibrosis). In Cohort 1, the median 
(range) estimated glomerular filtration rate using the Cockcroft-Gault equation was 
20.0 (14.4−35.8) mL/min, and in Cohort 2 it was 25.4 (17.5−39.1) mL/min. The majority of 
subjects in Cohort 1 (70.0%) were treatment-naive; the 3 subjects who were 
treatment-experienced had failed prior treatment with a DAA + pegylated interferon (Peg-IFN) + 
RBV regimen (2 subjects) or interferon + RBV (1 subject). The majority of subjects in Cohort 2 
(70.0%) were treatment-experienced; the majority of these subjects (71.4%, 5 of 7 subjects) had 
failed prior treatment with Peg IFN+RBV.
1.2.2.4.
Efficacy (Cohort 1 and 2)
The SVR12 rates were as follows:

Cohort 1 (SOF 200 mg + RBV 200 mg): 40.0% (95% CI: 12.2% to 73.8%) of subjects
(4 of 10) achieved SVR12

Cohort 2 (SOF 400 mg + RBV 200 mg): 60.0% (95% CI: 26.2% to 87.8%) of subjects
(6 of 10) achieved SVR12
In Cohort 1, 6 of 10 subjects (60.0%) did not achieve SVR12: 5 subjects (50.0%) relapsed and 
1 subject withdrew consent. In Cohort 2, 4 subjects (40.0%) did not achieve SVR12; all 
4 subjects relapsed. Two of these subjects prematurely discontinued study treatment on Day 64 
and Day 117, respectively, both due to an AE. No subjects in either cohort had on-treatment 
virologic failure (i.e., breakthrough, rebound, or nonresponse). The concordance observed 
between SVR12 and SVR24 was 100% in both cohorts. HCV RNA levels (log10 IU/mL) 
declined rapidly with similar decreases in HCV RNA observed in both treatment cohorts. After 
1 week of treatment, the mean (SD) change from baseline in HCV RNA levels was 
−4.41 (0.826) log10 IU/mL in Cohort 1 and –4.68 (0.635) log10 IU/mL in Cohort 2. The decreases 
were maintained from Week 2 through the end of treatment at Week 24.


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No nonstructural protein 5B (NS5B) nucleoside inhibitor (NI) resistance-associated variants
(RAVs) were detected in any of the subjects at baseline. The NS5B NI RAV E237G was 
detected in 3 subjects at the time of relapse (2 with genotype 1a [1 subject from each cohort] and 
1 with genotype 1b [Cohort 1]). E237G showed a small reduction in susceptibility to SOF 
(1.3-fold change) in a genotype 1a replicon assay, which was within assay variation, and was as 
susceptible as wild-type in the genotype 1b replicon assay (1.0-fold change).
1.2.2.5.
Pharmacokinetics/Pharmacodynamics (Cohort 1 and 2)
SOF AUCtau and Cmax were modestly higher in subjects receiving the 400-mg dose compared 
with the 200-mg dose and AUCtau was generally similar at Week 2 and Week 12 for both doses. 
Compared to historical reference data (SOF US NDA Phase 2/3 HCV-infected subjects without 
renal impairment [creatinine clearance CLcr, ≥ 60 mL/min] administered SOF 400 mg + RBV ± 
Peg-IFN), dose-adjusted SOF AUCtau and Cmax were ~137% and ~221% higher, respectively, for 
the 200-mg SOF dose. SOF AUCtau and Cmax were ~36% and ~100% higher than historical 
reference data, respectively, for the SOF 400-mg dose. Changes in the PK of GS-566500 were 
generally similar to those observed with SOF, consistent with historical data. Higher SOF AUC 
and Cmax (~503% and ~331%, respectively) were observed following the SOF 400-mg dose. No 
difference in GS-331007 exposure was observed between Week 2 and Week 12, suggesting 
subjects reached steady-state by Week 2. Overall, changes in SOF and GS-331007 PK were 
consistent with results of Phase 1 Study P7977-0915, which evaluated SOF PK in HCV-negative 
subjects with renal impairment.
Consistent with a long t1/2, RBV exposures in both cohorts were higher at Week 12 compared
with Week 2. The RBV AUCtau and Ctau values at Week 12 for both cohorts were similar to those
reported for the administration of RBV 1200 mg/day in subjects with normal renal function.
1.2.2.6.
Safety (Cohort 1 and 2)
Most subjects (Cohort 1: 60.0%, Cohort 2: 80.0%) received study drug for the protocol-specified 
duration of 24 weeks. In Cohort 1, the proportion of subjects with ≥ 90% adherence to SOF 
(80.0%) was higher than to RBV (40.0%). The lower adherence rate to RBV in Cohort 1 was 
primarily due to intentional RBV dose reductions or interruptions instituted by site investigators 
for the management of AEs. In Cohort 2, the proportion of subjects with ≥90% adherence to 
SOF (80.0%) was similar to RBV (70.0%).
Most subjects experienced at least 1 AE (Cohort 1: 100.0%, Cohort 2: 90.0%). In Cohort 1, the 
most commonly reported AEs (i.e., those occurring in ≥ 2 subjects) were headache (40.0%); 
anemia (30.0%); and hemolytic anemia, hypoesthesia, insomnia, irritability, muscle spasms, 
pruritic rash, and rash (20.0%, each). In Cohort 2, the most commonly reported AEs were anemia 
(40.0%) and dizziness (20.0%). Most AEs were of Grade 1 or Grade 2 severity. Grade 3 AEs 
were reported in 2 subjects (20.0%) in Cohort 1 and 3 subjects (30.0%) in Cohort 2. Anemia was 
the only Grade 3 AE reported in > 1 subject (1 subject in Cohort 1 and 2 subjects in Cohort 2). 
No Grade 4 AEs, deaths, or pregnancies were reported during the study. A total of 4 subjects
(20.0%, 2 subjects in each cohort) had at least 1 treatment-emergent serious adverse event
(SAE), with no SAEs reported for more than 1 subject. All SAEs were considered by the 


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investigators to be not related to study drug. A total of 4 subjects (20.0%, 2 subjects in each
cohort) had AEs leading to premature discontinuation of any study drug. The 2 subjects in
Cohort 1 had AEs leading to premature discontinuation of RBV only (anemia in 1 subject and
fatigue, irritability, and generalized rash in 1 subject; all of these AEs were considered to be
related to study drug). Of the 2 subjects in Cohort 2 experiencing AEs that led to premature
discontinuation of SOF and RBV, 1 subject had a Grade 2 AE of fatigue that was considered to
be related to study drug and 1 subject had a Grade 3 AE of renal failure and an SAE of 
pneumonia that were considered to be not related to study drug.
All subjects had at least 1 laboratory abnormality reported. 60.0% of subjects in Cohort 1 and 
70.0% of subjects in Cohort 2 had a Grade 3 or 4 laboratory abnormality. Across both cohorts, 
the observed Grade 3 or 4 hematology abnormalities were decreased hemoglobin and 
lymphocytes. Decreased hemoglobin and decreases in lymphocyte count are known effects of 
RBV therapy. Across both cohorts, the Grade 3 or 4 chemistry laboratory abnormalities were 
increased creatinine, decreased serum bicarbonate, increased serum glucose, and increased blood 
urea nitrogen. All 5 subjects with Grade 3 or 4 increases in creatinine (2 subjects in Cohort 1, 
3 subjects in Cohort 2) had Grade 2 or 3 elevations of creatinine at baseline and throughout study 
treatment. The 2 subjects with Grade 3 decreases in serum bicarbonate (1 subject in each cohort) 
had graded decreases in serum bicarbonate at baseline. All 3 subjects with Grade 3 increased 
serum glucose had a medical history of diabetes. The 1 subject in Cohort 2 who had a Grade 3 
increase in blood urea nitrogen had graded elevations in blood urea nitrogen at baseline and 
throughout study treatment.
Overall, there were 3 subjects (15.0%) with an AE under the Renal and Urinary Disorders
system organ class (SOC): 1 subject in Cohort 1 and 2 subjects in Cohort 2. Of these, 1 subject
(Subject 
 in Cohort 2 discontinued study treatment due to a Grade 3 AE of renal
failure and an SAE of pneumonia. The other AEs in the Renal and Urinary Disorders SOC were
Grade 1 or 2 (chronic kidney disease and nocturia) that did not lead to modification or
interruption of study treatment. One subject (Subject 
 in Cohort 2 started dialysis
during the study due to worsening of subject’s chronic kidney failure from Stage 4 to Stage 5,
which was considered by the investigator to be unrelated to study treatment.
No subjects had clinically significant ECG abnormalities during treatment with SOF+RBV. No
meaningful change in systolic function measured by ejection fraction was observed in either
treatment cohort. In addition, no subject had a decrease in ejection fraction below 50%. The
median (Q1, Q3) change in ejection fraction from baseline to Week 24 for Cohort 1 was 0.09%
(−0.97, 2.70), and in Cohort 2 was −0.73% (−4.28, 1.08). As compared to baseline
echocardiograms, there were overall no significant changes in fractional shortening, left
ventricular end diastolic volume (LVEDV), or left ventricular internal dimension in diastole
(LVIDD) at Week 12 or Week 24.
No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure,
or pulse rate) were observed during the study.
PPD
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1.2.2.7.
Conclusions (Cohort 1 and 2)
The conclusions for Cohorts 1 and 2 were as follows:

For subjects with severe renal impairment, the overall SVR12 rates following treatment with
SOF (200 mg or 400 mg) in combination with RBV for 24 weeks were as follows:
In Cohort 1 (SOF 200 mg + RBV 200 mg), the SVR12 rate was 40.0%.
In Cohort 2 (SOF 400 mg + RBV 200 mg), the SVR12 rate was 60.0%.

No subjects in either treatment cohort had on-treatment virologic failure (i.e., breakthrough,
rebound, or nonresponse).

Virologic relapse was associated with the emergence of the NS5B NI RAV E237G in 
3 of 9 subjects (33.3%).

SOF and GS-331007 exposures in HCV-infected subjects with severe renal impairment in
this study were higher than exposures observed in the reference US Phase 2/3 population of
HCV-infected subjects without renal impairment.
SOF AUCtau and Cmax were 36% and 100% higher, respectively, for the SOF 400-mg 
dose.
GS-331007 AUCtau and Cmax were 503% and 331% higher, respectively, for the SOF 
400 mg dose.
The effect of severe renal impairment on SOF and GS-331007 exposures in HCV
infected subjects administered the SOF 400 mg dose with RBV 200 mg was generally 
comparable with the results from a dedicated renal impairment study in HCV-negative 
subjects (Study P7977-0915).

