A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection
Phase: PHASE2
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination +/- Ribavirin in Adolescents and 
Children with Chronic HCV-Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
IND No.:
EudraCT Number:
115268
2014-003578-17
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-337-1116
Gilead Sciences Medical 
Monitor:
Name:
Bittoo Kanwar, MD
Telephone:
Mobile:
Fax:
E-mail:
Protocol Version/Date:
Original:
10 July 2014
Amendment 1.0:
08 October 2014
Amendment 2.0:
08 December 2014
Amendment 2.1:
09 January 2015 (United Kingdom Only)
Amendment 2.2: 
01 April 2015 (United Kingdom Only)
Amendment 3.0: 
28 May 2015
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD

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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....................................................................17
1.
INTRODUCTION ..............................................................................................................................................20
1.1.
Background ............................................................................................................................................20
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................21
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................21
1.3.
Ribavirin (RBV).....................................................................................................................................23
1.4.
Rationale for the Current Study .............................................................................................................24
1.5.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................25
1.6.
Overall Risk/Benefit Assessment...........................................................................................................27
2.
OBJECTIVES.....................................................................................................................................................29
3.
STUDY DESIGN................................................................................................................................................30
3.1.
Treatment Plan and Regimen .................................................................................................................30
3.1.1.
PK Lead-in ...........................................................................................................................30
3.1.2.
Treatment Phase ...................................................................................................................31
3.2.
Visit Schedule ........................................................................................................................................33
3.2.1.
PK Lead-in ...........................................................................................................................33
3.2.2.
Treatment Phase ...................................................................................................................33
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................34
3.4.
Treatment Discontinuations Criteria ......................................................................................................34
3.5.
Discontinuations.....................................................................................................................................35
3.6.
Pharmacogenomic Substudy ..................................................................................................................35
3.7.
Long-Term Follow-Up...........................................................................................................................35
3.8.
Breakthrough Futility Assessment .........................................................................................................35
3.9.
Reconsent...............................................................................................................................................35
4.
SUBJECT POPULATION..................................................................................................................................36
4.1.
Number of Subjects and Subject Selection ............................................................................................36
4.2.
Inclusion Criteria....................................................................................................................................36
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................39
5.1.
Randomization and Blinding..................................................................................................................39
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................39
5.2.1.
Description and Handling.....................................................................................................39
5.2.2.
Storage and Handling...........................................................................................................40
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................41
5.3.
Ribavirin (GT-3 Subjects Only).............................................................................................................42
5.3.1.
Description and Handling of RBV .......................................................................................42
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only).................................................43
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only).................................................43
5.5.
Study Drug Compliance.........................................................................................................................44
5.6.
Prior and Concomitant Medications.......................................................................................................44

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6.
STUDY PROCEDURES ....................................................................................................................................46
6.1.
Subject Enrollment.................................................................................................................................46
6.2.
Screening Assessments ..........................................................................................................................46
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................46
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................48
6.3.1.
Day 1 ....................................................................................................................................48
6.3.2.
Day 3 ....................................................................................................................................49
6.3.3.
Day 10 – Intensive PK..........................................................................................................49
6.4.
Treatment Phase: Treatment Assessments .............................................................................................51
6.4.1.
Day 1 ....................................................................................................................................51
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................52
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................53
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only................................54
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only................................54
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................55
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only ...............................56
6.4.8.
Unscheduled Visit/Early Termination Visit .........................................................................56
6.5.
Post-Treatment Assessments..................................................................................................................58
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................58
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................58
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................59
6.6.
Procedures and Specifications................................................................................................................60
6.6.1.
Clinical Laboratory Analytes ...............................................................................................60
6.6.2.
Medical History....................................................................................................................60
6.6.3.
Complete Physical Examination...........................................................................................61
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................61
6.6.5.
Height & Weight Measurement............................................................................................61
6.6.6.
Bone Age Assessment..........................................................................................................61
6.6.7.
Swallowability Assessment..................................................................................................61
6.6.8.
Vital Signs............................................................................................................................61
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................62
6.6.10.
Viral Sequencing (Archive)..................................................................................................62
6.6.11.
Pregnancy Testing................................................................................................................62
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................62
7.
TOXICITY MANAGEMENT............................................................................................................................63
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................63
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV...........................................................................63
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................64
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
8.1.1.
Adverse Events.....................................................................................................................64
8.1.2.
Serious Adverse Events........................................................................................................64
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................65
8.2.2.
Assessment of Severity ........................................................................................................66
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................66
8.4.
Gilead Reporting Requirements.............................................................................................................68
8.5.
Special Situations Reports......................................................................................................................68

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8.5.1.
Definitions of Special Situations..........................................................................................68
8.5.2.
Instructions for Reporting Special Situations.......................................................................69
9.
STATISTICAL CONSIDERATIONS................................................................................................................71
9.1.
Analysis Objectives and Endpoints........................................................................................................71
9.1.1.
Analysis Objectives..............................................................................................................71
9.1.2.
Primary Endpoints................................................................................................................72
9.1.3.
Secondary Endpoints............................................................................................................72
9.2.
Analysis Conventions.............................................................................................................................72
9.2.1.
Analysis Sets ........................................................................................................................72
9.2.2.
Data Handling Conventions .................................................................................................73
9.2.3.
Interim Analysis ...................................................................................................................74
9.3.
Demographic Data and Baseline Characteristics ...................................................................................74
9.4.
Pharmacokinetic Analysis......................................................................................................................74
9.5.
Safety Analysis.......................................................................................................................................76
9.5.1.
Extent of Exposure...............................................................................................................76
9.5.2.
Adverse Events.....................................................................................................................76
9.5.3.
Laboratory Evaluations ........................................................................................................77
9.5.4.
Other Safety Evaluations......................................................................................................77
9.6.
Efficacy Analysis ...................................................................................................................................77
9.6.1.
Key Efficacy Analysis..........................................................................................................78
9.6.2.
Secondary Efficacy Analysis................................................................................................78
9.6.3.
Subgroup Analysis ...............................................................................................................78
9.7.
Quality of Life Analysis.........................................................................................................................78
9.8.
Data Monitoring Committee ..................................................................................................................78
9.9.
Sample Size............................................................................................................................................79
10.
RESPONSIBILITIES..........................................................................................................................................80
10.1.
Investigator Responsibilities ..................................................................................................................80
10.1.1.
Good Clinical Practice..........................................................................................................80
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................80
10.1.3.
Informed Consent/Assent.....................................................................................................81
10.1.4.
Confidentiality......................................................................................................................81
10.1.5.
Study Files and Retention of Records ..................................................................................81
10.1.6.
Case Report Forms...............................................................................................................82
10.1.7.
Drug Accountability.............................................................................................................83
10.1.8.
Inspections............................................................................................................................83
10.1.9.
Protocol Compliance............................................................................................................83
10.2.
Sponsor Responsibilities ........................................................................................................................83
10.2.1.
Protocol Modifications.........................................................................................................83
10.2.2.
Study Report and Publications .............................................................................................84
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................84
10.3.1.
Access to Information for Monitoring..................................................................................84
10.3.2.
Access to Information for Auditing or Inspections ..............................................................84
10.3.3.
Study Discontinuation..........................................................................................................85
11.
REFERENCES ...................................................................................................................................................86
12.
APPENDICES ....................................................................................................................................................88
Appendix 1.
Investigator Signature Page....................................................................................................89
Appendix 2.
Study Procedures Table..........................................................................................................90
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............95

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Appendix 4.
Tanner Stages .......................................................................................................................119
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120
LIST OF IN-TEXT TABLES
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population PK 
Analysis).................................................................................................................................23
Table 3-1.
Subject Enrollment by HCV Genotype, Country and Treatment Duration ............................32
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................45
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................63
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................75
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted LDV, SOF and GS-331007 AUCtau following administration of LDV/SOF 
45 mg/200 mg in Children (6 to < 12 years of age)................................................................26
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................31

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination +/- Ribavirin in Adolescents and Children with 
Chronic HCV-Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV 
for 12 or 24 weeks in chronic HCV-infected pediatric subjects. 

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The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV treatment in chronic HCV infected
subjects (including the impact of HCV genotype, IL28B
genotype, and prior treatment experience), as assessed by the 
proportion of subjects with sustained virological response (SVR) 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV treatment in chronic HCV-infected 
subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after completion of treatment

To evaluate the emergence of viral resistance to LDV and SOF 
during treatment and after completion of treatment

To evaluate the effect of growth and development on pediatric 
subjects during and after treatment
The exploratory objective of this study is:

 
 
Study Design:
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of LDV/SOF FDC +/- RBV in chronic 
HCV-infected pediatric subjects.
The study will be divided into 2 parts and will commence with GT-1, 
-3, and -4 HCV-infected pediatric subjects as follows (subjects with 
GT-2, -5, and -6 will be included once adult data are available, if 
appropriate):
PK Lead-in Phase: PK Lead-in will evaluate and/or confirm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV/SOF FDC through 10 days of dosing for 
each of the three cohorts. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of chronic HCV and HCV RNA ≥1000 IU/mL at study entry will be 
evaluated.  Subjects must be treatment naïve without history of 
cirrhosis to participate in the PK Lead-in Phase.
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Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1. Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
Once Cohort 1 data is analyzed and a Cohort 2 dose is determined, 
Cohort 2 will open for screening. Cohort 2 subjects will receive 
45 mg/ 200 mg LDV/SOF FDC (2 x 22.5 mg/ 100 mg tablets or 
subject enrollment will be deferred until oral granulate formulation is 
available, if determined necessary based on the LDV/SOF FDC 
swallowability assessment) for 10 days with intensive PK conducted 
on Day 10.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.
Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase. These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.

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Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study will 
commence with GT-1, -3, and -4 HCV infected pediatric subjects and 
will subsequently enroll subjects with GT-2, -5, and -6 once adult 
data is available, if appropriate.
Subjects enrolled in the study will receive the following regimen:

United Kingdom:
GT-1 and GT-4 treatment-naïve with or without cirrhosis: 
LDV/SOF FDC for 12 weeks
GT-1 and GT-4 treatment-experienced without cirrhosis: 
LDV/SOF FDC for 12 weeks
GT-1 and GT-4 treatment-experienced with cirrhosis (as 
determined by liver biopsy): LDV/SOF FDC for 24 weeks
GT-3 treatment-experienced with or without cirrhosis: 
LDV/SOF FDC + RBV for 24 weeks

United States/Australia/New Zealand (GT-1 only):
GT-1 treatment-naïve with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced with cirrhosis (as determined by 
liver biopsy): LDV/SOF FDC for 24 weeks
The study will enroll both treatment-naïve and treatment experienced 
pediatric subjects, with up to 40 subjects allowed to be treatment 
experienced. Approximately 200 total subjects, including subjects 
that participated in the PK Lead-in Phase, will be enrolled in 
Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years 
of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of 
age)

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The following definitions will be used for treatment experienced 
subjects: 

Interferon intolerant: Subject who discontinued therapy 
(≤12 weeks total) due to ≥ 1 adverse event 

Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on treatment 
Relapse/breakthrough: Subject who achieved undetectable HCV RNA 
during treatment or within 4 weeks of the end of treatment but did not 
achieve a sustained virologic response (SVR)
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for subjects 
requiring 24 weeks of treatment) during the treatment phase followed 
by post-treatment visits 4, 12 and 24 weeks after discontinuation of 
therapy.
All subjects who do not attain SVR or have viral relapse will be 
encouraged to discuss treatment with standard-of-care (SOC) therapy 
with their healthcare provider.
Substudy and Long-
Term Follow-Up 
Study:
Pharmacogenomics (PG) Substudy
 
Long-Term Follow-up
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed every 6 months for the first 2 years followed by every 
12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
determined at Day 1. The study will commence with GT-1, -3, and -4
HCV-infected pediatric subjects and will subsequently enroll subjects 
with GT-2, 5 and -6 once adult data are available, if appropriate. 
Inclusion Criteria:

Chronic HCV infection documented by either:
A) positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or
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B) liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

PK Lead-in Only: subjects in Cohort 1 (age 12 to < 18 years of 
age) must weigh ≥ 45 kg

PK Lead-in Only: subjects in Cohort 2 (age 6 to < 12 years of 
age) must weigh ≥ 17 kg and < 45 kg

Females of childbearing potential (as defined in Appendix 5) must 
have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within the 
protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception of 
certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, laboratory
abnormality or other circumstance that might confound the results 
of the study, or interfere with the subject’s participation for the 
full duration of  the study, such that it is not in the best interest of 
the subject to participate.