SOF was safe and well tolerated. The AE and laboratory safety profile observed was
consistent with that reported for SOF+RBV in subjects without renal impairment. There were
no new safety signals or toxicities observed in this study of subjects with severe renal
impairment.
1.2.2.8.
Preliminary Data from Cohort 3
As of August 2016, 10 subjects have been enrolled and treated in Cohort 3. Preliminary data 
suggest LDV/SOF has been well tolerated. No subjects have discontinued treatment. There have 
been 4 SAEs reported; hypoglycemia and syncope in one subject (Subject 
 and 
acute renal failure (Subject 
 in one subject, and acute kidney injury in one subject 
(Subject 
 The syncope experienced by Subject 
 was assessed as 
secondary to hypoglycemia. No SAE was assessed as related to study drugs. An analysis of 
echocardiogram data for 8 subjects demonstrates stable parameters from screening through the 
PPD
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end of treatment, and does not suggest an impact of LDV/SOF treatment on cardiac function. 
Eight subjects who have reached posttreatment Week 12 to date have achieved SVR12 (100%, 
8/8).
1.2.3.
Additional Non-Clinical Toxicology Information
In dogs, repeated administration of GS-9851 (the diastereomeric mixture of SOF and 
GS-491241) or SOF at exposures similar to those expected in ESRD patients may decrease 
erythropoiesis and lower the numbers of circulating red cells (reflected by the decrease in red 
blood cells, hemoglobin concentration, and/or hematocrit). In the 4- and 13-week studies in dogs, 
there were slightly lower average circulating red cell indices, and minimally decreased 
erythropoiesis (observed by bone marrow cytology) at 500 and ≥ 100 mg/kg/day, respectively. 
However, in the 39-week dog study, while minimally decreased erythropoiesis was observed in a 
few dogs, there were no SOF-related effects on circulating red cell indices at 500 mg/kg/day. In 
mice and rats, SOF did not affect hematology parameters at any dose level; specifically, there 
were no effects in mice dosed up to 1000 mg/kg/day for up to 13 weeks or in rats dosed up to 
500 mg/kg/day for up to 26 weeks. There were also no bone marrow cytology findings in rats 
dosed up to 26 weeks. In vitro, the diastereomic mixture GS-9851 also showed low cytotoxicity 
to erythroid cell lines.
Rationale for This Study
1.3.
The GS-US-337-4063 study is a Phase 2, open-label, multicenter study evaluating the efficacy 
and safety of treatment of LDV/SOF for 8, 12, or 24 weeks in subjects on dialysis for ESRD. 
Approximately 100 subjects will be enrolled.
LDV/SOF (Harvoni®) is approved in the US, EU, and other regions for the treatment of genotype 
1, 3 (EU only), 4, 5, and 6 HCV infection. However, subjects with severe renal impairment were 
not eligible for the registration LDV/SOF clinical studies. There is therefore no dosing 
recommendation provided for HCV-infected subjects with severe renal impairment or those on 
dialysis in the prescribing information in the US, EU, and other regions.
There remains a medical need for highly effective treatment for HCV-infected subjects with 
ESRD on dialysis. Chronic HCV infection has a significant negative impact on morbidity and 
mortality in subjects on dialysis {Fabrizi 2007}. The Kidney Disease International Working 
Group (KDIGO) recommend that HCV infection be treated prior to kidney transplant as there is 
evidence that this leads to improved graft and patient outcomes {Kidney Disease: Improving 
Global Outcomes 2008}.
Although, some regions do have approved HCV treatment options for HCV-infected subjects
with severe renal impairment including Viekira Pak® and Zepatier™{AbbVie Inc 2016,
Merck & Co Inc 2016}, both regimens have limitations. The use of Viekira Pak® is limited since
many populations require the addition of ribavirin for optimal efficacy and RBV-induced 
toxicities are exacerbated in subjects with renal impairment. In addition, the components of 
Viekira Pak® (ombitasvir, paritaprevir, ritonavir, and dasabuvir) have drug-drug interaction 
potential which adds increasing complexity to the management of subjects with severe renal 


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impairment who frequently have multiple comorbid conditions and concomitant medications. 
The use of Zepatier is limited by the requirement for baseline resistance testing for subjects with 
genotype 1a infection and addition of RBV is required for some populations. Furthermore, both 
regimens carry the risk of alanine aminotransferase (ALT) elevations and/or hepatotoxicity and 
neither regimen is pangenotypic.
SOF-based regimens are currently the most widely prescribed treatments for HCV infection. 
Despite the lack of dosing recommendations for subjects with severe renal impairment in the 
prescribing information for SOF-based regimens, it is apparent from the number of publications 
of small cohort studies describing treatment of subjects with severe renal impairment with 
SOF-based regimens that such treatment is not uncommon {Bhamidimarri 2015, Desnoyer 2016, 
Hundemer 2015, Navarro-Millan 2013, Nazario 2016}. The simplicity of SOF-based dosing 
regimens, relative lack of drug-drug interactions, and absence of a requirement for baseline 
NS5A polymorphism testing or RBV use makes SOF-based regimens a viable option for 
physicians, even when considering the lack of dosing recommendations in this population. 
The unmet medical need of the population and the ongoing off-label use of SOF-based regimens 
provide a strong rationale for the conduct of this study as the data obtained will address the gaps 
in knowledge regarding the use of SOF-based regimens in subjects with HCV infection who are 
on dialysis for ESRD.
Rationale for Dose Selection of LDV/SOF
1.4.
Subjects in this study will be administered LDV/SOF, a co-formulation of LDV 90 mg and SOF 
400 mg that is approved in the US, EU, and other regions as Harvoni® for the treatment of HCV 
infection in adults. The treatment durations evaluated are aligned with those outlined for 
RBV-free treatment in the EU prescribing information for subjects without cirrhosis or with 
compensated cirrhosis; specifically

Subjects who are treatment naïve and without cirrhosis; LDV/SOF for 8 weeks

Subjects who are treatment experienced and without cirrhosis: LDV/SOF for 12 Weeks

Subjects who have compensated cirrhosis: LDV/SOF for 24 weeks
The results of a Phase 1 single dose study of LDV in subjects with severe renal impairment 
indicates that no relevant differences in LDV exposure were observed between subjects with 
normal renal function and subjects with severe renal impairment. In a Phase 1 study of the PK of 
SOF in subjects with renal impairment, the SOF and GS-331007 AUC were 171% and 451% 
higher, respectively, in subjects with severe renal impairment compared to subjects with normal 
renal function. In subjects with ESRD, SOF and GS-331007 AUC was 28-60% and 1280-2070% 
higher, respectively, compared to subjects with normal renal function.


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Available data from the Study GS-US-334-0154 indicates that administration of SOF 400 mg 
with RBV 200 mg for 24 weeks in subjects with severe renal impairment was well tolerated with 
no specific safety signal associated with the elevated exposures of SOF or the predominant 
metabolite GS-331007. The exposures of SOF and GS-331007 in the GS-US-334-0154 study are
consistent with the results of the Phase 1 study of SOF in subjects with severe renal impairment 
or ESRD. Preliminary data from the GS-US-334-0154 study suggests that the administration of 
LDV/SOF (90/400 mg) for 12 weeks is well tolerated and is more efficacious that administration 
of SOF 200 mg or 400 mg with RBV 200 mg for 24 weeks. 
Based on these data, the approved dose of LDV/SOF will be evaluated in this study. Refer to the 
LDV/SOF IB for additional information.
Risk/Benefit Assessment for the Study
1.5.
This study will provide data of the safety and efficacy of LDV/SOF in subjects with ESRD on 
dialysis. It is anticipated that these data will support dosing recommendations for LDV/SOF in 
subjects with severe renal impairment and subjects with ESRD on dialysis.
The potential benefits of LDV/SOF over the currently available treatment options are:

LDV/SOF has broad antiviral activity against a range of HCV genotypes; it is currently 
approved in the US and EU for the treatment of genotypes 1, 3 (EU only), 4, 5, and 6 HCV 
infection. LDV/SOF may therefore provide a treatment option for a broader range of HCV 
infected subjects with severe renal impairment and ESRD on dialysis than the currently 
available treatment options which are restricted to the treatment of genotype 1 and 4 HCV 
infections.

LDV/SOF will provide a highly effective and well-tolerated RBV-free treatment option for 
subjects on dialysis. As RBV-associated toxicities can be exacerbated in subjects with severe 
renal impairment, the availability of a RBV-free treatment option will enable a greater 
proportion of subjects with ESRD to be treated. 

The components of LDV/SOF have limited drug-drug interaction potential with medications 
commonly prescribed to subjects with severe renal impairment or ESRD on dialysis. This 
should reduce the complexity of patient management compared with the use of other antiviral 
treatments.
The risks associated with the evaluations of LDV/SOF in subjects with ESRD on dialysis are 
associated with concerns about the high exposure of the predominant SOF metabolite, 
GS-331007, in subjects with renal impairment and the limited data on the safety and efficacy of 
LDV/SOF in subjects with renal impairment. In non-clinical studies, GS-331007 exposure 
similar to that projected for patients with ESRD administered LDV/SOF resulted in decreased 
red cells counts (See Section 1.2.3).


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These risks are mitigated by the following:

Approximately 5000 subjects have been administered LDV/SOF with or without RBV to 
date.

During the conduct of the study, hematologic assessments will be performed routinely and 
results will be reviewed by the investigator and sponsor. 

During the conduct of the study, a Data Monitoring Committee (DMC) will evaluate safety 
data in the study after the first n=12 subjects have completed 8 weeks of treatment, or early 
termination (ET), and then every 3 months until the last subject enrolled completes treatment 
with study drugs. Furthermore, the Sponsor and the Investigators will perform ongoing safety 
reviews throughout the study.
Given the medical need for a well-tolerated, highly effective, RBV-free treatment options for 
HCV infected subjects with ESRD on dialysis; the benefit/risk assessment of this study favors 
the conduct of the study.
Compliance
1.6.
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are as follows:

To evaluate the antiviral efficacy of treatment with LDV/SOF for 8,12, or 24 weeks in 
subjects with chronic hepatitis C virus (HCV) infection who are on dialysis for ESRD, as 
measured by the proportion of subjects with sustained viral response 12 weeks after cessation 
of treatment (SVR12)

To evaluate the safety and tolerability of each treatment regimen
The secondary objectives of this study are as follows: 

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
each study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of LDV and SOF, and its metabolites in 
subjects who are on dialysis for ESRD
The exploratory objectives of this study are:
CCI


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3.
STUDY DESIGN
Study Design
3.1.
This is a multicenter, open-label Phase 2 study that will evaluate the safety, tolerability, and 
antiviral efficacy of LDV/SOF in subjects on dialysis for ESRD with genotype 1, 4, 5, or 6 HCV 
infection.
Visit Schedule
3.2.
Screening assessments will be completed within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for extenuating circumstances with Sponsor approval.
All subjects will complete the following study visits: Screening, Day 1, on-treatment visits at the 
end of Weeks 2, 4, 6, and 8. Subjects in group 2 and 3 will also complete a Week 12 visit, and 
subjects in group 3 only, will also complete visit at Weeks 16, 20, and 24. All subjects will 
complete posttreatment visits at Weeks 4 and 12, after completion of treatment. Subjects who 
achieve SVR12 will also complete the posttreatment Week 24 visit.
Duration of Treatment
3.3.
Approximately 100 subjects will be enrolled to one of 3 groups and will receive treatment with 
LDV/SOF for 8, 12, or 24 weeks. The treatment group to which subjects are assigned will be 
determined by genotype, the absence or presence of cirrhosis and whether the subject is 
treatment naïve or treatment experienced. 
Group 1:
Treatment naïve genotype 1 subjects without cirrhosis will be treated with LDV/SOF 
for 8 weeks
Group 2:
Treatment experienced genotype 1 subjects and treatment naïve or treatment 
experienced genotype 4, 5, and 6 subjects without cirrhosis will be treated with 
LDV/SOF for 12 weeks
Group 3:
Subjects with compensated cirrhosis will be treated with LDV/SOF for 24 weeks
The total time to complete all study visits is up to a maximum of 52 weeks depending on the 
treatment duration (54 weeks for those requiring an extension of the screening period):

28 days (4 weeks) screening period (or 42 days for extenuating circumstances)

8, 12, or 24 week study treatment period

24 week posttreatment period


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Stopping Rules and Discontinuation Criteria
3.4.
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 (Section 6.4). If this is not possible or acceptable to the
subject or Investigator, the subject may be withdrawn from the study.
There is no option for LDV/SOF dose reduction due to toxicity. If LDV/SOF is withheld due to 
toxicity, the subject must discontinue treatment and complete an ET visit.
For subjects who have completed an ET visit, the posttreatment Week 4 and 12 visits will be
scheduled after last dose of any of the study drug. Subjects who achieve SVR12 (HCV RNA 
< LLOQ at posttreatment Week 12) will complete the posttreatment Week 24 visit.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
Study drug(s) must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 3.4.1) or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study-specific procedures or is considered 
to not be in the subject’s best interest

Virologic failure (as defined in Section 3.4.2)

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 determine 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, regulatory agency or an Institutional
Review Board (IRB)/Independent Ethics Committee (IEC)
3.4.1.
Toxicity-Based Stopping Criteria
Subjects who meet any of the following laboratory or adverse event criteria must stop treatment 
with LDV/SOF:

Elevation of ALT and/or AST above the upper limit of normal and > 5x Day 1 or nadir, 
confirmed by immediate repeat testing

Elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by immediate repeat 
testing


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
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 assessed as related to LDV/SOF
3.4.2.
Virologic Response Base Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from on-treatment nadir

HCV RNA ≥LLOQ at Week 8
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after
an initial observation indicating virologic failure during the on-treatment phase. All subjects who 
terminate treatment early will complete the ET visit and posttreatment Week 4 and 12 visits.
HIV Virologic Rebound Criteria
3.5.
Subjects who have at least two consecutive post-baseline visit plasma HIV-1 RNA levels 
≥400 copies/mL (at least two weeks apart) will be considered to have HIV virologic rebound. 
Following an initial HIV-1 RNA result of ≥ 400 copies/mL, subjects will continue to take their 
current ARV regimen and be asked to return to the clinic after 2 weeks for a scheduled or 
unscheduled blood draw for confirmation of HIV virologic rebound. If HIV virologic rebound is 
confirmed at the scheduled or unscheduled visit, the blood samples from this visit will be used 
for HIV-1 genotype/phenotype testing. If no resistance to the subject’s current ARV regimen is 
detected, the subject may continue on the current ARV regimen.  
HCV study drug should be continued unless safety events warrant the discontinuation of the 
study drug, as outlined is Section 3.4 of the protocol.
Please refer to Figure 3-1 for the management of subjects who meet the criteria for HIV virologic 
rebound.