Sexually active subjects who are not willing to use 2 forms of an 
effective method of contraception , as referenced in Appendix 5
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: medical history (including 
parental height, if available), complete physical examination, vital 
signs (including body height and weight), concomitant medications,
LDV/SOF FDC Swallowability Assessment (may be performed at 

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screening up to Day 1), hematology, safety laboratory tests, 
coagulation tests, HCV RNA, serum β-human chorionic gonadotropin 
(hCG - females of childbearing potential only), urinalysis, and urine 
drug screen, IL28B genotyping, serology (HIV, HAV, HCV, and 
HBV, HCV genotyping), HbA1c, thyroid stimulating hormone
(TSH), alpha fetoprotein, alpha-1 anti-trypsin.
For subjects continuing from PK Lead-in into the Treatment Phase, a 
screening visit for the Treatment Phase will not be required.
PK Lead-in Phase: 
Study Visits will occur at Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects 
< 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status), quality of life survey (Day 1 only), safety 
laboratory tests, HCV RNA, viral sequencing sampling and 
urinalysis. Coagulation testing and urine pregnancy tests (females of 
child bearing potential only) will be performed at Day 1 and Day 10 
only. LDV/SOF FDC swallowability assessment with placebo will be 
performed (if not performed at Screening) on Day 1 to assess a 
subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 100 mg
FDC tablet (only subjects administered LDV/SOF FDC in tablet 
form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Study visits will occur at Day 1, and at the end of Weeks 1, 2, 4, 8, 
and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of 
treatment). All Treatment Phase subjects will then return for 
follow-up visits at 4, 12 and 24 weeks after discontinuation of 
therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 

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≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety laboratory
tests, coagulation tests, HCV RNA, viral sequencing, urine pregnancy 
tests (females of childbearing potential only), PK samples, a quality 
of life survey, and urinalysis. Tanner Pubertal Stage assessment will 
be performed at Day 1 and end of treatment visits; parental heights 
will be recorded at Day 1. The Bone Age Assessment will be 
performed at the Day 1 visit. LDV/SOF FDC swallowability 
assessment will be performed (if not performed at Screening) on
Day 1 to assess a subject’s ability to swallow a placebo to match the 
90 mg/ 400 mg or 22.5 mg/ 100 mg LDV/SOF FDC tablet (only 
subjects administered LDV/SOF FDC in tablet form). For subjects 
continuing from the PK Lead-in, the screening, Day 1, and Week 1 
visits of the Treatment Phase will not be required. Samples for viral 
RNA sequencing/phenotyping will be collected at Day 1 and every 
visit thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laboratory tests, HCV RNA, Tanner 
Pubertal Stage assessment (only post-treatment Week 12 and 
post-treatment Week 24), Bone Age Assessment (only post-treatment 
Week 24) and urine pregnancy tests (as defined in Appendix 5).  
 
 
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration.  LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablets (as 
determined by LDV/SOF FDC Swallowability Assessment at 
Screening or at any time during the study) will be re-assigned to 
4 x 22.5 mg/ 100 mg LDV/SOF FDC tablets daily.
(Cohort 2) LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg) 
will be administered once daily. Subjects unable to swallow the 
LDV/SOF FDC 22.5 mg/ 100 mg tablets (as determined by 
LDV/SOF FDC Swallowability Assessment) will be deferred until 
oral granulate formulation is available.
PPD

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Amendment 3.0
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Intensive PK and safety results from the PK Lead-in of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Cohort as well 
as to determine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort.
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of 
the appropriateness of the dose.
RBV Weight-Based Dosing (GT-3 Subjects only):
The RBV dose is:
Body Weight kg
(lbs.)
RBV Daily 
Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV 
oral solution if necessary.
The morning dose of RBV will be taken with food with an 
age-appropriate dose of LDV/SOF FDC. The evening dose of RBV 
will be taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 

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Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.
PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 
12 hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of GS-331007,
SOF and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, SOF, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by the 4 regimens based on treatment-experience,
cirrhosis status and genotype, by age group, by regimen and age 
group, and overall. The key efficacy endpoint is SVR12 in all 
enrolled and treated subjects and will be summarized the 4 regimens 
based on by treatment-experience, cirrhosis status and genotype, by 
age group, by regimen and age group, and overall. Point estimate and 
its 95% confidence interval will be provided. 
Subgroup analysis on SVR12 will be performed by 
treatment-experience and cirrhosis status, by IL28B genotype, and by 
GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in these 
subsets are available for analysis). 

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Amendment 3.0
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All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). All categorical endpoints will be summarized by 
number and percentage of subjects who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data by the 4 regimens based on 
treatment-experience, cirrhosis status and GT, by age group, by 
regimen and age group, and overall.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
Direct acting antiviral
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HAV
Hepatitis A Virus

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count

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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {19801}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {20286}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {20285}.

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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result in 
dose reductions of 1 or both of the drugs. The most common adverse events have consisted of 
influenza-like illness (91%), headache (62%), and injection site reactions (45%), often leading to 
poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {20282}. Many pediatricians currently advocate delay of treatment past adolescence 
or even into adulthood when options with DAAs are possible {20282}. Unfortunately, in the 
25% of pediatric patients who do meet the criteria for treatment (elevated transaminases and viral 
loads), the option of PEG+RBV therapy remains inadequate in regard to both efficacy in GT-1 
and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT1 HCV-infection. Harvoni® (LDV/SOF FDC) has 
been approved in the United States by the Food and Drug Administration (FDA) for treatment of 
HCV infection GT-1 adult patients. Harvoni® is indicated for both treatment-naïve and 
treatment-experienced subjects with or without cirrhosis with a 12 week treatment duration. For 
treatment-experienced subjects with cirrhosis a 24 week treatment duration is recommended. 
Harvoni® is also approved in the EU for treatment of HCV infection GT-1 and GT-4 adult 
patients as outlined above and for GT-3 treatment-experienced adults with cirrhosis and/or prior 
treatment failure subjects for 24 weeks treatment duration with ribavirin (RBV).
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment experienced subjects, respectively, infected with GT-1 HCV. Both 
studies enrolled up to 20% of HCV-infected subjects who had documented compensated 
cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 8 weeks and 
LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects with GT-1 
HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a high degree of 
efficacy (> 93%) for treatment-naïve and treatment experienced subjects with GT-1 
HCV-infection in subjects with and without cirrhosis and achieved their primary efficacy 
endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± RBV was 
safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The inclusion of RBV 
to the treatment regimen was associated with an increase in the total incidence of adverse events 
and in graded laboratory abnormalities of anemia and increased bilirubin. 

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LDV/SOF FDC indication in GT-3 HCV infection is supported by the Phase 2 Study 
GS-US-337-0122 (ELECTRON-2). In this Phase 2 open-label study, the safety and efficacy of 
LDV/SOF FDC were evaluated with or without RBV in 51 treatment-naïve patients with GT-3 
HCV infection, with or without cirrhosis. Subjects were treated with LDV/SOF FDC (n = 25) or 
LDV/SOF FDC + RBV (n = 26) for 12 weeks. SVR12 rates were 64% (16/25) and 100% (26/26) 
in the LDV/SOF FDC and LDV/SOF FDC + RBV treatment groups, respectively. The relative 
efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 
24-week regimen of sofosbuvir + ribavirin has not been investigated. Therefore, 24 weeks of 
therapy is advised in all treatment-experienced GT3 patients and those treatment-naïve GT3 
patients with cirrhosis to maximize therapeutic benefit to achieve SVR.
Both nonclinical and clinical data support the inclusion of GT-4 HCV-infected subjects in the 
Study GS-US-337-1116.
LDV displays potent antiviral activity against GT-4. In the replicon system the EC50 value of 
LDV for GT-4d HCV was 0.60 nM and 0.39 nM for GT-4a HCV (final report in preparation). 
For reference, the EC50 values of LDV for GT-1a and GT-1b is 0.031 nM and 0.004 nM, 
respectively.
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with GT-4d HCV infection were 
inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both subjects 
achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF FDC and 
Subject 
 was treated for 24 weeks with LDV/SOF FDC + RBV.
In Study GS-US-337-1119, a European study investigating the efficacy and safety of LDV/SOF
FDC in treatment-naive and treatment-experienced subjects with chronic GT-4 or GT-5 HCV 
infection, a total of 44 subjects with GT-4 HCV infection, of whom 10 (23%) have cirrhosis and 
22 (50%) are treatment experienced, have been enrolled to receive LDV/SOF FDC for 12 weeks. 
SVR12 has been achieved by 41/44 (93%) subjects, with 21/22 treatment naïve subjects and 
20/22 treatment-experienced subjects having achieved SVR12. 
In addition, preliminary data are available from Group E of the NIAID/NIH collaborative Study 
CO-US-337-0117. In this group, 21 subjects with GT-4 HCV infection are receiving 12 weeks of 
LDV/SOF FDC treatment. In total, 6 subjects have cirrhosis. Post-treatment week 12 data is 
available for 20 subjects. 20 of 21 subjects have achieved SVR12.
Preliminary data are also available for Cohort 1 adolescent subjects (N=10) who enrolled in the 
PK lead-in and received adult clinical doses of LDV/SOF 90 mg/400 mg. Mean exposures of 
LDV, SOF and GS-331007 in these subjects were comparable to observed exposures in the adult 
subjects in the Phase 2/3 LDV/SOF clinical program; thereby confirming the appropriateness of 
adult dose in the adolescent population (12 to < 18 years of age) Table 1-1.
Safety data available for Cohort 1 adolescent subjects (N=10) who enrolled in the PK lead-in and 
received adult clinical dose of LDV/SOF FDC 90 mg/ 400 mg resulted in no significant safety 
concerns.
PPD
PPD

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Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in normalization of serum ALT activity and improvement in 
liver histology. When combined with interferon or PEG therapy, RBV decreases substantially the 
relapse rate seen after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment.  A comprehensive review of RBV is contained in the package 
insert/SmPC.

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1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with LDV/SOF 
FDC +/- RBV for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration within GT-1 and GT-4 HCV infected subjects.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC +/- RBV would provide an all-oral, IFN-free regimen 
with a shorter treatment duration (12 or 24 weeks of LDV/SOF FDC +/- RBV treatment versus 
standard-of-care 24 to 48 weeks of treatment) for GT-1, -3, and -4 HCV infection subjects and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
In vitro viral replicon assay has data demonstrating LDV has potent, picomolar antiviral activity 
against GT-1a and GT-1b HCV-infection. In the LDV/SOF FDC phase 3 program, LDV/SOF 
FDC without RBV has been shown to have good efficacy and safety in adults infected with GT-1 
HCV-infection.  In the GS-US-337-0102 (ION-1), GS-US-337-1119, and CO-US-337-0117, 
LDV/SOF FDC without RBV has been shown to have good efficacy and safety in adults infected 
with GT-4 HCV-infection. In study GS-US-337-0122, a phase 2 open-label study of GT-3 
treatment-naïve adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted 
in an SVR12 of 64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% 
{29292}. The clinical data to support the use of Harvoni in patients infected with HCV GT3 are 
limited. As a result, the current study will include a 24-week RBV treatment regimen for only 
treatment experienced pediatric subjects who enroll with GT-3 HCV-infection.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies have been planned and/or initiated with LDV/SOF 
FDC in adult subjects with GT-2, -5, and -6.  If emerging LDV/SOF FDC data in these 
additional GTs support treatment in these genotypes in adults, pediatric subjects with GT-2, -5 
and -6 will be enrolled in the current study.  Of note, there is an ongoing study enrolling GT-2 
and -3 pediatric patients, GS-US-334-1112, for treatment with SOF + RBV for 12 and 24 weeks, 
respectively.