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Figure 3-1.
HIV Virologic Rebound Schema
a
HCV study drug should be continued unless safety events warrant the discontinuation of these study drugs, as outlined in
Section 3.4 of the protocol
b
If virologic rebound is not confirmed, the subject should remain on their current ARV regimen.
c
If virologic rebound is confirmed, the HIV-1 genotype and phenotype (reverse transcriptase and protease) should be 
analyzed. Based on the results of the genotype and phenotype assays, the subject may remain on their ARV regimen or a 
new ARV regimen may be configured at the discretion of the Investigator. If the genotype and/or phenotype assay fails to 
provide results, a new ARV regimen may be configured at the discretion of the Investigator in consultation with the Medical
Monitor.
HIV-1 RNA ≥ 400 copies/mL
Continue current ARV regimen and return for 
scheduled/unscheduled (at least 2 weeks apart) HIV-1 
RNA and potential genotype/phenotype samplinga
HIV-1 genotype/phenotype
Unconfirmed 
virologic rebound: 
remain on current 
regimenb
Confirmed virologic reboundc
If no resistance to the subject’s current 
ARV regimen is detected, may 
continue on current ARV regimen
Study Period
(On-Treatment)
If resistance to the subject’s current 
ARV regimen is detected, 
discontinue and construct a new 
ARV regimen
 
 
 
 


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3.6. 
3.6.1. 
I 
3.6.2. 
Biomarker Testing 
3.7. 
3.7.1. 
Samples for Optional Future Research 
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4.
SUBJECT POPULATION
Approximately 100 subjects will be enrolled in this study. In order to manage the total study 
enrollment, Gilead Sciences, Inc., at its discretion, may suspend screening and/or enrollment at 
any site or study-wide at any time.
Inclusion Criteria
4.1.
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to provide written informed consent
2) Male or female age ≥ 18 years
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ LLOQ at screening
5) Genotype 1,4, 5, and 6 HCV as determined at Screening
6) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or hemodialysis (HD)
7) The most recent HCV treatment must have been completed at least 8 weeks prior to screening
8) Subjects must have a determination of treatment experience (treatment naïve vs. treatment 
experienced). Treatment naïve is defined as having never been exposed to an approved or 
experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with 
interferon or ribavirin. All other subjects will be considered treatment experienced.
9) Subjects must have appropriate testing for determination of cirrhosis status.
a) Presence of cirrhosis is defined as any one of the following:
i)
Fibroscan with a result of > 12.5 kPa 
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≥ 0.75 
at screening
b) Absence of cirrhosis is defined as any one of the following:
i)
Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest ® score < 0.75 at 
screening


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10) Liver imaging within 6 months of Baseline/Day 1 is required in cirrhotic subjects only, to 
exclude HCC
11) Subjects with HIV-1 coinfection may be eligible, provided they satisfy these additional 
inclusion criteria:
i)
Completed at least 3 months of any prior HIV ARV therapy and maintained HIV 
RNA<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 50 ≥copies/mL) 
and CD4 T-cell count > 100 cells/mm3 prior to Screening. Subjects with an isolated or 
unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ 
is 50≥ copies/mL) are not excluded
ii) On a stable ARV regimen for ≥ 8 weeks prior to Screening and is expected to continue 
the current ARV regimen through the end of study (See exclusion criteria 16). 
12) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal).
13) 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.
14) Lactating females must agree to discontinue nursing before the study drug is administered.
15) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments
Exclusion Criteria
4.2.
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 (other than HCV, HIV and kidney disease or co-morbidities 
associated with ESRD except as noted below) any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol; subjects 
currently under evaluation for a potentially clinically significant illness (other than HCV
or ESRD) are also excluded.
b) Current or prior history of significant cardiac disease including or resulting in: 

Hospital admission for significant cardiovascular disease (myocardial infarction, 
unstable angina, heart failure, hypertensive emergency) or has had a cardiovascular 
procedure (e.g. CABG or PTCA), within 6 months of Screening

Cardiomyopathy with ejection fraction <50%


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c) Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug.
d) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
e) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
f)
Solid organ transplantation other than failed kidney transplants (current use of ≤5 mg/day 
of prednisone, or equivalent dose of corticosteroid, allowed).
g) Significant pulmonary disease
h) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 2 years.
i)
Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under 
evaluation for possible malignancy are not eligible
2) Screening ECG with clinically significant abnormalities
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
4) Opportunistic infection (Appendix 5) within 6 months prior to Screening
5) Infection (other than HIV or HCV) requiring parenteral therapy within 30 days prior to 
baseline.
6) Life threatening SAE during the screening period
7) Subjects have the following laboratory parameters at screening:
a) ALT > 10 X the upper limit of normal (ULN)
b) AST > 10 X ULN
c) Direct bilirubin > 1.5 X ULN. For subjects receiving ritonavir boosted atazanavir 
regimen, a direct bilirubin > 1.5 x ULN will be allowed if < 25% of the total bilirubin
d) Platelets < 25,000/μL
e) HbA1c > 9%
f)
Hemoglobin < 9 g/dL


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g) Albumin < 2.8 g/dL
h) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
i)
Hepatitis B surface antigen positive
8) Prior exposure to any HCV NS5A inhibitor.
9) Male with pregnant female partner.
10) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the 
course of the study and up to 30 days of the last dose of study drug
11) Males who may wish to donate sperm during the course of the study until at least 30 days 
after the last dose of study drug.
12) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
13) Use of any prohibited concomitant medications as described in Section 5.4.
14) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
15) Known hypersensitivity to LDV, SOF, the metabolites, or formulation excipient.
16) For subjects with HIV-1 coinfection only:

HIV-1 RNA >50 copies/mL

CD4 T-cell count <100 cells/mm3

HIV-2 positive test


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
Randomization, Blinding and Treatment Codes
5.1.
This is an open-label study. An Interactive Web Response System (IWRS) will be employed to
manage subject enrolment and the study drug dispensing as well as re-supply of study drug.
Description and Handling of LDV/SOF FDC
5.2.
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.
Packaging and Labeling
LDV/SOF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. Each
bottle contains either 28 or 30 tablets, a silica gel desiccant canister and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with 
an induction-sealed, aluminum-faced liner.
All LDV/SOF FDC bottles to be distributed to centers in the EU, North America and 
Asia Pacific shall be labelled to meet all applicable requirements of the US Food and Drug 
Administration (FDA), Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products and local regulations as applicable.
5.2.3.
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).
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.
Sufficient quantities of LDV/SOF FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Clinical Supply Management Team (or its 
designee).


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5.3. 
Dosage and Administration of LDV /SOF FDC 
LDV /SOF FDC tablet is to be administered once dail with or without food. 
Final 
Amendment 3.0 
For a missed dose ofLDV/SOF FDC tablet, subjects should be instructed to take the missed dose 
of study drng as soon as possible during the same day. Subjects should be cautioned never to 
double the next dose with a missed dose of study drng under any circumstances. 
Study chugs should not be cut or split. LDV/SOF tablets will be provided by Gilead Sciences for 
all subjects. 
5.4. 
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 drng, need to be recorded in the source documents and elech'onic case 
repo1i fonn(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 ti·eatinent: 
• 
Granulocyte colony stimulating factors (GCSF) and thrombopoietin (TPO) mimetics 
• 
Investigational agents or devices for any indication 
• 
Chronic use of systemic immunosuppressants including, but not limited to, co1iicosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathiop1ine, or monoclonal 
antibodies (e.g., infliximab. 
Concomitant use of ce1iain medications or herbaVnatural supplements (inhibitors or inducers of 
dmg ti·anspo1iers, i.e., BCRP and P-gp) with study ch11g may result in PK interactions resulting 
in increases or decreases in exposure of study chug. 
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of ti·eatinent; 
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 ti·eatinent are listed below in Table 5-1. 
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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, 
H2-Receptor Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronec
Digoxind
Herbal/Natural Supplementsb
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorse
Rosuvastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to
famotidine 40 mg twice daily. Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF. Proton-pump inhibitors should not be taken before LDV/SOF. 
b
May result in a decrease in the concentrations of study drug.
c
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment. 
d
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when co-administered with LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin. Monitor for signs and symptoms of 
muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (e.g., active cancer) are not listed 
under this Concomitant Medication section and are disallowed in the study.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must
notify Gilead as soon as he/she is aware of the use of the excluded medication.
Accountability for LDV/SOF FDC
5.5.
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgement of receipt of each shipment 
of study drug (quantity and condition). All used and unused study drug dispensed to subjects 
must be returned to the site.


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LDV/SOF FDC accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for information pertaining to study drug return and disposal.


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6_ 
STUDY PROCEDURES 
Final 
Amendment 3.0 
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular f01m in Appendix 2 and described in the text that follows. Additional info1mation is 
provided in the study procedures manual. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
6.1.1. 
6.1.1.1. 
Subject Enrollment and Treatment Assignment 
Pretreatment Assessments 
Screening Visit 
Subjects will be screened within 28 days of the Day 1 visit before enrollment to detennine 
eligibility for paiiicipation in the study. The screening window can be extended up to 42 days for 
subjects requiring additional HCV genotyping (if initial testing is inconclusive) or for 
extenuating circumstances with Sponsor approval. 
The following will be perfo1m ed and documented at screening: 
• 
Obtain written info1med consent 
• 
Detennine inclusion and exclusion eligibility 
• 
Obtain medical histo1y, including: 
-
Detennination of treatment experience (treatment nai've vs. treatment experienced). 
Treatment nai've is defined as having never been exposed to an approved or 
experimental HCV-specific direct acting antiviral agents or prior treatment ofHCV 
with interferon or ribavirin. All other subjects will be considered treatment 
experienced. 
-
Hepatitis C histo1y 
Regimen( s) 
Dates of previous treatment(s) 
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Response to previous treatment (e.g., non-responder, relapse, discontinuation including 
reason)
Renal dialysis history
■
Type: hemodialysis or peritoneal dialysis
■
Date of initiation
■
Stop date (if applicable)
Renal transplant history (if applicable)
■
Date of transplant
■
Date of transplant failure
■
Current immunosuppression

Determine cirrhosis status as defined in Section 4.1.
Record liver biopsy or Fibroscan results (if applicable)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging should be 
performed or confirmed to have been performed within 6 months of screening to exclude 
the presence of HCC

Obtain details of concomitant medications

Perform 12-lead ECG

Complete physical examination including vital signs (resting blood pressure, pulse, 
respiratory rate and temperature), body weight, and height

Pregnancy prevention counseling

Obtain blood samples for tests as listed in Section 6.9.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral genotype and subtype


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HCV antibody, HIV 1/2 antibody, HBV surface antigen (HBsAg), HBV core antibody 
(HBcAb), and HBV surface antibody (HBsAb)
HbA1c
IL28B genotyping
Serum β-hCG pregnancy test for females of childbearing potential only
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
Fibrotest®
Serum drug screen

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after screening for enrollment into the study. The screening window can be 
extended up to 42 days for extenuating circumstances with Sponsor approval.
Retests of Screening labs are permitted only if the initial exclusionary value was either due to a
sample processing error or due to extenuating circumstances such as intercurrent illness.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/eCRF). 
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history CRF/eCRF. 
See Section 7 Adverse Events and Toxicity Management for additional details.
Day 1 Assessments
6.2.
The following baseline tests and procedures must be completed prior to enrollment and
dosing/dispensation of study drug:

Confirm eligibility (See Sections 4.1 & 4.2)

Perform complete physical examination, including vital signs and body weight

Perform 12-lead ECG (prior to study drug administration)

Assessment of AEs and concomitant medications

Pregnancy prevention counselling 


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
Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing/phenotyping
Serum β-hCG pregnancy test for females of childbearing potential only
HIV-1 RNA and CD4 cell count will only be collected and analyzed for co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)

Pharmacogenomic sample (for subjects who have consented). May be collected at a 
subsequent visit if necessary.

Study Drug Administration
Dispense study drug as directed by the IWRS
Instruct the subject on the packaging, storage and administration of the study drugs
Observe the subject taking the first dose of study drug and record the time of first dose
and whether it was taken with or without food.
Treatment Assessments
6.3.
6.3.1.
Week 2 (± 3 days): Group 1, 2, and 3
The following procedures/assessments are to be completed at the end of Week 2:

Obtain vital signs

Assessment of AEs and concomitant medications
CCI


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
Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample

Assess adherence with study drug dosing regimen including pill count
6.3.2.
Week 4 (± 3 days): Group 1, 2, and 3
The following procedures/assessments are to be completed at the end of Week 4:

Obtain vital signs

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample
Serum β-hCG pregnancy test for females of childbearing potential only
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS


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6.3.3.
Week 6 (± 3 days): Group 1, 2, and 3
The following procedures/assessments are to be completed at the end of Week 6:

Obtain vital signs 

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample
Intensive PK (for subjects who have consented)
Hemodialysis PK (for subjects who have consented)

Assess adherence with study drug dosing regimen including pill count
6.3.4.
Week 8 (± 3 days): Group 2 and 3 (For Group 1 Week 8, see End of 
Treatment Visit)
The following procedures/assessments are to be completed at the end of Week 8 for 
Groups 2 and 3 only:

Obtain vital signs 

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping


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Sparse PK sample
Serum β-hCG pregnancy test for females of childbearing potential only
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)
Intensive PK (for subjects who have consented)
Hemodialysis PK (for subjects who have consented)

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS 
6.3.5.
Week 12, 16, and 20 (± 3 days): Group 3 (For Group 2 Week 12, see End of 
Treatment Visit)
The following procedures/assessments are to be completed at the end of Week 12, 16, and 20 for 
Group 3 only:

Obtain vital signs 

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)
Sparse PK sample


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Serum β-hCG pregnancy test for females of childbearing potential only
Week 12 only: Intensive PK (for subjects who have consented)
Week 12 only: Hemodialysis PK (for subjects who have consented)

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS
6.3.6.
End of Treatment Visit: Group 1 Week 8 (± 3 days), Group 2 Week 12 
(± 3 days), Group 3 Week 24 (± 3 days) or Early Termination (ET)
The following procedures/assessments are to be completed at the end of Week 24/ET:

Perform complete physical examination, including vital signs and body weight

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing/phenotyping
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)
Sparse PK sample
Serum β-hCG pregnancy test for females of childbearing potential only


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
Group 1, Week 8: Intensive PK (for subjects who have consented)
Group 1, Week 8: Hemodialysis PK (for subjects who have consented)
Group 2, Week12: Intensive PK (for subjects who have consented)
Group 2, Week 12: Hemodialysis PK (for subjects who have consented)

Assess adherence with study drug dosing regimen including pill count

Subjects should return all bottles of study drug 
Post-treatment Assessments
6.4.
6.4.1.
Posttreatment Week 4 Visit (± 5 days): Group 1, Group 2, and Group 3
The following procedures/assessments are to be completed at Posttreatment Week 4:

Perform complete physical examination, including vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counselling

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (only in subjects who are HBcAb+ at Screening)
Serum β-hCG pregnancy test for females of childbearing potential only
CCI


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6.4.2.
Posttreatment Week 12 Visit (± 5 days): Group 1, Group 2 and Group 3
The following procedures/assessments are to be completed at Posttreatment Week 12 and 24:

Perform complete physical examination, including vital signs

Assessment of SAEs 

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI 

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
HBV DNA (only in subjects who are HBcAb+ at Screening)
Viral sequencing/phenotyping
6.4.3.
Posttreatment Week 24 Visit (±5 Days): Only for Subjects who Achieved 
SVR12
The following procedures/assessments are to be completed at Posttreatment Week 24:

Perform complete physical examination, including vital signs

Assessment of SAEs 

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
HBV DNA (only in subjects who are HBcAb+ at Screening)
Viral sequencing/phenotyping


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Early Termination (ET)
6.5.
For subjects who have completed an ET visit, the posttreatment Week 4 and 12 follow-up visits 
will be scheduled after last dose of any of the study drug. Subjects who achieve SVR12 
(HCV RNA < LLOQ at posttreatment Week 12) will complete the posttreatment Week 24 visit.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 3.4, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
Unscheduled Visit
6.6.
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 HCV or HIV virologic failure and a sample for 
HCV or HIV viral sequencing/phenotyping must be collected.
End of Study
6.7.
The end of study will occur at the posttreatment Week 24 visit.
Discontinuation from study drug dosing and discontinuation from the overall study, including the
Posttreatment period, will be collected as two separate events.
Post Study Care
6.8.
No post study ongoing care will be provided.
Procedures and Specifications
6.9.
6.9.1.
Clinical Laboratory Analytes
Hematology:
Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC),
white blood cell count (WBC) with differential (absolute and percentage) 
including lymphocytes, monocytes, neutrophils, eosinophils, basophils, 
reticulocyte count and mean corpuscular volume (MCV).
Coagulation:
INR, Prothrombin time (PT), Activated partial thromboplastin time
(APTT)


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Chemistry:
Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), albumin, alkaline phosphatase, creatinine, total bilirubin,
direct bilirubin; glucose, potassium, and sodium. Fibrotest® will be done at 
screening only.
Virological Tests:
Serologies for HCV and HBV (HBsAg, HBsAb, and HBcAb). HBV DNA 
(only in subjects who are HBcAb+ at Screening). Serology testing for HIV 
(including reflex testing as necessary), HCV RNA will be measured using 
the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use 
with the High Pure System, HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype, INNO-LiPA 
2.0 Assay. HIV-1 RNA will be measured using the AmpliPrep/COBAS®
TaqMan® HIV-1 Test, v2.0. If HIV-1 virologic rebound is confirmed, 
HIV-1 genotype/phenotype will be determined using the PhenoSense™
Integrase HIV, GeneSeq™ Integrase HIV, PhenoSense™ HIV, GenoSure 
MG, GeneSeq™ HIV, and PhenoSense GT™. 
Gilead reserves the right to use alternate assays for HCV RNA, HIV RNA, 
HCV genotype, and HIV-1 genotype/phenotype should the above assays 
become unavailable or the results 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 alternate assays for IL28B 
determination should the above assay become unavailable.
Pregnancy Tests:
Serum β-hCG
Additional Tests:
Serum drug screen (for amphetamines, cocaine, methadone, opiates), 
HbA1c, CD4 T-lymphocyte (absolute count and %)
6.9.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether
condition(s) is currently ongoing, and medication history will be collected on all subjects during
screening. Obtain HCV treatment, renal dialysis, and kidney transplant history as per Section 4.
6.9.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue;
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails;
musculoskeletal; neurological.


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6.9.4.
Height & Weight Measurement
Height will be collected at Screening. Weight measurement will be collected at Screening, Day 1 
and Week 8 (Group 1), Week 12 (Group 2), Week 24 (Group 3) or ET visits
6.9.5.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature and will be conducted pre-dose as outlined in Appendix Table 1, 
Appendix Table 2 and Appendix Table 3.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.9.6.
Body Mass Index (BMI)
BMI is calculated by the following equation:
BMI=
weight (pounds)
or
Weight in kilograms
(height in inches)2
(height in meters)2
6.9.7.
12-Lead ECG
Subjects will be required to rest in a supine position for ≥5 minutes prior to making a recording.
The Investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. End of treatment or ET results will be compared to the 
subject’s Day 1 ECG as part of routine safety monitoring.
6.9.8.
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) which will be 
completed by subjects at Day 1, and at the on-treatment Week 8 (Group 1), Week 12 (Group 2), 
Week 24 (Group 3) visits, ET (if applicable), and posttreatment Week 12 visit.
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.


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6.9.9. 
Viral Sequencing/Phenotyping (Archive) 
Final 
Amendment 3.0 
Plasma samples will be collected at Day 1 and each subsequent visit for HCV or HIV viral 
sequence and phenotyping analysis. At any unscheduled visit initiated for the purpose of 
confinning HCV virologic breakthrough, HCV viral sequencing/phenotype plasma sample must 
also be collected. Unused samples may be archived. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.9.10. 
Sparse PK Sample 
Sparse PK blood samples will be collected for all subjects at each on-treatment visit and archived 
for PK analysis ofLDV and SOF (and metabolites). 
The exact time of the dose taken prior to collection of the PK sample, the exact time the PK 
sample is drawn, the exact time of completion of last dialysis, and the type of dialysis (peritoneal 
or hemodialysis) will be recorded in source documents and eCRFs. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.9.11. 
I 
6.9.12. 
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6.9.13. 
Pharmacogenomics Testing 
Final 
Amendment 3.0 
For subjects who provide specific and separate consent to paiiicipate will allow the Sponsor to 
obtain and test a subject's blood sample taken on Baseline/Day 1 for phan nacogenomics 
discove1y research. If not obtained at Baseline/Da 1, the sam le ma be drawn at an time 
-
Y· 
6.9.14. 
Archive sample 
6.9.15. 
Pregnancy Testing 
All females of childbearing potential will have sernm pregnancy testing eve1y 4 weeks dming the 
dosing period and 30 days after last dose of LDV/SOF, or the last visit of the study, whichever 
comes last. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
7.1.
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 post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures 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 7.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).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.
7.1.4.
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 (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., 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, (e.g., venipuncture).
7.1.5.
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.
Investigator Requirements and Instructions for Reporting Adverse Events 
7.2.
and Serious Adverse Events to Gilead
7.2.1.
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 (CRF/eCRF): all SAEs, and all adverse events related 
to protocol-mandated procedures.
7.2.2.
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 CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.2.3.
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 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study paiiicipation has concluded 
and the event is deemed relevant to the use ofIMP, he/she should promptly document and repo1i 
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. 
7.2.4. 
Electronic Serious Adverse Event ( eSAE) Reporting Process 
Site personnel must record all SAE data in the eCRF database and transmit the SAE infonnation 
to Gilead DSPH within 24 hours of the investigator's knowledge of the event. Detailed 
instrnctions can be found in the eCRF completion guidelines. 
If it is not possible to record and submit the SAE info1m ation electronically, because the eCRF 
database cannot be accessed or is not available (including at study staii), record the SAE on the 
paper serious adverse event repo1i fonn and submit by e-mail or fax within 24 hours of the 
investigator's knowledge of the event to: 
GileadDSPH 
Fax: 
E-mail: 
PPD 
PPU 
As soon as it is possible to do so, any SAE repo1ied via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines. 
If an SAE has been repo1ied via a paper f 01m because the eCRF database has been locked, no 
fmther action is necessaiy. 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, 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 ti·aceability of a document to the subject identifiers. 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1is. 
Any medications necessa1y for ti·eatinent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
f01m . 
7.3. 
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 countiy-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulato1y agencies reports of SAEs, serious adverse drng reactions (SADRs), or 
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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. 
Toxicity Management 
7.4.
7.4.1.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.
Special Situations Reports
7.5.
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE,
pregnancy reports regardless of an associated AE, and an AE in an infant following exposure 
from breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.