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1.5.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/400 mg) fixed-dose combination tablet +/- RBV has 
demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects across 
different patient populations in phase 2 and 3 clinical trials. These doses represent the marketed 
dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection
in adults.
Selection of doses of LDV/SOF FDC +/- RBV for adolescents and younger age groups will 
target systemic exposures similar to those observed in adults at the proposed marketed dose. 
LDV and SOF are substrates for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). LDV is also a subject to slow oxidative metabolism via an unknown 
mechanism. SOF is extensively metabolized to the pharmacologically active nucleoside analog 
phosphate. The activation pathway involves hydrolysis by intestinal and hepatically expressed 
carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {20287}, {20288}.  SOF is also 
converted to GS-331007, an inactive circulating metabolite, which is eliminated renally by active 
tubular secretion and glomerular filtration.  Available data suggest comparable hepatic 
expression of CES1 in adolescents and adults with modestly decreased expression in children.  
However, little is known about the developmental regulation of Pgp, CES, and CatA.  When 
adjusted for BSA, the processes of active secretion and glomerular filtration approximate adult 
activity by 6 to 12 months of age {5914}. 
The adult clinical dose of LDV/SOF FDC (90 mg/ 400 mg) is being evaluated in adolescent 
subjects (12 to <18 years old, weighing ≥ 45 kg).  The appropriateness of adult dose for this age 
range is supported by data from the Cohort 1 PK Lead-in subjects which demonstrated 
comparable LDV, SOF and GS-331007 exposures in adolescent subjects and in adult subjects in 
Phase 2/3 population PK analyses.
LDV/SOF FDC (45 mg/ 200 mg) dose is proposed for an evaluation in children (6 to < 12 years 
of age, weighing ≥ 17 kg and < 45 kg). This proposed dose was supported by scaling of adult 
exposures based on correlations between body weight and clearance capacity (liver volume/size 
for LDV and SOF, and renal capacity for GS-331007) for the expected body weight range in 
childen (6 to < 12 years of age) as demonstrated in Figure 1-1 {34882}, {5914}. Additionally, the 
dose of LDV/SOF FDC 45 mg/ 200 mg provides comparable dosing to the clinical adult dose on 
mg/kg basis (LDV range: 0.5 to 2.1 mg/kg; SOF range: 2.3 to 9.5 mg/kg) in Phase 2/3 program. 
Based on these scaling approaches, the dose of LDV/SOF FDC 45 mg/ 200 mg is expected to 
achieve mean systemic exposures of LDV, SOF and GS-331007 that as observed in the 
Phase 2/3 population. Safety and PK data in children (6 to < 12 years of age) who enroll in the 
PK-lead will be evaluated to confirm the appropriatness of the dose for this age group and inform 
dose selection for children < 6 years old.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 26
28 May 2015
Figure 1-1.
Predicted LDV, SOF and GS-331007 AUCtau following administration 
of LDV/SOF FDC 45 mg/ 200 mg in Children (6 to < 12 years of age)
'C 
Cll 
(ii 
(,)
-
~E 
=-.:: 
I~ ..c 
u 
• 
:::> 
C) 
<{ c 
u.. 
100000 
LDV/SOF 45 mg/200 mg 
·················································································· 
max 
~············ ···· ···· 
r o, 
95th percentile !5 :::; 
10000 ~·················'<. 
,A 
.AA 
vv 
Q3 
Q2 
cne: 
o.,. 
,"' 
1000 
~ 
············ 
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• 
• • 
• • . • • • • • • • • • . • •. • • • • • • •••• ~ • •••• ! Y.'lV.V 
~······· ········ 
, ••• , •••, •• ., •• :~.... 
.AAA 
......... "':'::': ...... . 
Q1 
-w 
~, 
3 0 
CQ_"U 
5th percentll e 
~ ~ 
0 
- · 
3 g 
!9. 
···············•······························ ········· ·· · ························ 
min 
I 
I 
I 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
10000 
weight (kg) 
o 
5th percentile 
0 
Q1 
6 
Q2 
9 
03 
o 
95th percentile 
LDV/SOF 45 mgt 200 mg 
......................................................... ......................... 
max 
r 
~-u 
_::r 
(J)I» 
01/) 
.,~ 
"' 
-w 
95th percentile ~ -u 
3 0 
Q3 
CQ. -g 
g 
1000 
Q2 
~a 
Q1 
0 -· 
3 g 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
weight (kg) 
5th percentile !8. 
min 
o 
5th percentile 
0 
Q1 
A
Q2 
'V'Q3 
o 
95th percentile 

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 27
28 May 2015
Age-appropriate formulations of LDV/SOF FDC (a smaller, 22.5 mg/ 100 mg strength tablet and 
a non-tablet formulation currently under development) that offer an important option in the 
treatment of HCV-infection in the pediatric population are planned for evaluation in children 
below 12 years of age or children who are unable to swallow the adult dose tablet formulation.
1.6.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and normal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {20273}. It is the 
last two groups of children in whom therapy may be indicated to prevent end-stage disease, 
either during childhood/adolescence or in early adulthood.
Given that the current SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 28
28 May 2015
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shorter treatment duration and/or lead to a regimen without RBV or interferon. These 
in turn could result in reduction in adverse events.  LDV/SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG.
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 29
28 May 2015
2.
OBJECTIVES
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC
in chronic HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF 
FDC in chronic HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV-infected pediatric subjects
The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
PPD

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 30
28 May 2015
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC +/- RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry 
will be evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in 
the PK Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old, weighing ≥45kg

Cohort 2:  6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Cohort 2: Subjects will receive LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg tablets or 
subject will be deferred until oral granulates formulation is available, if determined necessary 
based on LDV/SOF FDC swallowability assessment).
Following completion of study treatment in the PK Lead-in of Cohort 2 and pending PK and 
safety results, the PK Lead-in of Cohort 3 will initiate and receive study treatment 
(age-appropriate dose and formulation). 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately enroll 
in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling over from the 
PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 visit of the 
Treatment Phase.

LDV/SOF FDC
Protocol GS-US-337-1116
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Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 31
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Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:
a) United Kingdom:
GT-1 & GT-4 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 
12 weeks
GT-1 & GT-4 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 
12 weeks
GT-1 & GT-4 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 
24 weeks
GT-3 treatment-experienced subjects with or without cirrhosis: LDV/SOF FDC + RBV 
for 24 weeks

LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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28 May 2015
b) United States/Australia/New Zealand:
GT-1 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 24 weeks
Table 3-1.
Subject Enrollment by HCV Genotype, Country and Treatment 
Duration
GT-1
GT-4
GT-3
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-
cirrhotic or 
Cirrhotic 
Subjects 
(TE)
United States
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
Australia
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
New Zealand
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
United Kingdom
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks of 
treatment 
with 
LDV/SOF 
FDC + RBV
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable
Subjects with GT -1, -3, and -4 will be enrolled first.  If emerging LDV/SOF FDC data in GT-2,
-5, and -6 support treatment in these GTs in adults, pediatric subjects with GT-2, -5, and -6 will 
be subsequently enrolled.  

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 33
28 May 2015
The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.
3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Subjects requiring 12 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, and 12.

Subjects requiring 24 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 34
28 May 2015
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.  Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 7) 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.

Pregnancy of female subject or female partner of male subject.

Efficacy failure as defined in Section 3.3.

Significant protocol violation including non-compliance with study assessments.

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC).

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 35
28 May 2015
3.5.
Discontinuations
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Termination visit as described in the Section 6.4.8.
Subjects who permanently discontinue the study drug for any reason including safety and/or 
tolerability concerns prior to completion of the assigned dosing period will be followed 
according to the post-treatment study assessments described in Section 6.5.
3.6.
Pharmacogenomic Substudy
 
 
 
3.7.
Long-Term Follow-Up
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up study 
will continue for 5 years.
3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If 3 or more of the first 10 subjects enrolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA > LLOQ through 
8 weeks of treatment) then further enrollment of subjects will be suspended. Virologic 
breakthrough is defined as confirmed HCV RNA > LLOQ while on treatment after 
two consecutive visits with HCV RNA < LLOQ.
If a holding rule has been met and following an internal safety review it is deemed appropriate to
restart enrollment, a request to restart enrollment with pertinent data will be submitted to the 
appropriate regulatory agencies.  Enrollment will only resume after review by the appropriate 
regulatory agencies.  Any subject on treatment when a holding rule has been met will be allowed 
to continue to treatment.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.9.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as adults to allow them to continue participating in the clinical trial.
PPD

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 36
28 May 2015
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh 17 kg and 
< 45 kg
5. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, 
or other approved or experimental HCV-specific DAA agent
6. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
7. Chronic HCV-infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test 
at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection

LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 37
28 May 2015
8. Infection with HCV as determined at Screening:
a) United Kingdom Only: The study will commence with GT-1, -3, and -4 HCV-infected 
pediatric subjects and will subsequently enroll subjects with GT-2, -5, and -6 once adult 
data is available, if appropriate.
b) United States/ Australia/ New Zealand Only: The study will commence with GT-1, 
HCV-infected pediatric subjects and will subsequently enroll subjects with 
GT-2, -3, -4, -5, and -6 once adult data is available, if appropriate.
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL or 12 g/dL for GT-3 males only).
11. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
12. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Treatment-naïve subjects with GT-3 HCV infection as determined at Screening. Treatment 
naïve is define by no prior exposure to any IFN, RBV, or other approved or experimental 
HCV-specific DAA agent
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 38
28 May 2015
9. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10. Co-infection with HIV, acute HAV, or HBV
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. 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
18. Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.6
21. PK Lead-in only: subjects with history of cirrhosis (as determined by liver biopsy)
22. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their 
psychiatric illness within the last 5 years. Subjects with psychiatric illness (without the prior 
mentioned conditions) that is well-controlled on a stable treatment regimen for at least 
12 months prior to enrollment or has not required medication in the last 12 months may be 
included.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 39
28 May 2015
5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
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. 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, 
FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and/or 2 of this study. The formulation, composition, acceptability (including 
palatability) will be available and reflected in a protocol amendment which will be submitted for 
approval prior to dosing subjects who are unable to swallow tablets.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 40
28 May 2015
5.2.1.2.
Packaging and Labeling
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
The packaging and labeling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow tablets.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest of the countries shall be labeled to meet all applicable requirements of the 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.
5.2.2.
Storage and Handling
LDV/ SOF FDC tablets, 90 mg/ 400 mg, 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).
Placebo to match LDV/ SOF FDC tablets, 90 mg/ 400 mg, for Swallowability Assessment 
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).  
LDV/SOF FDC tablets, 22.5 mg/ 100 mg, 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).

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 41
28 May 2015
Placebo to match LDV/ SOF FDC tablets, 22.5 mg/ 100 mg, for Swallowability Assessment 
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).
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the Investigational Medicinal Product (IMP) 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, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences 
(or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: 
Cohort 1: LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily with or without 
food. Subjects determined unable to swallow the placebo to match the 90 mg/ 400 mg LDV/SOF 
FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) 
will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who weigh < 45 kg will be 
excluded.
Cohort 2: LDV/SOF FDC 2 x 22.5 mg/ 100 mg tablets will be administered once daily with or 
without food. Subjects determined unable to swallow the placebo to match the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment) will be deffered 
until oral granulate formulation is available. Subjects must weigh ≥ 17 kg and < 45 kg.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of that Cohort 
as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in of the 
next Cohort.
Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue in 
the Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose is confirmed by PK and safety data from the PK-Lead-in.  Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the 
dose.  

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 42
28 May 2015
An additional age-appropriate formulation for LDV/SOF FDC Oral Granulates is currently under 
development. The dose for this formulation will be dependent on the PK results obtained from 
Cohorts 1 and/or 2 of this study. The strength, composition, and dosing administration will be 
available and reflected in a protocol amendment which will be submitted for approval prior to 
dosing subjects who are unable to swallow tablets.
Subjects should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken.  If vomiting occurs more than 5 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, subjects should be instructed to 
take the tablet as soon as possible and then subjects should take the next dose at the usual time.  
If it is after 18 hours then subjects should be instructed to wait and take the next dose at the usual 
time.  Subjects should be instructed not to take a double dose.
5.3.
Ribavirin (GT-3 Subjects Only)
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule 
contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose 
monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule shell 
contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene glycol, 
ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with blue ink.
REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble 
gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains the 
following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric 
acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30C (86 F).
RBV oral solution should not be stored above 30°C (86°F).

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 43
28 May 2015
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only)
RBV dose will be administered by weight as follows:
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the morning and 
evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
The morning dose of RBV will be taken with food and LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only)
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

LDV/SOF FDC

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the study medication at the correct time, it may be taken later in the 
day; however, no more than 90 mg/ 400 mg dose of LDV/SOF FDC should be taken on any 
calendar day.  The subject should resume the standing dosing schedule on the next day. Study 
medications should not be cut or split.  