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7.5.2. 
7.5.2.1. 
Instructions for Reporting Special Situations 
Instiuctions for Repo1iing Pregnancies 
Final 
Amendment 3.0 
The investigator should repo1i pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drng follow-up 
period, to Gilead DSPH using the pregnancy repo1i fo1m within 24 hours of becoming aware of 
the pregnancy. 
Refer to Section 7 .2 and the eCRF completion guidelines for full instiuctions on the mechanism 
of pregnancy repo1iing. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to te1minate a 
pregnancy without medical reasons. 
Any premature te1mination of pregnancy (e.g., a spontaneous abo1iion, an induced therapeutic 
abo1iion due to complications or other medical reasons) must be repo1ied within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE te1m. 
A spontaneous abo1iion is always considered to be an SAE and will be repo1ied as described in 
Sections 7 .1.1 and 7 .1.2. Fmthennore, any SAE occun ing as an adverse pregnancy outcome post 
study must be repo1ied to Gilead DSPH. 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be repo1ied to Gilead DSPH using the pregnancy outcome repo1i 
fo1m. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be repo1ied directly to Gilead DSPH. 
Gilead DSPH contact infonnation is as follows: 
Email: 
IPIPD 
Fax: 
IPIPD 
Pregnancies of female paiiners of male study subjects exposed to Gilead or other study diugs 
must also be repo1ied and relevant info1mation should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome fo1ms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be repo1ied directly to Gilead DSPH. 
Email: 
IPIPD 
Fax: 
IPIPD 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbeai·ing Potential, 
and Contl'aceptive Requirements. 
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7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded 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 do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.5 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
Analysis Objectives and Endpoints
8.1.
8.1.1.
Analysis Objectives
The primary objectives of this study are as follows:

To evaluate the antiviral efficacy of treatment with ledipasvir/sofosbuvir (LDV/SOF) for 
8, 12 or 24 weeks in subjects as measured by the proportion of subjects with sustained viral 
response 12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability of each treatment regimen
The secondary objectives of this study are as follows: 

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
each study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of LDV and SOF and its metabolites in 
subjects who are on dialysis for ESRD
The exploratory objectives of this study are:
8.1.2.
Primary Endpoint
The primary end point is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of treatment) in 
the Full Analysis Set (FAS) population.
The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
CCI


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8.1.3.
Secondary Endpoint
Secondary endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

The proportion of subjects with HCV RNA < LLOQ on treatment

HCV RNA change from Baseline/Day 1

The proportion of subjects with virologic failure

The proportion of subjects who develop viral resistance to LDV and SOF during treatment 
and after cessation of treatment

The steady-state pharmacokinetics of LDV and SOF and its metabolites
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include effect of treatment with LDV/SOF on HRQoL 
endpoints.
Analysis Conventions
8.2.
All individual subject data will be listed as measured. All statistical summaries and analyses will
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study are LDV/SOF. Last dose of study drug will be used in the 
definition of treatment emergent AEs and laboratory abnormalities as well as the efficacy 
endpoints of SVR at various posttreatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis will be the FAS, which includes all enrolled 
subjects who took at least 1 dose of study drug.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes 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 date 
of the study drug through the last dose date of study drug plus 30 days.


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8.2.1.3. 
Phaimacokinetics 
Final 
Amendment 3.0 
The PK Analysis Set includes all subjects who took at least 1 dose of the study drng and have at 
least 1 nonmissing postdose concentration value for the conesponding analyte in plasma. The 
analytes of interest may include LDV and SOF (and its metabolites GS-566500 and GS-331007). 
8.2.1.3.1. 
8.2.1.3.2. 
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 ai·e "< 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 ai·e "< 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 te1med a bracketed success; othe1wise, the data point will 
be te1med a bracketed failme (i.e.,~ LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be te1med a failure (i.e.,~ LLOQ detected) except for 
SVR24, which will be imputed according to the SVR12 status. Success for SVR12 who have no 
fmther HCV RNA measmements collected will be counted as a success for SVR24 due to the 
high conelation between these 2 endpoints. 
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Where appropriate, safety data for subjects who 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 the summary statistics for that time point. If the 
subject is missing a predose value, then the subject will be excluded from the calculation of 
the summary statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the Baseline/Day 1 value will be assumed to be normal 
(i.e., no grade [Grade 0]) for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Baseline/Day 1 result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for the 
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).
For PK plasma/blood concentrations and analysis of PK parameters natural logarithmic 
transformation will be used. For the intensive PK samples, plasma concentration values that are 
below the lower limit of quantitation (BLQ) will be presented as “BLQ” in the concentration 
data listing. Values that are BLQ will be treated as 0 at predose time points, and one-half the 
value of the lower limit of quantitation (LLOQ) at postbaseline time points, where LLOQ is 
corrected for the dilution factor (i.e., reported LLOQ/dilution factor) for determination of 
summary and order statistics. 
For the presentation of summary and order statistics, if at least 1 subject has a concentration 
value of BLQ for the time point, then the minimum value will be displayed as “BLQ”. If more 
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the 
minimum and Q1 values will be displayed as “BLQ”. If more than 50% of the subjects have a 
concentration data value of BLQ for a given time point, then the minimum, Q1, and median 
values will be displayed as “BLQ”. If more than 75% of the subjects have a concentration data 
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be 
displayed as “BLQ”. If all subjects have concentration data values of BLQ for a given time point, 
then all order statistics (minimum, Q1, median, Q3, and maximum) and summary statistics will 
be displayed as “BLQ”.


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8.4. 
Demographic Data and Baseline Characteristics 
Final 
Amendment 3.0 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by ti·eatment group and overall. 
Demographic summaries will include sex, self-identified race/ethnicity, and age. 
Baseline data will include a summaiy of body mass index, HCV RNA level (logl 0 IU/mL), 
genotype and subtype of HCV infection, IL28B genotype, and additional endpoint as necessaiy. 
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
The primaiy endpoint is SVR12 in the Full Analysis Set (FAS) population. 
In the primaiy efficacy analysis, the point estimate and the 2-sided 95% exact confidence 
interval of SVR12 rate will be provided for the overall FAS population and by ti·eatment group. 
8.5.2. 
Secondary Analyses 
The propo1tion of subjects with HCV RNA below the LLOQ over time (including SVR 
endpoints) will be presented by ti·eatment group in tabulai· and graphical fonn. 
Descriptive summai·ies and listings will be provided for additional efficacy evaluations of the 
propo1tion of subjects who experience virologic failure, HCV RNA actual values and change 
from baseline. 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborato1y tests (including HIV-1 RNA and 
CD4 T-cell count for HCV/HIV co-infection subjects), physical exaininations, vital signs 
measurements at vai·ious time points during the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study drng administration up to 30 days after 
the last dose of study drng will be summai·ized by ti·eatment group according to the study diug 
received. 
8.6.1. 
Extent of Exposure 
A subject's extent of exposure to study drng will be generated from the study diu g 
adininisti·ation page of the CRF. Exposure data will be sUIIllnai·ized by ti·eatment group. 
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8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
study drug up to the date of last dose of study drug plus 30 days.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of the study drug

All AEs leading to temporary interruption of the study drug
All AEs collected during the study will be presented in the data listings. 
8.6.3.
Laboratory Evaluations
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3. The incidence of treatment-emergent laboratory abnormalities, defined as values 
that increase by at least one toxicity grade from Baseline/Day 1 at any time postbaseline, up to 
the date of last dose of study drug plus 30 days will be summarized by treatment group.
Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the Baseline/Day 1 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


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8.7. 
Other Safety Evaluations 
Final 
Amendment 3.0 
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abn01malities or descriptive statistical 
summaries (n, mean, SD, median, Ql, Q3, minimum, and maximum), as appropriate. 
8.8. 
Pharmacokinetic Analysis 
In the PK analysis set, plasma concentrations of the study dmg over time will be listed. Details 
of the analysis will be provided in the pha1macokinetic rep01ting and analysis plan. 
8.9. 
Sample Size 
With a sample size of 100 subjects, a 2-sided 95% exact confidence inte1val will extend at the 
most 20% in length. 
8.10. 
Data Monitoring Committee 
An external multidisciplina1y data monitoring committee (DMC) will review the progress of the 
study and perf01m an interim review of safety data once the first 12 subjects have completed 8 
weeks of treatment, or early te1mination. After the initial meeting, safety reviews will be 
conducted at approximately 3 month inte1vals during the trial until the last emolled subject 
completes study treatment. These safety reviews will alternate between the following: 
• 
A review by the DMC chair of all SAEs and deaths 
• 
A review of safety data by the DMC meeting as specified in the DMC cha1ter 
The DMC will provide recommendation to Gilead on whether the nature, frequency, and severity 
of adverse effects associated with study treatment wauant the early te1mination of the study in 
the best interests of the pa1ticipants, whether the study should continue as planned, or the study 
should continue with modifications. The DMC may also provide recommendations as needed 
regarding study design, conduct, and the need for additional meetings or an alternative meeting 
schedule. The DMC's specific activities will be defined by a mutually agreed chaiter, which will 
define the DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regai·ding future conduct of the study, including 
possible early study te1mination, Gilead retains final decision-making authority on all aspects of 
the study. 
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9.
RESPONSIBILITIES
Investigator Responsibilities
9.1.
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject.: These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IECReview and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. 


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


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
Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of 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 (i.e., 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 casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 


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source data verification within the EDC system. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g. data entry error). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock (as 
instructed by Gilead), the investigator will use his/her log in credentials to confirm that the forms 
have been reviewed, and that the entries accurately reflect the information in the source 
documents. At the conclusion of the trial, Gilead will provide the site with a read-only archive 
copy of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, IMP should be destroyed at the site. If the site does not have acceptable
procedures in place for drug destruction, arrangements will be made between the site and Gilead 
Sciences (or Gilead Sciences’ representative) for return of used and unused IMP supplies.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide
appropriate instruction for destruction of unused 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 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.
Refer to the Pharmacy Binder for study drug disposal/return instructions.
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/IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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Amendment 3.0
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Sponsor Responsibilities
9.2.
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/IECs in
accordance with local requirements and receive documented IRB/IECs approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
Joint Investigator/Sponsor Responsibilities
9.3.
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Gilead Sciences, Inc. 
Amendment 3.0
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10.
REFERENCES
AbbVie Inc. VIEKIRA XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release 
tablets, for oral use. US Prescribing Information. North Chicago, IL. Revised 
July.  2016:
Allison RD, Tong X, Moorman AC, Ly KN, Rupp L, Xu F, et al. Increased Incidence of Cancer 
and Cancer-related Mortality Among Persons with Chronic Hepatitis C Infection, 
2006-2010. J Hepatol 2015.
Arias A, Aguilera A, Soriano V, Benitez-Gutierrez L, Lledo G, Navarro D, et al. Rate and 
predictors of treatment failure to all-oral HCV regimens outside clinical trials. 
Antivir Ther 2016.
Bhamidimarri KR, Czul F, Peyton A, Levy C, Hernandez M, Jeffers L, et al. Safety, efficacy and 
tolerability of half-dose sofosbuvir plus simeprevir in treatment of Hepatitis C in 
patients with end stage renal disease. J Hepatol 2015;63 (3):763-5.
Bristol-Myers Squibb. DAKLINZA™ (daclatasvir) tablets, for oral use. US Prescribing 
Information. Princeton, NJ. Revised April.  2016:
Desnoyer A, Pospai D, Le MP, Gervais A, Heurgue-Berlot A, Laradi A, et al. Pharmacokinetics, 
safety and efficacy of a full dose sofosbuvir-based regimen given daily in 
hemodialysis patients with chronic hepatitis C [Article in Press]. J Hepatol 2016.
Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P. The impact of hepatitis C virus 
infection on survival in dialysis patients: meta-analysis of observational studies. J 
Viral Hepat 2007;14 (10):697-703.
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised November 2015a:
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. Revised August 2015b:
Gilead Sciences Inc. EPCLUSA® (sofosbuvir and velpatasvir) tablets, for oral use. US 
Prescribing Information. Foster City, CA. Revised June.  2016:
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype 
distribution of the hepatitis C virus infection. J Hepatol 2014.
Hundemer GL, Sise ME, Wisocky J, Ufere N, Friedman LS, Corey KE, et al. Use of sofosbuvir-
based direct-acting antiviral therapy for hepatitis C viral infection in patients with 
severe renal insufficiency. Infectious diseases 2015;47 (12):924-9.


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Gilead Sciences, Inc. 
Amendment 3.0
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Ioannou GN, Beste LA, Chang MF, Green PK, Lowey E, Tsui JI, et al. Effectiveness of 
Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and 
Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans 
Affairs National Healthcare System [Accepted Manuscript]. Gastroenterology 
2016;151:457-71.
Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the 
prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney 
disease. Kidney international. Supplement 2008 (109):S1-99.
Merck & Co Inc. ZEPATIER™ (elbasvir and grazoprevir) tablets, for oral use. US Prescribing 
Information. Whitehouse Station, NJ. Revised January.  2016:
Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of Hepatitis C 
Virus Infection and the Development of Hepatocellular Carcinoma. Ann Intern 
Med 2013;158 (5 (Part I)).
Navarro-Millan I, Sattui SE, Curtis JR. Systematic review of tumor necrosis factor inhibitor 
discontinuation studies in rheumatoid arthritis. Clin Ther 2013;35 (11):1850-61 
e1.
Nazario HE, Ndungu M, Modi AA. Sofosbuvir and simeprevir in hepatitis C genotype 1-patients 
with end-stage renal disease on haemodialysis or GFR <30 ml/min. Liver Int 
2016;36 (6):798-801.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus 
and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J 
Hepatol 2006;45 (4):529-38.
Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of 
pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic 
hepatitis C. Gastroenterology 2002;122 (5):1303-13.
van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association 
between sustained virological response and all-cause mortality among patients 
with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308 
(24):2584-93.
Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained 
virologic response and clinical outcomes in patients with chronic hepatitis C and 
advanced fibrosis. Ann Intern Med 2007;147 (10):677-84.
World Health Organization (WHO). Hepatitis C Fact Sheet No. 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed 20 June 2014:1-
7.