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 44
28 May 2015
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC and/or RBV in the original 
container on Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 
4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab)

Investigational agents or devices for any indication

Drugs disallowed per prescribing information of REBETOL® for GT-3 subjects only
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to Day 1 through the end of treatment are listed 
below. In addition, the use of amiodarone is prohibited from 60 days prior to 
Baseline/Day 1 through the end of treatment.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 45
28 May 2015
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
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronee
Digoxinb, Dabigatranb
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a.
It is recommended to separate antacid and LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC 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 FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b.
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c.
May result in a decrease in the concentrations of study drug.
d.
Use with study drug may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for signs 
and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
e.
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.
Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 46
28 May 2015
6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
Hepatitis C history
Hepatitis C treatment history
Family history (including height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 47
28 May 2015

Obtain blood samples for tests as listed in Section 6.6.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral GT and subtype
HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
HbA1c
TSH
IL28B
Serum -hCG pregnancy test for females of childbearing potential only
Alpha fetoprotein (AFP)
Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 48
28 May 2015
6.3.
PK Lead-in: Treatment Assessments 
6.3.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)

 

Obtain urine samples for the following procedures:
Urinalysis
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.
PPD

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 49
28 May 2015
6.3.1.1.
Drug Administration

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 

LDV/SOF FDC
Protocol GS-US-337-1116
Final
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Amendment 3.0
CONFIDENTIAL
Page 50
28 May 2015
If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to the 
Day 10 visit, the Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be counseled regarding proper dosing and be scheduled to return for the 
Day 10 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
Hematology 
Chemistry 

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Amendment 3.0
CONFIDENTIAL
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Coagulation tests
HCV RNA
Viral sequencing (archive)

Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status). 

LDV/SOF FDC
Protocol GS-US-337-1116
Final
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Amendment 3.0
CONFIDENTIAL
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28 May 2015

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)

 

Obtain urine sample for:
Urinalysis
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire

Perform LDV/SOF FDC swallowability assessment (for subjects administered 
LDV/SOF FDC in tablet form only if not previously completed at screening) 
6.4.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

GT-3 subjects only: Instruct the subject on the appropriate RBV dose after weight-based 
dosage is calculated using Day 1 weight

Instruct the subject on the packaging, storage, and administration of study drug

Observe the subject taking the first dose of study drug (with or without food) and record the 
time of first dose
6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in the Treatment Phase at 
Week 2.  The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination
PPD

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
Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS

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6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

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
Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS  
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS

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6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and blister cards (if applicable) of study drug at the 
Week 24 Visit
6.4.8.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.

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The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and/or blister cards (if applicable) of study drug at the Early 
Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.

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6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
Female subjects of childbearing potential on treatment with LDV/SOF FDC + RBV should be 
provided with Urine Pregnancy Test-Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6-months after their last dose of RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months may be added.  The subject should be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy 
test.
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment

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
Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
HCV RNA
Viral sequencing (archive)

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.

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All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will 
continue for 5 years.
6.6.
Procedures and Specifications
6.6.1.
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 MCV.
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT) 
Chemistry Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using the 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT and subtype will be determined using the Siemens VERSANT® HCV Genotype 
INNO-LiPA 2.0 Assay. Gilead reserves the right to use alternate assays for HCV RNA and 
HCV GT should the above assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
6.6.2.
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. Parental heights will be recorded at Screening.

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6.6.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
6.6.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. Date of first menses 
will be documented. 
6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist will determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1. 
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, 
enrollment of the subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.

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6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; and for 
adolescent males ≥12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 6 months following the last dose of RBV or for a minimum 
of 30 days following the last dose of LDV/SOF FDC if not taking RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months for RBV or 30 days for subjects not 
taking RBV may be added. In the event of a positive urine pregnancy result, subjects will be 
instructed to stop study drug immediately (if applicable) and return to the clinic as soon as 
possible for a serum pregnancy test.
GT-3 subjects only: Pregnancy test kits will be dispensed to female subjects of child bearing 
potential at the 4 Week Post-Treatment visit. The subject will be contacted by telephone monthly 
to confirm that urine pregnancy testing has been performed post-treatment and to record the 
outcome. Alternatively, if required by local regulations or preferred by the investigator or 
subject, the subject may return to the clinic for urine pregnancy tests.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, End of Treatment, Early Termination (if applicable), 12-Week Post-Treatment, and 
24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey accompanied by the respective parent proxy survey will be 
administered to the subject and their parent/legal guardian (with the exception of the Toddlers 
Report which will only be completed by the parent/legal guardian) for the current age group at 
the time of survey administration.  

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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV (GT-3 subjects only) due to toxicity should be performed according to 
the product label. Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/daya if:
Discontinue RBV if:
Hemoglobin in subjects with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac disease
2 g/dL decrease in hemoglobin during any 
4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
a.
Dose reduction in pediatric patients taking the oral solution is accomplished by modifying the recommended RBV dose from 
original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted, RBV should be stopped (GT-3 subjects only), and the subject should 
complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC

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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical 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-mandated procedures, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen.

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions).

Overdose without clinical sequelae (see Section 8.5.1)

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
8.1.2.
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 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.
8.1.3.
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 8.1.1 and 8.1.2. 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).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. 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 AE 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 AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
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 adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug must be reported 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.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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-mandated procedures performed
after informed consent is signed 

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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 
the investigator learns of any SAEs that occur after study participation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event directly to Gilead DSPH.  
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com
Gilead Sciences, Medical 
Monitor:
Name:
Phone:
Mobile:
Fax:
E-mail:
Bittoo Kanwar, MD

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, 
no further action is necessary.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.
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PPD
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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  

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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy should continue until the conclusion of the pregnancy. If the end of the 
pregnancy occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number +1 (650) 522-5477 or email Safety_FC@gilead.com. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1 800-593-2214 (see also http://www.ribavirinpregnancyregistry.com ).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
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. 

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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE 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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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives and Endpoints
9.1.1.
Analysis Objectives
The primary objective of PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC
in chronic HCV-infected pediatric subjects
The secondary objective of PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV-infected pediatric subjects
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining 
steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters 
of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½)
will be estimated and summarized as described in Section 9.4.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements, 
including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will 
be evaluated as a secondary safety endpoint.
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary 
safety endpoints of growth and development measurements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment).
9.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study drug and for whom at least one non-missing PK concentration data, during the intensive 
sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who were enrolled and have 
received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, in general, values for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
preceded and followed in time by values that are deem successes, then the missing data point 
will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points subsequent to the date of discontinuation. If no HCV RNA 
values are obtained after the last dose of study medication, the subject will be considered a 
treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.

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Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from baseline 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and by the 4 regimens based on 
treatment-experience, cirrhosis status and genotype, by age group, by regimen and age group, 
and overall for Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-331007 and GS-566500) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 
(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and 
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 
of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects (Table 9-1), the GS-331007, 
SOF, and LDV exposure data from this study will be compared to the integrated adult data. The 
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 

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(ANOVA) for log-transformed GS-331007, SOF, and LDV AUCtau. The 90% confidence 
intervals will be constructed for the ratio of geometric means of each PK parameters. The 
equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 and SOF exposure, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.
In all pediatric age groups, the targeted exposures for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) 
assuming a 2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau
in the pediatric population compared to adults, the predicted 90% CIs of the geometric mean 
ratio (GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies)
Mean (%CV) PK Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a.
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.

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9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase 
respectively. Safety data will be summarized by age group and overall for PK Lead-in Phase and 
by the 4 regimens based on treatment-experience, cirrhosis status and genotype, by age group, by 
regimen and age group, and overall for the Treatment Phase respectively.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
Safety endpoints will be analyzed by the number and percent of subjects with events or 
abnormalities for categorical values or 8-number summary (n, mean, standard deviation, median, 
Q1, Q3, minimum, maximum) for continuous data.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 new or worsening 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 preferred term) will be provided by cohort:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

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
Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. Incidence of treatment-emergent laboratory abnormalities, defined as 
values that increase by at least one toxicity grade from baseline at any time post baseline up to 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. Age of first menses will be summarized descriptively.
9.5.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized at 
each visit.
9.6.
Efficacy Analysis
Efficacy will be evaluated using scheduled assessments of HCV RNA performed using COBAS®
TaqMan® HCV Test, v2.0 for use with the High Pure System.
Efficacy analysis will be performed by the 4 regimens based on treatment-experience, cirrhosis 
status and genotype, by age group, by regimen and age group, and overall for Treatment Phase.
All continuous endpoints will be summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be summarized 
by number and percentage of subjects who meet the endpoint definition.

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9.6.1.
Key Efficacy Analysis
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. Point estimate and its 95% confidence interval will be 
provided.  
9.6.2.
Secondary Efficacy Analysis
For the PK Lead-in Phase, serum HCV RNA actual values and change from baseline will be 
summarized at each visit.
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabular and graphical form. In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including serum HCV RNA actual values and change from baseline, proportion of subjects with
virologic failures, and other endpoints of interest including ALT normalization.
 
 
 
 
9.6.3.
Subgroup Analysis
Subgroup analysis on SVR12 will be performed by treatment experience and cirrhosis status, by 
IL28B genotype, and by GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of subjects in these subsets are available for 
analysis).
Details on efficacy analyses will be described in the statistical analysis plan.
9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
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While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.

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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed the protocol 
defined activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. Additionally, modifications 
should be submitted to competent authorities, as necessary.

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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
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, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences 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 Sciences. 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.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and 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, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);

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
Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years 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 contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 

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withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.

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10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.

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10.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.

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11.
REFERENCES
5914
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman 
RE. Developmental pharmacology--drug disposition, action, and therapy in 
infants and children. N Engl J Med 2003;349 (12):1157-67.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 
weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of 
chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
19799
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in 
children: a systematic review. PLoS ONE 2010;5 (7):e11542.
19801
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. 
Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
2010;50 (2):123-31.
20273
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
term course of chronic hepatitis C in children: from viral clearance to end-stage 
liver disease. Gastroenterology 2008;134 (7):1900-7.
20282
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the 
child? European review for medical and pharmacological sciences 2011;15 
(9):1057-67.
20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.

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20286
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. 
High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
20287
Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human 
carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual 
variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and 
permethrin. Biochem Pharmacol 2009;77 (2):238-47.
20288
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and 
activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab 
Dispos 2009;37 (9):1819-25.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370 
(20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
28587
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
Engl J Med 2014;370 (20):1879-88.
29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 
34663
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. 
Archives of disease in childhood 1970;45 (239):13-23.
34664
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. 
Archives of disease in childhood 1969;44 (235):291-303.
34882
Fanta S, Jonsson S, Backman JT, Karlsson MO, Hoppu K. Developmental 
pharmacokinetics of ciclosporin--a population pharmacokinetic study in 
paediatric renal transplant candidates. Br J Clin Pharmacol 2007;64 (6):772-84.

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12.
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.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination+/- Ribavirin in Adolescents 
and Children with Chronic HCV -infection 
GS-US-337-1116, Protocol Amendment 3.0, 28 May 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
EIT(L{) 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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28May2015 

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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X

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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b.
Day 1 assessments must be performed prior to dosing
c.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d.
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g.
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j.
Parental height will be collected (if available)
PPD
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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability 
Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X

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Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b.
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c.
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f.
g.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Parental height will be collected (if available) 
j.
Subjects on 12 Week Treatment regimen only
k.
Subjects on 24 Week Treatment regimen only
l.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
PPD
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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
X
Xe
a.
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c.
At Post Treatment Week 12 and 24, only SAEs will be captured
d.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
e.
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject 
should be contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic 
for a serum pregnancy test.

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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 96
28 May 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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
—
—

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 97
28 May 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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 FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 98
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 99
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 100
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 101
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 102
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 103
28 May 2015
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 104
28 May 2015
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 105
28 May 2015
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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28 May 2015
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF

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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
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake

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

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

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

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

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

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

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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
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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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

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Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {34663}, {34664}

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 120
28 May 2015
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information.
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC in pregnant 
women. Please refer to the latest version of the investigator’s brochure for additional 
information.
2. Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to dosing. They must also agree to one of the 
following from 3 weeks prior to Day 1 until 6 months after last dose of RBV or 30 days after last 
dose of LDV/SOF FDC if not taking RBV:

Complete abstinence from intercourse. Abstinence is acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
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 
6 months after last dose of RBV or 30 days  after the last dose of LDV/SOF FDC if not 
taking RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 121
28 May 2015
vasectomy in male partner
implants of levonorgestrel
injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from Day 1
until 7 months after last dose of RBV or 90 days after the last dose of LDV/SOF FDC if not 
taking RBV. 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 
7 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC if not taking RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC if not taking RBV.
4. 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 6 months (7 months for partners of male subjects) of 
last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF FDC dose if 
not taking RBV. Subjects who become pregnant or who suspect that they are pregnant must 
report the information to the investigator and discontinue study drug immediately. Subjects 
whose partner has become pregnant or suspects she is pregnant must report the information to 
the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 8.5.2.1.