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Amendment 3.0
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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
Appendix 5.
Opportunistic Infections
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 1
Appendix Table 2.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 2
Appendix Table 3.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 3


LDV/SOF 
Protocol GS-US-337-4063 
Final 
Gilead Sciences, Inc. 
Amendment 3.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir in Subjects with Genotype 1, 4, 5 and 6 Chronic HCV Infection Who are 
on Dialysis for End Stage Renal Disease 
GS-US-337-4063, Amendment 3.0, 02 March 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
[P~D 
_ iP_P_D _
___ _ 
PPD 
Signature 
Medical Monitor 
Date 
..- ,..... 
INVESTIGATOR STATEMENT 
I have read the protocol, incJuding 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 78 
02 March 2017 


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Amendment 3.0
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Appendix 2.
Study Procedures Table
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 1
Screen
Baseline/Day 1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs/SAEb
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
Health-Related Quality of Lifec
X
X
X
Review of Study Medication 
Compliance
X
X
X
X
Study Drug Dispensingd
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
Viral Sequencing/Phenotypinge
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
Intensive PK g, h
Xh
Xh


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Gilead Sciences, Inc. 
Amendment 3.0
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Screen
Baseline/Day 1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8/ET
4
12
24
Hemodialysis PKg, i
Xi
Xi
Serum β-hCG Pregnancy Testj
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping
X
HCV, HIV, HBV Serology
X
HBV DNAk
X
X
X
X
X
X
HbA1c
X
Fibrotest®
X
Archive Samplef
X
X
Pharmacogenomic Samplef
X
CD4 Cell Countl
X
X
X
X
X
HIV-1 RNAl
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
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, 
Week 8, ET (if applicable), and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e.
Plasma samples will be collected for possible viral resistance testing and other virology studies
f
Subjects may opt out of archive/pharmacogenomics sample collection.
g
Only for subjects who have provided consent for this sample and testing. 
h
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6 or 8, 
per investigator discretion.
i
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment group), evaluations 
will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected from both 
the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally, a single blood sample will be collected within 10 minutes after hemodialysis 
concludes.
j
For females of child bearing potential only
k.
Only for subjects who are HBcAb+ at Screening
l
For HIV/HCV co-infected subjects only.


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Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 81
02 March 2017
Appendix Table 2.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 2
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs/SAEb
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
Health-Related Quality of Lifec
X
X
X
Review of Study Medication 
Compliance
X
X
X
X
X
Study Drug Dispensingd
X
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral Sequencing/Phenotypinge
X
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
X
Intensive PK g, h
Xh
Xh
Xh
Hemodialysis PKg, i
Xi
Xi
Xi


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Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 82
02 March 2017
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12/ET
4
12
24
Serum β-hCG Pregnancy Testj
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping 
X
HCV, HIV, HBV Serology
X
HBV DNAk
X
X
X
X
X
X
X
HbA1c 
X
Fibrotest®
X
Archive Samplef
X
X
Pharmacogenomic Samplef
X
CD4 Cell Countl
X
X
X
X
X
X
HIV-1 RNAl
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
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, 
Week 12, ET (if applicable), and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e
Plasma samples will be collected for possible viral resistance testing and other virology studies
f
Subjects may opt out of archive/pharmacogenomics sample collection.
g
Only for subjects who have provided consent for this sample and testing. 
h
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6, 8, or 
12 per investigator discretion.
i
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment regimen),
evaluations will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected 
from both the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally, a single blood sample will be collected within 10 minutes after 
hemodialysis concludes. 
j
For females of child bearing potential
k.
Only for subjects who are HBcAb+ at Screening
l
For HIV/HCV co-infected subjects only.


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 83
02 March 2017
Appendix Table 3.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 3
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12
16
20
24/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs/SAEb
X
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
X
X
X
Health-Related Quality 
of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
X
Study Drug Dispensingd
X
X
X
X
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing/
Phenotypinge
X
X
X
X
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
X
X
X
X
Intensive PK g, h
Xh
Xh
Xh
Hemodialysis PKg, i
Xi
Xi
Xi


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Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 84
02 March 2017
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12
16
20
24/ET
4
12
24
Serum β-hCG
Pregnancy Testj
X
X
X
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B 
Genotyping 
X
HCV, HIV, HBV 
Serology
X
HBV DNAk
X
X
X
X
X
X
X
X
X
X
HbA1c
X
Fibrotest®
X
Archive Samplef
X
X
Pharmacogenomic 
Samplef
X
CD4 Cell Countl
X
X
X
X
X
X
X
X
X
HIV-1 RNAl
X
X
X
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
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, 
Week 24, ET (if applicable), and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e
Plasma samples will be collected for possible viral resistance testing and other virology studies
f
Subjects may opt out of archive/pharmacogenomics sample collection.
g
Only for subjects who have provided consent for this sample and testing. 
h
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6 8, or 
12 per investigator discretion.
i
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment regimen),
evaluations will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected 
from both the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally a single blood sample will be collected within 10 minutes after 
hemodialysis concludes.
j
For females of child bearing potential
k.
Only for subjects who are HBcAb+ at Screening
l
For HIV/HCV co-infected subjects only.


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Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 85
02 March 2017
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL
85 to 100 g/L
7.5 to 8.5 g/dL
75 to 85 g/L
6.5 to 7.5 g/dL
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 86
02 March 2017
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN
1.50 to 3.00 ULN
3.00 ULN
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
# 
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 87
02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L            
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L            
2.0 t o <2.5 mmolL
2.0 mEq/L               
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L            
6.5 to 7.0 mmol/L
7.0 mEq/L               
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 88
02 March 2017
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
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 89
02 March 2017
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


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 90
02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 91
02 March 2017
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
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 92
02 March 2017
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
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 93
02 March 2017
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
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 94
02 March 2017
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
Protocol GS-US-337-4063
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
Page 95
02 March 2017
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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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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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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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 (e.g., 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 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (e.g., 
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 (e.g., 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident
(CVA, stroke) with 
neurological deficit


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities
Sensory alteration or
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure
2–4 seizures
Seizures of any kind that are
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., 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 (e.g., 
severity or focality)
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., 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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Amendment 3.0
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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


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


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


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


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Amendment 3.0
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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 (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of LDV/SOF on pregnant women is limited or not available. There is no suspicion of 
human teratogenicity based on class effects or genotoxic potential. Relevant non clinical 
reproductive toxicity studies for human pregnancy do not indicate a strong suspicion of human 
teratogenicity/fetotoxicity. Data from clinical pharmacokinetic interaction studies of LDV/SOF 
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 
investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to enrollment. Thereafter, a pregnancy 
test will be performed every 4 weeks through the posttreatment Week 4 visit. Female subjects 
must also agree to one of the following from Screening until 30 days of the last dose of 
LDV/SOF


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Amendment 3.0
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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in
addition to a male partner who correctly uses a condom from the date of Screening until 
30 days after the last dose of LDV/SOF. 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal sterilization
Essure® micro-insert system
Vasectomy in the male partner 
Barrier methods
■
Female barriers: Diaphragm with spermicide or cervical cap with spermicide
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms until 30 days after the last dose of LDV/SOF treatment when engaging in intercourse of 
reproductive potential. If their female partner is of childbearing potential (as defined above), 
their female partner must use 1 of the methods of birth control listed above from the date of 
Screening until 30 days after the last dose of LDV/SOF.


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Amendment 3.0
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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 become pregnant at any time during 
the study, or if they become pregnant within 30 days of last dose of LDV/SOF. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.5.2.1.


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Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
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02 March 2017
Appendix 5.
Opportunistic Infections
Non-inclusive list of opportunistic infections base on AIDS-Indicator Conditions from CDC 
Classification System for HIV Infection Clinical Category C:

Bacterial pneumonia, recurrent (two or more episodes in 12 months)

Candidiasis of the bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical carcinoma, invasive, confirmed by biopsy

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month in duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Encephalopathy, HIV-related

Herpes simplex: chronic ulcers (>1 month in duration), or bronchitis, pneumonitis, or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1-month in duration)

Kaposi sarcoma

Lymphoma, Burkitt, immunoblastic, or primary central nervous system

Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or 
extrapulmonary

Mycobacterium tuberculosis, pulmonary or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)

Progressive multifocal leukoencephalopathy (PML)

Salmonella septicemia, recurrent (nontyphoid)

Toxoplasmosis of brain

Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) 
associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or 
chronic weakness and documented fever for ≥1 month

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Multicenter, Open-Label Study to Evaluate the
Efficacy and Safety of Ledipasvir/Sofosbuvir in Subjects with
Genotype 1, 4, 5 and 6 Chronic HCV Infection Who are on
Dialysis for End Stage Renal Disease
Name of Test Drug:
ledipasvir/sofosbuvir (LDV/SOF)
Study Number:
GS-US-337-4063
Protocol Version/Date:
Amendment 3: 02 March 2017
Analysis Type:
SVR12 and Final Analyses
Analysis Plan Version:
Version 1.1
Analysis Plan Date:
06 November 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT-TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1.
DMC Analyses.........................................................................................................................................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 Analysis Set.......................................................................................................9
3.1.2.
Full Analysis Set ....................................................................................................................9
3.1.3.
Safety Analysis Set.................................................................................................................9
3.1.4.
Pharmacokinetic (PK) Analysis Set .......................................................................................9
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Examination of Subject Subsets.............................................................................................................10
3.4.
Missing Data and Outliers......................................................................................................................11
3.4.1.
Missing Data ........................................................................................................................11
3.4.2.
Outliers.................................................................................................................................12
3.5.
Data Handling Conventions and Transformations .................................................................................12
3.6.
Visit Windows........................................................................................................................................13
3.6.1.
Definition of Study Day .......................................................................................................13
3.6.2.
Analysis Windows................................................................................................................14
3.6.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................15
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.....................................................................................................18
4.3.
Protocol Deviations................................................................................................................................19
5.
BASELINE DATA .............................................................................................................................................20
5.1.
Demographics ........................................................................................................................................20
5.2.
Other Baseline Characteristics ...............................................................................................................20
5.3.
Medical History......................................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22
6.1.
Primary Efficacy Endpoint.....................................................................................................................22
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................22
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint ............................................................22


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6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................22
6.2.
Secondary Efficacy Endpoints ...............................................................................................................22
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................22
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................23
6.3.
Exploratory Efficacy Endpoints.............................................................................................................24
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................24
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................24
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................25
7.
SAFETY ANALYSES........................................................................................................................................26
7.1.
Adverse Events and Deaths....................................................................................................................26
7.1.1.
Adverse Event Dictionary ....................................................................................................26
7.1.2.
Adverse Event Severity........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................26
7.1.4.
Serious Adverse Events........................................................................................................26
7.1.5.
Treatment-Emergent Adverse Events...................................................................................26
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................27
7.2.
Laboratory Evaluations ..........................................................................................................................28
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................29
7.2.2.
Graded Laboratory Values ...................................................................................................29
7.3.
Body Weight, Height, and Vital Signs...................................................................................................30
7.4.
Concomitant Medications ......................................................................................................................31
7.5.
Electrocardiogram Results .....................................................................................................................31
7.6.
Other Safety Measures ...........................................................................................................................32
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................32
8.
PHARMACOKINETIC ANALYSES ................................................................................................................33
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
Appendix 1
Schedule of Assessments........................................................................................................38
LIST OF IN-TEXT-TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................15


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
APRI
AST:platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
BPM
beats per minute
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
EOT
end of treatment
ESRD
End Stage Renal Disease
FAS
full analysis set
FDC
fixed-dose combination
FU
follow-up
GT
genotype
HCV
hepatitis C virus
HLGT
high level group term
HLT
high level term
HRQoL
health related quality of life
INR
international normalized ratio of prothrombin time
IWRS
interactive web response system
LDV
ledipasvir
LLOQ
lower limit of quantitation
LLT
lower level term
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
Peg-IFN
pegylated interferon
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan


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SD
standard deviation
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 normal
VF
virologic failure
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-337-4063. This SAP is based on the amended study protocol dated 02 March
2017 and the electronic case report form (eCRF). The SAP will be finalized prior to database 
finalization. Any changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objectives of this study are:

To evaluate the antiviral efficacy of treatment with ledipasvir/sofosbuvir (LDV/SOF) for 8, 
12, or 24 weeks in subjects with chronic hepatitis C virus (HCV) infection who are on 
dialysis for End Stage Renal Disease (ESRD), as measured by the proportion of subjects with 
sustained viral response 12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability of each treatment regimen
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
each study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of LDV and SOF and its metabolites in 
subjects who are on dialysis for (ESRD)
The exploratory objectives of this study are:
CCI


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1.2.
Study Design
This is a multicenter, open-label Phase 2 study that will evaluate the safety, tolerability, and 
antiviral efficacy of LDV/SOF in subjects on dialysis for ESRD with genotype 1, 4, 5, or 6 HCV 
infection.
Approximately 100 subjects with genotype 1, 4, 5, or 6 HCV infection will be enrolled to 1 of 
3 groups and will receive treatment with LDV/SOF for 8, 12, or 24 weeks. The treatment group 
to which subjects are assigned will be determined by genotype, the absence or presence of 
cirrhosis and whether the subject is treatment naïve or treatment experienced.
Group 1: Treatment naïve genotype 1 subjects without cirrhosis will be treated with LDV/SOF 
for 8 weeks
Group 2: Treatment experienced genotype 1 subjects and treatment naïve or treatment 
experienced genotype 4, 5, and 6 subjects without cirrhosis will be treated with LDV/SOF for 
12 weeks
Group 3: Subjects with compensated cirrhosis will be treated with LDV/SOF for 24 weeks
The total time to complete all study visits is approximately 52 weeks (42 weeks for those
requiring extension of the Screening period):

28 days (4 weeks) screening period (or 42 days for extenuating circumstances)

Up to 24 week treatment period

Up to 24 week posttreatment period
The schedule of assessments is provided as an appendix to the SAP (Appendix 1).
1.3.
Sample Size and Power
With a sample size of 100 subjects, a 2-sided 95% exact confidence interval will extend at the
most 20% in length.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of safety data in order to protect subject welfare and 
preserve study integrity. The DMC will recommend to the sponsor whether the nature, 
frequency, and severity of adverse effects associated with study treatment warrant the early 
termination of the study in the best interests of the participants, whether the study should 
continue as planned, or whether the study should continue with modifications.
Reviews will be conducted after the first 12 subjects have completed 12 weeks of treatment, or 
early termination. After the initial meeting, safety reviews will be conducted at approximately 
3 month intervals during the trial until the last enrolled subject completes study treatment. These 
safety reviews will alternate between the following:

A review by the DMC chair of all SAEs and deaths

A review of safety data by the DMC meeting as specified in the DMC charter.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency. 
2.2.
Interim Analysis
2.2.1.
Posttreatment Week 4 Analysis
A posttreatment Week 4 analysis will be conducted for administrative purposes after all subjects 
complete the posttreatment Week 4 visit or prematurely discontinue from study. All safety and 
efficacy data through the posttreatment Week 4 visit will be included. The results will be 
restricted to a limited group of individuals within Gilead. There will be no changes to the study 
design, study conduct, or the sample size as a result of this administrative analysis. 
2.2.2.
Posttreatment Week 12 Analysis
The analysis for the primary efficacy endpoint SVR12 will be conducted when all subjects have 
completed the posttreatment Week 12 visit or have prematurely discontinued from study. All the 
safety and efficacy data through the Posttreatment Week 12 visit will be cleaned, finalized and 
included for the analysis.
2.3.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved, and the 
database has been cleaned and finalized, the final analysis of the data will be performed.


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GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each catego1y will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard enor (SE), median, first 
quaiiile (Ql ), third qua1iile (Q3), minimum, and maximum will be presented. 
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless othe1wise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless othe1wise specified. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
ai·e 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 summai·ized or provided in 
a by-subject listing by genotype. 
3.1.1. 
All Enrolled Analysis Set 
All Enrolled Analysis Set includes all subjects enrolled in the study after screening. Subjects ai·e 
grouped within the All Enrolled Analysis Set by treatment group to which they were enrolled. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes subjects who ai·e enrolled into the study and received at 
least 1 dose of study dmg. Subjects are grouped within the FAS by genotype and treatment group 
to which they were enrolled. 
This is the prima1y 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 dmg. Subjects 
are grouped within the Safety Analysis Set according to the treatment they actually received. 
This is the prima1y analysis set for safety analyses. 
3.1.4. 
Pharmacokinetic (PK) Analysis Set 
The PK Analysis Set includes all subjects who took at least 1 dose of the study dmg and have at 
least 1 nonmissing postdose concentration value for the conesponding analyte in plasma. The 
analytes of interest may include LDV and SOF (and its metabolites GS-566500 and GS-331007). 
3.1.4.1. 
Intensitive PK Substudy Analysis Set 
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3.2. 
Subject Grouping 
Version 1.1 
For analyses based on the All Emolled Analysis Set, FAS, or demographic and baseline 
characteristics tables, subjects will be grouped according to the HCV genotype and treatment 
group. Unless othe1wise specified, groups by genotype including GTla, GTlb, GTl Other, GTl 
total, GT4, GT5, and GT6, Indetenninate, and Total. 
For analyses based on the Safety Analysis Set, subjects will be grouped according to the actual 
treatment received. The actual treatment received is defined as the emolled treatment except for 
subjects who received treatment that differs from the emolled 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. 
Examination of Subject Subsets 
Subject subsets within each genotype will also be explored by baseline characteristics for the 
prima1y efficacy endpoint, SVR12. The baseline characteristics include the following: 
• 
age ( < 65 years, 
65 years) 
• 
sex (male, female) 
• 
cinhosis (presence, absence) 
• 
prior HCV treatment experience (treatment naive, treatment experienced) 
• 
prior HCV treatment for treatment experienced subjects [DAA Naive (Peg-IFN + RBV, 
Other)] 
• 
HCV genotype 
• 
baseline HCV RNA ( < 800,000 IU/mL, 
800,000 IU/mL) 
• 
baseline body mass index (BMI) (< 30 kg/m2, 
30 kg/m2) 
• 
baseline alanine aminotransferase (ALT) (~ 1.5 x upper limit of nonnal (ULN), 
> 1.5 x ULN) 
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
IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

type of current dialysis (Hemodialysis, Peritoneal Dialysis)

adherence to study regimen (< 80%, ≥ 80%)
3.4.
Missing Data and Outliers
3.4.1.
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 3.6.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 
time of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of any study drug is greater than or equal to the lower bound of a visit window, and the 
value at the visit is missing, then the value will be imputed. If the study day associated with the 
last dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing. 
If a HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantification (LLOQ) target not detected (TND),” then the missing data point 
will be set to “< LLOQ TND.” If a data point is missing and preceded and followed by values 
that are “< LLOQ detected,” or preceded by “< LLOQ detected” and followed by 
“< LLOQ TND,” or preceded by “< LLOQ TND” and followed by “< LLOQ detected,” then the 
missing value will be set to “< LLOQ detected.” In these situations the data point will be termed 
a bracketed success; otherwise, the data point will be termed a bracketed failure 
(ie, ≥LLOQ detected). If a data point is missing and is not bracketed, the missing data point will 
also be termed a failure (ie, ≥LLOQ detected) except for SVR24, which will be imputed 
according to SVR12 status. Success for SVR12 who have no further HCV RNA measurements 
collected will be counted as a success for SVR24 due to the high correlation between these 
2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ − 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data. 
For health-related quality of life data including SF-36, CLDQ-HCV, FACIT-F, and 
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12) visit will not be imputed. For SF-36, if there are multiple responses to an item, the response 
will be set to missing.
3.4.2.
Outliers
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be conducted. All data will be included in the data analysis.
3.5.
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 within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. 
Non-pharmacokinetic (PK) data that are continuous in nature but are less than the lower limit of 
quantitation or above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 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).
COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0 will be used to determine 
HCV RNA results in this study. The lower limit of quantitation (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.


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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 “No HCV RNA 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).
Natural logarithm-transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 
at predose time points, and one-half the value of the lower limit of quantitation (LLOQ) at 
postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.6.
Visit Windows
3.6.1.
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.


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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 will be the end date on study drug administration eCRF for the record where 
the “subject permanently discontinued” flag is ‘Y’. The last dose date will be defined as the 
maximum of the last dose dates of the study drugs. 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).
3.6.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purposes 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.
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
Nominal Day (Lower 
Limit, Upper Limit)
8-Week Groups
Nominal Day (Lower 
Limit, Upper Limit)
12-Week Groups
Nominal Day (Lower 
Limit, Upper Limit)
24-Week Groups
Baseline
1 (none, 1)
1 (none, 1)
1 (none, 1)
Week 2
14 (12, 21)
14 (12, 21)
14 (12, 21)
Week 4
28 (22, 35)
28 (22, 35)
28 (22, 35)
Week 6
42 (36, 49)
42 (36, 49)
42 (36, 49)
Week 8
56 (50, ≥ 57)
56 (50, 70)
56 (50, 70)
Week 12
NA
84 (71, ≥ 85)
84 (71, 98)
Week 16
NA
NA
112 (99, 126)
Week 20
NA
NA
140 (127, 154)
Week 24
NA
NA
168 (155, >=168)


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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 
FU a 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).
3.6.3.
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. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.


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


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each country and investigator. The 
summary will present the number and percentage of subjects in the Safety Analysis Set. For each 
column, the denominator for the percentage calculation will be the total number of subjects 
analyzed for that column. 
A summary of subject disposition will be provided by genotype and treatment group. This 
summary will present the number of subjects screened, the number of subjects not enrolled, the 
number of subjects enrolled, the number of subjects enrolled but never treated, the number of 
subjects enrolled and treated (ie, safety analysis set), in FAS, and the number and percentage of 
subjects in each of the categories listed below. The denominator for the percentage calculation 
will be the total number of subjects in the Safety Analysis Set for each column. 

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
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 
Assessment and thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 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 enrolled, and the number of subjects in each 
of the disposition categories listed above will be depicted by a flowchart.


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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, 4.8 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), Week 4 (Day 28), Week 
8 (Day 56), Week 12 (Day 84), Week 16 (Day 112), Week 20 (Day 140), and Week 24 (Day 
168). A 3-day window is applied to the last planned on-treatment visit to match with the 
protocol-specified visit window, i.e. number of subjects exposed through Week 8 will be 
calculated as the number of subjects who were exposed to study drug for at least 53 days. 
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. Number of subjects exposed through week 24
will be calculated as the number of subjects who were exposed to study drug for at least 165
days.
4.2.2.
Adherence to Study Drug
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:







returned
Tablets
of
No.
 Dispensed
Tablets
of
No.
ed
Administer
 Doses
of
Number 
Total
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed at baseline. 


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The level of adherence will be expressed in percentage using the following formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of LDV/SOF prescribed for 8 weeks would require 56 tablets, for 
12 weeks would require 84 tablets, and for 24 weeks would require 168 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 study drug bottles are 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 
(eg, {< 80%, ≥ 80 to < 90%, ≥ 90%}) will be provided by treatment group for the Safety 
Analysis Set. Categorical displays also will be provided for the number of subjects who are at 
least 80% adherent to their drug regimen (ie, adherence is ≥80% for 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.


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5.
BASELINE DATA
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by genotype 
and using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for age
and BMI (kg/m2), and using the numbers and percentages of subjects for age categories 
(< 65 years, ≥65 years), BMI categories (< 30 kg/m2, ≥ 30 kg/m2), 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 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 by HCV genotype and treatment group.
A by-subject demographic listing, which includes first dose date, will be provided by subject ID 
number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

HCV genotype and subtypes

IL28B (CC, Non-CC (including CT, and TT))

baseline HCV RNA as a continuous variable and as categories (< 800,000 IU/mL,
≥800,000 IU/mL)

baseline ALT as a continuous variable and for categories (≤1.5 × ULN, > 1.5 × ULN)

prior HCV treatment experience (treatment naïve, treatment experienced)

cirrhosis (presence, absence, missing)

renal transplant (yes, no)

prior HCV treatment for treatment experienced subjects [DAA Naive (Peg-IFN + RBV, 
Other]

prior HCV treatment response (non-responder, relapse/breakthrough, early treatment 
discontinuation, and unknown) for treatment experienced subjects

type of current dialysis (Hemodialysis, Peritoneal Dialysis)


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These baseline characteristics will be summarized by genotype 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 will be provided for all subjects at 
screening.
A separate by-subject data listing for prior HCV treatment and response will be provided for all 
treatment experienced subjects. The listing will display the prior HCV regimen(s) and 
treatment(s) including the treatment duration, and the prior HCV treatment response.
5.3.
Medical History
Medical history collected at screening will be coded using the current Medical Dictionary for
Regulatory Activities (MedDRA). Medical history will be summarized by system organ class
(SOC), preferred term (PT), treatment group, and overall. Subjects who report 2 or more medical
history items that are coded to the same SOC and/or PT will be counted only once by the unique
coded term in the summary. The summary will be provided for the Safety Analysis Set. No
inferential statistics will be generated.
A by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).
A by-subject listing of renal transplant will be provided by subject ID number.


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6.
EFFICACY ANALYSES 
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ 12 weeks after
discontinuation of study drug in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Quantitative Test, v2.0 will be used to measure HCV RNA. The LLOQ for this assay is 
15 IU/mL.
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint
The SVR12 rate in each of genotype will be calculated along with 2-sided 95% exact CI based 
on Clopper-Pearson method {Clopper 1934}.
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint
The point estimates and 95% exact CIs of the SVR12 rates will be displayed by genotype for 
subgroups outlined in Section 3.3.
SVR12 rates will be summarized by categories of early viral response to explore possible early 
on-treatment predictors of SVR12. The relationship between SVR12 and study drug interruption
may also be explored.A forest plot will graphically present estimates and 95% CIs in SVR12
rates for each of the subgroups.
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 at 4 and 24 weeks after discontinuation
of treatment (SVR4 and SVR24)

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 


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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

The steady-state pharmacokinetics of LDV and SOF and its metabolites in subjects who are 
on dialysis for End Stage Renal Disease (ESRD)

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy
with SOF/VEL.
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 3.6.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.4.1. The 2-sided 95% exact CI based on 
Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit within each genotype. 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 in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed by genotype.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL), by genotype and by visit through EOT. Imputation rules described in
Section 3.4.1 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, and Other by genotype will be created. All subjects who achieve 
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"on-ti·eatment virologic failure" and relapse (which will be broken down by study drng 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for virologic 
failure will be categorized as "Other." The denominator for relapse will be the nlllllber of 
subjects who had HCV RNA < LLOQ on their last observed on-ti·eatment HCV RNA 
measurement; othe1wise, the denominator will be the nlllllber of subjects in the FAS. 
A concordance table between SVR12 and SVR24 will be provided for each genotype. Subjects 
with both observed SVR12 and observed SVR24 data will be included for this analysis. 
Drng resistant substitutions will be analyzed and repo1ted based on change from baseline 
sequence and/or change from HCV genotype reference sti·ain as pait of the Virology Study 
Repo1t . 
6.3. 
Exploratory Efficacy Endpoints 
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Changes From Protocol-Specified Efficacy Analyses 
There are no planned changes from protocol-specified efficacy analyses. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
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 case report form 
(CRF) to the question of “Related to Study Treatment.” Events for which the investigator did not 
record the relationship to study drug will be considered to be related to study drug for summary 
purposes. However, by-subject data listings will show the relationship as missing from that 
captured on the CRF.
7.1.4.
Serious Adverse Events
Serious adverse events 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 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 30th day after the 
date of the last dose of study drug 
An AE with a completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dose date of study drug, will be considered to be treatment-emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by 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, and any AE that
led to premature discontinuation of LDV/SOF, and any AE that led to interruption of LDV/SOF. 
All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized and included in this table. 
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT based on the safety analysis set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs 

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 LDV/SOF

Adverse Events Leading to Interruption of LDV/SOF


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Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed in alphabetic order of SOC and then by PT in order of descending 
incidence within each SOC. In summaries by severity grade, the most severe grade will be used 
for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will also be summarized by PT only, in order of 
descending incidence for:

All AEs

AEs that occurred in at least 5% of subjects 

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of LDV/SOF

AEs leading to interruption of LDV/SOF
In addition to the summaries described above, data listings will be provided for the following:

All AEs

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of LDV/SOF

AEs leading to interruption of LDV/SOF

AE with changes other than resolution dates between the SVR12 and SVR24 analyses 
(provided only at the final analysis)
All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized.
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 last dose of any study drug plus 30 days 
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the limit of quantitation, they will be 


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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. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, coagulation, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a severity grade of 1 or 
higher on the 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 
for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, white blood 
cell (WBC) counts, neutrophils, lymphocytes, hemoglobin, platelets, reticulocytes, and 
international normalized ratio (INR) as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to reported number of digits, SD to reported number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, WBC, neutrophils, lymphocytes, and platelets will be plotted using a 
line plot by visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3 (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.
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 criteria for an abnormality of at least Grade 1. Some laboratory tests 


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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, or all 
available data in the database snapshot for subjects still on treatment at the time of the interim 
analysis. 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; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is 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). 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 3.6.3 (Selection of Data in the Event of Multiple Records in a Window). 
No inferential statistics will be generated.


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A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], 
pulse [beats/min], respiration [breaths/min], and body temperature [°C]) 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.
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 prior to the initial study drug dosing date.

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).

Prior and concomitant medications: any medications taken both prior to and on or after the 
initial study drug dosing date and within the study drug’s treatment period (including study 
drug’s therapeutic reach); or any medications taken prior to the baseline visit date with a stop 
date of “continuing”.
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects. 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 frequency of preferred 
names. For drugs with the same frequency, sorting will be done alphabetically.For purposes of 
analysis, any medication with a stop date that is on or prior to the initial study drug dosing date 
or start date that is after the last study drug dosing date will be excluded from a concomitant 
medication summary. If a partial stop date is entered, any medication with the month and year (if 
day is missing) or year (if day and month are missing) prior to the initial study drug 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. Summaries will be based on the Safety Analysis Set. No inferential 
statistics will be generated.
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 by-subject listing for ECG assessment results will be provided by subject ID number and visit
in chronological order.


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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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PHARMACOKINETIC ANALYSES 
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Plasma concentrntions of SOF (and its metabolites GS-566500 and GS-331007) and LDV in 
plasma will be detennined using validated bioanalytical assays. 
Population PK models for SOF, GS-331007 and LDV, previously developed for the Phase 2/3 
LDV /SOF US NDA population analyses, will be applied to the data from all PK samples 
collected in this study. Details of the population PK analysis will be provided in a separate 
population PK analysis plan. 
The systemic concentrntion of study drng prior to and immediately following hemodialysis will 
also be summarized using descriptive summary statistics (sample size, mean, SD, coefficient of 
variation [%CV], median, Ql, Q3, minimum, maximum). For concentration values BLQ, the 
number of subjects with values of BLQ will be presented. 
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9.
REFERENCES
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
WinNonlin® Phoenixsoftware v6.3 (Pharsight Corporation, Mountain View, CA).


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11.
SAP REVISION
CCI


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12.
APPENDICES
Appendix 1
Schedule of Assessments


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Appendix 1
Schedule of Assessments
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 1
Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs /SAEb
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
Health Related Quality of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
Study Drug Dispensingd
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
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Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8/ET
4
12
24
Viral Sequencing/Phenotypinge
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
Intensive PK g,h
Xh
Xh
Hemodialysis PK g,i
Xi
Xi
Serum β-hCG Pregnancy Testj
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping
X
HCV, HIV, HBV Serology
X
HBV DNA k
X
X
X
X
X
X
HbA1c
X
Fibrotest ®
X
Archive Samplef
X
X
Pharmacogenomic Samplef
X
CD4 Cell Count l
X
X
X
X
X
HIV-1 RNA l
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b 
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c 
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,
Week 8, ET (if applicable), and posttreatment Week 12.
d 
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e. 
Plasma samples will be collected for possible viral resistance testing and other virology studies
f 
Subjects may opt out of archive/pharmacogenomics sample collection.
g 
Only for subjects who have provided consent for this sample and testing.
h 
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6 or 8,
per investigator discretion.


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i 
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment group), evaluations
will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected from both
the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally, a single blood sample will be collected within 10 minutes after hemodialysis
concludes.
j 
For females of child bearing potential only
k. 
Only for subjects who are HBcAb+ at Screening
l 
For HIV/HCV co-infected subjects only.


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Appendix Table 2.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 2
Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8
12/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs /SAEb
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
X
Health Related Quality of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
Study Drug Dispensingd
X
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral Sequencing/Phenotypinge
X
X
X
X
X
X
X
X
X


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Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8
12/ET
4
12
24
Sparse PK
X
X
X
X
X
Intensive PK g,h
Xh
Xh
Xh
Hemodialysis PK g,i
Xi
Xi
Xi
Serum β-hCG Pregnancy Testj
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping
X
HCV, HIV, HBV Serology
X
HBV DNA k
X
X
X
X
X
X
X
HbA1c
X
Fibrotest ®
X
Archive Samplef
X
X
Pharmacogenomic Samplef
X
CD4 Cell Count l
X
X
X
X
X
X
HIV-1 RNA l
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b 
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c 
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,
Week 8, ET (if applicable), and posttreatment Week 12.
d 
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e. 
Plasma samples will be collected for possible viral resistance testing and other virology studies
f 
Subjects may opt out of archive/pharmacogenomics sample collection.
g 
Only for subjects who have provided consent for this sample and testing.
h`
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6 or 8,
per investigator discretion.


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i 
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment group), evaluations
will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected from both
the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally, a single blood sample will be collected within 10 minutes after hemodialysis
concludes.
j 
For females of child bearing potential only
k. 
Only for subjects who are HBcAb+ at Screening
l 
For HIV/HCV co-infected subjects only.


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Appendix Table 3.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits for Group 3
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week
(±5 Days)
2
4
6
8
12
16
20
24/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs/SAEb
X
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
X
X
X
Health-Related Quality 
of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
X
Study Drug Dispensingd
X
X
X
X
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing/
X
X
X
X
X
X
X
X
X
X
X
X


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Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week
(±5 Days)
2
4
6
8
12
16
20
24/ET
4
12
24
Phenotypinge
Sparse PK
X
X
X
X
X
X
X
X
Intensive PK g, h
Xh
Xh
Xh
Hemodialysis PKg, i
Xi
Xi
Xi
Serum β-hCG
Pregnancy Testj
X
X
X
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B 
Genotyping 
X
HCV, HIV, HBV 
Serology
X
HBV DNAk
X
X
X
X
X
X
X
X
X
X
HbA1c
X
Fibrotest®
X
Archive Samplef
X
X
Pharmacogenomic 
Samplef
X
CD4 Cell Countl
X
X
X
X
X
X
X
X
X
HIV-1 RNAl
X
X
X
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
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, 
Week 24, ET (if applicable), and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
e
Plasma samples will be collected for possible viral resistance testing and other virology studies
f
Subjects may opt out of archive/pharmacogenomics sample collection.


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g
Only for subjects who have provided consent for this sample and testing. 
h
Intensive PK evaluations will be assessed at the following timepoints: 0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6 ,8, 10, and 12 hours post dose once either on Week 6  8, or 
12 per investigator discretion.
i
Hemodialysis PK blood samples will be collected at one hemodialysis session between Week 6 and Week 12, inclusive (as appropriate based on treatment regimen),
evaluations will include: 1. A single blood sample will be collected within 10 minutes before hemodialysis initiates. 2. During hemodialysis, a single sample will be collected 
from both the arterial and venous sides of the dialyzer within 1 hour of hemodialysis concluding. 3. Finally a single blood sample will be collected within 10 minutes after 
hemodialysis concludes.
j
For females of child bearing potential
k.
Only for subjects who are HBcAb+ at Screening
l
For HIV/HCV co-infected subjects only.